2008 kaplan usmle step 1 home study program-brand new volume iv: organ systems book 2

Contents

Section l: Musculoskeletal System, Connective Tissue, and Integument

Chapter l . Embryology: Musculoskeleta l . . . . . . . .3

Chapter2. Hi$ology: Connect iveTissue . . . . . . . .9

ChapterS. Histo logy: Muscle . . . . . .21

Chapter4. Histology: lntegument . . . . . . .29

Chapter 5. Anatomy: Musculoskeletal . . . .33

Chapter 6. Physiology: Musculoskeletal . . .67

ChapterT . Patho logy . . . . . . .81

Chapter 8. Pharmacology . . 107

Section ll: Gastrointestinal System

Chapter l . Embryo logy . . . .119

Chap te r2 .H is to logy . . . . . . 125

Chap te r5 .Ana tomy . . . . . . . 137

Chaptera. Physiology . . . . . 145

Chap te r5 .Pa tho logy . . . . . . 169

Chapter 6. Pharmacology . . .211

ilitshical vii

Section lll: Endocrine System

Chap te r l . H i s to logy . . . . . . 221

Chap te r2 .Ana tomy . . . . . . 229

Chapter 5. Physiology . . . . .231

Chapter4 . Patho logy. . . . .265

Chapter 5. Pharmacology . . 28.l

Section lV: Reproductive System

Chapter l . Embryology . . . .297

Chap te r2 . H is to logy : Ma le . . . . . . 303

ChapterS. Histology: Female . . . .309

Chap te r4 .Ana tomy . . . . . . . 5 , | 9

Chapter5 .Phys io logy . . . .325

Chapter6 . Patho logy: Male . . . . . .343

ChapterT. Pathology: Female . . . .555

Chapter 8. Pharmacology . .379

Index . . . . 385

viii iliBhical

SECTION I

Musculoskeletal System,Connectlve Tlssue, and

lntegument

Musculoskeletal Embryology

The components of the skeletal system are derived from mesenchymal elements that arise frommesoderm and neural crest. Mesenchymal cells differentiate into fibroblasts, chondroblasts, andosteoblasts, which produce connective tissue, cartilage, and bone tissue, respectively. Bone organseither develop directly in mesenchymal connective tissue (intramembranous ossification) or frompreformed cartilage models (endochondral ossification). In general, the skeletal muscles differentiatefrom paraxial mesoderm. The splanchnic mesoderm gives rise to cardiac and smooth muscle.

The integument consists of the epidermis and its derivatives (glands, hairs, nails), and the underlyingdermis. The epidermis is derived from ectoderm, whereas the dermis is formed from mesenchyme.Melanocytes, which may occur in both layers, originate from neural crest.

SKELETAL SYSTEMA. Origin

l. The skeletal system develops from paraxial mesoderm, which forms a column of tissueblocks, called the somites, on either side of the neural tube. Each somite becomes differ-

entiated into a ventromedial part, the sclerotome, and a dorsolateral part, the dermomy-otome. By the end of the fourth week, the sclerotome cells form embryonic connective tis-sue, known as mesenchyme. Mesenchyme cells migrate and differentiate to form fibrob-lasts, chondroblasts, or osteoblasts.

2. Bone organs are formed by two methods:

a. Flat bones are formed by a process known as intramembranous ossification, inwhich bones develop directly within mesenchyme.

b. Longbones are formed by a process known as endochondral ossification, in which mes-

enchymal cells give rise to hyaline cartilage models that subsequently become ossified.

B. Skull formation. The neurocranium provides a protective case around the brain, and theviscerocranium forms the skeleton of the face.

1. Neurocranium is divided into two portions:

a. The membranous neurocranium consists of flat bones that surround the brain as avault. The bones appose one another at sutures and fontanelles, which allow overlapof bones during birth and remain membranous until adulthood. Palpation of the

anterior fontanelle, where the two parietal and frontal bones meet, provides informa-

tion about the progress of ossification and intracranial pressure.

Musculoskeletal System, Connective Tissue, and Integument

b. The cartilaginous neurocranium (chondrocranium) of the base of the skull isformed by fusion and ossification of a number of separate cartilages along the medi-an plate.

2. Viscerocranium arises primarily from the first two pharyngeal arches (Table I-1-1).

Thble I-f -f . Origins of viscerocranial bones.

Pharyngeal Arch

MaxillaZygomatic bonePart of temporal bone

Mandible

Ear ossicles: malleus,incus, stapes

Hyoid bone

Laryngeal cartilages

Dorsal part of first arch

Ventral part of first arch

Tip of ventral part of firstarch and second arch

Arches 3-6

C. Appendicular system. The pectoral and pelvic girdles and the limbs comprise the appen-dicular system.

1. Except for the clavicle, most bones of the system are endochondral. The limbs begin asmesenchymal buds with an apical ectodermal ridge covering, which exerts an inductiveinfluence over the mesenchyme.

2. Bone formation occurs by ossification of hyaline cartilage models.

a. The process begins at the end of the embryonic period in the primary ossification cen-ters, which are located in the shaft, or diaphysis, of the long bones. At the epiphyses,or bone extremities, ossification begins shortly after birth.

b. The cartilage that remains between the diaphysis and the epiphyses of a long bone isknown as the epiphysial plate. It is the site of growth of long bones until they attaintheir final size and the epiphysial plate disappears.

D. Vertebral column

1. During the fourth week, sclerotome cells migrate medially to surround the spinal cordand notochord. After proliferation of the caudal portion of the sclerotomes, the vertebraeare formed, each consisting of the caudal part of one sclerotome and cephalic part of thenext.

2. While the notochord persists in the areas of the vertebral bodies, it degenerates betweenthem, forming the nucleus pulposus. The latter, together with surrounding circular fibersof the annulus fibrosis, forms the intervertebral disc.

MUSCUTAR SYSTEMA. Skeletal (voluntary) system

1. Origin. The dermomyotomematome.

further differentiates into the myotome and the der-

a. Cells of the myotome migrate ventrally to surround the intraembryonic coelom andthe somatic mesoderm of the ventrolateral body wall. These myoblasts elongate,become spindle-shaped, and fuse to form multinucleated muscle fibers.

4

Embryology: Musculoskeletal

b. Myofibrils appear in the cytoplasm, and, by the third month, cross-striations appear. :Individual muscle fibers increase in diameter as myofibrils multiply and becomearranged in groups surrounded by mesenchyme.

c. Individual muscles form. as well as tendons that connect muscle to bone, :

2. Tlunk rnuscrrlature. By the end of the lifth week body-wall musculature divides into a ,dorsal epimere, supplied by the dorsal primary ramus of the spinal nerve, and a ventralhypomere, supplied by the ventral primary ramus

a- Epimere muscles forrn the extensor muscles of the vertebral column, and hypomere '

muscles give rise to lateral and ventral flexor musculature.

b. The hypomere splits into tfuee layers.

(1) In the thorax, the three layers form the extemal intercostal, intemal intercostal, andtransrrerse thoracic muscles.

(2) In the abdomen, the three layers form the extemal oblique, intemal oblique, andtransverse abdominal muscles.

3. Head musculature

a. The extrinsic and intrinsic muscles of the tongue are thought to be derived fromoccipital myotomes that migrate forward.

b. The extrinsic muscles of tle eye may derive from preoptic myotomes that originallysurround t}re prochordal plate.

Bdd$ toc. The muscles of nastication, facial expression, t}te pharynx, and the larynx are derived Genenl Prindples

from different pharyngeal arches and maintain their innervation by the nerve of thearch oforigin. Ihe Pharyngealarch

4. Limb muscuLfirre originates in th€ seventh week ftorn somatic mesoderm that migrates deriratives are raie €d in the

into the limb bud. with time, the limb rnusculature splits into t";J;;;;;.; Embryology section of General

extensor groups. ^ Principles Book 2 (volume lD.

a. The lirnb is innervated by spinal nerrrcs, which penetrate the lirnb bud mesodermalcondensations. Segmental branches of the spinal nerves firse to form large dorsal andventral nerv€s,

b. The cutaneous innervation of the limbs is also derived from spinal nerves and reflects Ithe level at which the limbs arise.

B. Smoo0r musde, The smooth muscle components of the gut, trachea, bronchi, and bloodvessels of the associated mes€nteries are derived from splanchnic mesoderm surroundingthe gastrointestinal tract. Vessels elsewhere in the body obtain their smooth muscle ftom Ilocal mesenchyme.

C. Cardiac muscle, like smooth muscle, is derived ftom splanchnic mesoderm


CONGEN ITAI ABNORMATITI ESA. Cranioschisis (acrania) is an almost complete absence of the cranial vault. It is often accom-

panied by a large spinal defea and is incompatible with life when combined with anencephaly.

B. Microcephaly is a bony deformation in which the skull fails to expand secondary to failureof the brain to grow.

C. Amelia (absence of one or two extremities), meromelia (absence of an arm or leg with pres-ence of the hand or foot), and micromelia (shortened extremities) are usually rare abnor-malities. There were increased incidences between 1957 and 1962 as a result of the adminis-tration of thalidomide as a sleeping pill and antinauseant.

D. Polydactyly refers to supernumerary digits. It is inherited as a dominant trait.

E. Syndactyly is fused or webbed digits. It is due to failure of interdigital mesenchyme to breakdown. It is inherited as an autosomal dominant or recessive gene.

F. Clubfoot is an inward flexing of the sole of the foot while the foot is adducted and the plan-tar is flexed. It is often combined with syndactyly.

G. Congenital dislocation of the hip is an underdevelopment of the acetabulum and head ofthe femur as well as a laxity of the hip joint. It occurs most often in females and results in dis-location after birth. It may be associated with breech posture during pregnancy.

H. Spina bifida occulta is the failure of dorsal portions of one or two vertebrae, usually in thelumbosacral region, to fuse with one another.It is usually not noticeable at the surface exceptas a dimple or tuft of hair and is not associated with neurological symptoms.

I. Meningocele involves several vertebrae such that the meninges or the spinal cord(myelomeningocele) and its nerves bulge out through the opening covered only by a thinmembrane.

L Achondroplasia results in dwarfism. It is due to abnormal endochondral ossification in theepiphyseal plates of long bones.

K. Acromegaly is an enlargement of the face, hands, and feet due to hyperpituitarism.

L. Gigantism is a general excessive growth that is also due to hyperpituitarism.

INTEGUMENTARY SYSTEMA. Epidermis

1. Origins. The superficial epidermis and deep connective tissue dermis of the skin have dif-ferent origins.

a. The epidermis arises from the surface ectoderm covering the entire embryo.

b. The dermis arises from underlying mesenchyme, which is derived from dermatome,lateral somatic mesoderm, or neural crest, depending on the location in the embryo.

2. Differentiation of keratinocytes. In the beginning of the second month, the single layerof embryonic epidermis differentiates into an outer periderm and an inner basal layer.

a. Continued mitosis in the basal layer leads to the definitive four-layer arrangement ofkeratinocytes by the end of the fourth month.

b. The cells of the periderm are eventually sloughed off into the amniotic fluid.

Embryology: Musculoskeletal

3. Dermatoglyphics are patterns observed on the finger tips, palms of the hands, and solesof the feet that are due to ridges and hollows of the basal germinative layer and underly-ing dermis. In children with chromosomal abnormalities, these patterns are abnormal.

4. Melanocytes. Invasion of the epidermis by melanin-secreting dendritic cells of neural-crest origin is responsible for pigmentation of the skin.

B. Epidermal derivatives. The germinative layer also gives rise to epidermal derivatives byforming epithelial cord or bud-like ingrowths into the dermis, which secondarily hollow outby death of the central cells.

1. Hair follicles and associated sebaceous glands. The dermal root sheath and arrector pilimuscle of each follicle are derived from surrounding mesenchyme. Fine lanugo hair, shedat the time of birth, first appears by the end of the third month. Secretions from the seba-ceous glands cover the fetus with a protective substance, the vernix caseosa, consisting ofdegenerated epidermis, hair, and fatty sebaceous secretions.

2. Sweat glands and mammaryglands. In the mammary gland, the lactiferous ducts devel-op in the persisting midthoracic portion of the mammary line, which is a band-like epi-dermal thickening that extends from the base of the forelimb to the region of thehindlimb when it first appears. The epidermal-derived epithelial lining of the lactiferousducts and alveoli are supported by mesenchy-ul connective tissue.

3. Nails appear approximately at the beginning of the sixth month.

4. Teeth. Oral cavity ectoderm gives rise to tooth enamel. Associated mesenchyme gives riseto the associated tooth structures.

C. Dermis consists of two layers: an upper papillarylayer, which forms the papillae that containcapillaries and sensory nerve endings and project upward into the epidermal ridges; and a

deeper reticular layer, which develops into dense irregular connective tissue.

D. Abnormalities

1. Ichthyosis involves excessive keratinization (cornification) of the skin, giving it a scale-like appearance.

2. Nevi are skin malformations, such as birthmarks or hemangiomas. They are due to local-ized collections of differentiated cells, such as epidermal, pigmented, vascular, or connec-tive tissue, or any combination thereof. They occur frequently and may be superficial ordeep.

3. Hypertrichosis is an excessive amount of hair as a result of increased formation of folli-

cles. It may be localized to the midline region or it may be more generalized.

4. Atrichia is an absence of hair that is usually associated with abnormalities of teeth andnails.

5. Polythelia is a development of supernumerary nipples along abnormally persisting frag-

ments of the mammary line.

6. Polymastia is a development of supernumerary complete mammary glands.

7. Inverted nipple is a failure of the original epithelial pit, into which the lactiferous ducts

open, to evert. It may also be caused by the presence of a fast-growing tumor in the gland,

leading to the retraction of the nipple.

Connective Tissue Histology

Connective tissue provides the body with a continuous system of support, nutrition, defense, andmaintenance. lt makes up the framework of tissue and organ structures, and possesses the tensilestrengh to allow tissues to withstand shearing forces. Connective tissue is composed of cellsembedded in an extracellular matrix, consisting of fibers and ground substance infiltrated with tissuefluid. In contrast to the other primary tissues (e.g., epithelum, muscle, nerve) that are mainly cellularin composition, connective tissue has a relatively greater amount of extracellular components.

CETLS OF CONNECTIVE TISSUEA. Fibroblasts are the most numerous connective tissue cells. They are responsible for the syn-

thesis of the matrix components: fibers (i.e., collagen, elastin) and ground substance (gly-cosaminoglycans, proteoglycans, glycoproteins ).

1. Fibroblasts contain abundant euchromatin, nucleoli, and rough endoplasmic reticulum(RER).

2. They are spindle-shaped cells with large, pale, elongated nuclei and a prominent Golgiapparatus.

3. Resting (inactive) fibroblasts, sometimes called fibrocFtes, are smaller and contain a moreacidophilic cytoplasm due to a reduced endoplasmic reticulum. Resting fibroblasts thatare stimulated to synthesize new matrix components, as in wound healing, resume theappearance of active fibroblasts.

4. Myofibroblasts are connective tissue cells that resemble both fibroblasts and smooth mus-cle cells. They contain large amounts of the contractile proteins actin and myosin, which areimportant in contraction of wounds during the healing process.

B. Mesenchymalcells have the appearance of undifferentiated fibroblasts. These cells are foundin connective tissue and in association with blood vessels (pericytes). They function as apluripotential reserve of mesenchy-ul stem cells.

C. Adipose cells (adipocytes) are derived from mesenchymal cells or fibroblasts. They arespecialized for the synthesis and storage of lipid.

D. Mast cells are large round or oval-shaped cells that contain large cytoplasmic granules and a sin-gle round nucleus.

1. The granules have a strong afiinity for basic dyes. With dyes such as toluidine blue, theyalso stain metachromatically. Mast cell metachromasia is a result of their proteoglycanand heparin content.

Note

Cells of connective tissuemay be divided into threecategories:

. Cells responsible forsynthesis and maintenanceof extracellular matrix(fibroblasts, mesenchyme)

. Cells responsible forstorage of and metabolismof fat (adipose)

. Cells with defense andimmune function (mastcells, histiocytes)


Clinical Correlate

Mast cells are involved ini mmed iate hypersensitivity

flype l) reactions. Antigenscan bind to lgE on the surfaceof mast cells and induce therelease of histamine --

allergic reaction. A potentiallyfatal type of immediatehypersensitivity reaction isanaphylactic shock.

Bridge to Heme/tymph

Blood cells are discussed indetail in theH ematologi{Lym phoreticu la rHistology chapter in OrganSystems Book t (Volume lll).

ln a Nutshell

Precursor cells in bone marrow--+ moflocytes (which circulatein blood) - miSration intoconnective tissue --+ matureinto macrophages.

In a Nutshell

The Major Functions ofMacrophages. Ingestion of particles and

their digestion bylysosomes

. Resistance to infection bybacteria, viruses, protozoa,fungi, and metazoa

. Cell-mediated resistance totumors

. Destruction of agederythrocytes

. Antigen presentation tolymphocytes

2. Mast cells are induced to degranulate by mechanical trauma, radiant energy, chemicals,and the binding of allergens to IgE molecules (from plasma cells), attached to specificreceptors on mast cell membranes. This attachment accounts for their role in allergicreactions. Substances released from mast cells include histamine, eosinophil chemotacticfactor of anaphylaxis (ECF-A), leukotrienes, and neutral proteases.

3. Mast cells resemble basophils of the blood (also found in connective tissue) but are derivedfrom different precursors in the bone marrow and, thus, are considered a separate cell type.Mast cells differentiate in connective tissue whereas basophils differentiate in bone marrow.

E. Formed elements of the blood (i.e., neutrophils, eosinophils, basophils, monocftes, lym-phocytes), in response to tissue injury and immune reactions, migrate into the connectivetissue, where they carry out their respective functions.

F. Plasma cells are oval-shaped basophilic cells with an eccentrically placed nucleus containingclumped chromatin with a "spoked-wheel" appearance. Plasma cells are derived from B 1y--phocytes.

1. The intense amount of cytoplasmic basophilia is due to the extensive RER that is used forthe synthesis of large quantities of antibodies.

2. Each plasma cell produces one specific antibody.

G. Macrophages of connective tissue (histiocytes) are derived from monocftes that migrate fromthe blood into the connective tissues.

1. They contain a small irregular nucleus with a prominent nucleolus and extensive cyto-plasm that may contain a variety of particles and vacuoles.

2. These cells are active in phagocytosis of particulate matter and are members of themononuclear phagocyte system (MPS) that also includes osteoclasts, microglia,Langerhans cells of the epidermis, as well as macrophages of the liver (Kupffer cells), thelung (dust cells), and immune organs.

3. They act as scavengers by recycling damaged and dead cells and as protectors by ingestingand killing bacteria and foreign substances.

4. The macrophage recognizes its prey by the interaction of its membrane receptor with spe-cific regions of an antibody or complement that coats the foreign particle.

5. They respond to a variety of chemotactic stimuli, including lymphokines (signalmolecules released by lymphocytes).

6. When macrophages encounter large foreign bodies, they fuse together to form large cellswith multiple nuclei, called multinuclear giant cells.

7. The macrophage is an antigen-presenting cell and, thus, is an important participant in theimmune response. This function is reviewed in the Basic Immunology chapter of GeneralPrinciples Book 1 (Volume I).

t0

Histology: Connective Tissue

EXTRACELLUTAR MATRIXA. Fibrous components (Figure l-2-l).

l .

Microfibri l

Figure l-2-1. Collagen microfibrils, fibrils, fibers, and bundles.

Collagen is the most abundant body protein. It contains many positively charged aminoacids and, thus, stains with eosin. Type I collagen, the most abundant type found in con-nective tissue, is synthesizedby fibroblasts in the following way:a. Ribosomes synthesize two types of peptide chains (cr, and or) that are rich in glycine,

lysine, and proline.

b. In cisterna of RER, three units (two a, and one crr) bind via disulfide bridges andintertwine to form a triple helix. Component lysines and prolines become hydroxy-lated in the cisterna to form hydroxylysine and hydroxyproline.

c. In the Golgi, sugars (i.e., galactose, glucose) bind to the hydroxylysine, and the "fin-ished" glycoprotein procollagen is secreted from the fibroblast.

d. Peptidases outside the fibroblast excise the ends of the procollagen molecule, forminga soluble substance called tropocollagen. These helices aggregate to form low-tensilestrength microfibrils.

e. Another extracellular enzyme,lysyl oxidase, covalently binds lysine and hydrorylysineresidues to form aldehydes, which cross-link adjacent tropocollagen helices to forminsoluble, high-tensile strength collagen fibrils.

f. These fibrils intertwine and form noncovalent bonds with matrix glycoprotein to pro-duce collagen fibers. The characteristic cross-banding of collagen is due to the over-lapping of the parallel end-to-end fibers. Large, white, collagen fibers are visible withthe naked eye in tendons, ligaments, and other sheets of dense connective tissue.

g. More than two dozen types of collagen have been identified. All have the sametropocollagen substructure but differ in their amino acid and hexose content. Many

Note

Major Types of Collagen

Type I. Most abundant. Found in dermis, bone,

tendon, dentin, fascias,organ capsules, fibrouscartilage

Type ll. Hyaline and elastic

ca rtila ges; i ntervertebraldisc; notochord

Type lll. Major component of

reticular fibers. Can co-polymerize with

other types of collagen. Found in smooth muscle,

arteries, liver, spleen,kidney, and lung

Type lV. Found in basal lamina of

basement membranes

Type V. Placenta, liver, lung; now

classified as V/Xt family

Type Vll. Basement membranes;

major component ofanchoring fibrils

t l


Clinical Correlate

Diseases Resultingfrom Defects in CollagenSynthesis

Ehlers-DanlosDefect: Deficient type lll collagen,faulty lysine hydroxylation, or J inprocollagen peptidase activity.Symptoms: Increased skinelasticity, and articular mobility;aortic or intestinal rupture.

ScurvyDefect:Vit C deficiency (Vit C iscofactor for proline hydroxylase)Symptoms: Ulceration of gums,hemonhages

Osteogenesis impedecta (Ol)Defect: Single base substitution ingene for collagen type ISymptoms: Spontaneousfractures, cardiac insuff iciency

Note

Cround substance is formedby two classes of components:

. Proteoglycans consisting ofglycosaminoglycans andproteins

. Adhesive glycoproteins

cell types, including chondroblasts, smooth muscle cells, and epithelial cells, are alsoable to synthesize collagen.

2. Reticular fibers are delicate branching fibers composed mainly of type III collagen.

a. They form a delicate supporting reticulum for cells and tissues and are abundant inthe framework of the spleen, lymph nodes, bone marrow liver, kidney, and endocrineglands.

b. Reticular fibers are abundant in embryonic connective tissue, or mesenchyme, but arereplaced by collagen fibers during tissue maturation.

c. They are able to react with silver salts (argyrophilia) and thus appear black under thelight microscope.

d. Because they are collagen fibrils, they demonstrate the characteristic cross-band pattern.

3. Elastic fibers are abundant in tissues that must stretch and recoil, such as skin, lung, bloodvessels, and vertebral ligaments.

a. Like collagen, elastic fibers are synthesized as subunits by fibroblasts. They are easilydistinguished from collagen fibers because they are thinner, lack longitudinal stria-tions, and appear yellow to the naked eye.

b. Under the light microscope, elastic fibers stain weakly with eosin. They are best seenwhen stained purple-black by special elastic stains.

c. Under the electron microscope, elastin may be resolved into its two components: acentral pale elastin fiber bulk surrounded by glycoprotein microfilaments.

d. The amino acid composition of elastin is similar to collagen (i.e., proline, glycine). Inaddition, it contains two specific lysine derivatives, desmosine andisodesmosine, thatare mainly responsible for the elastic properties of these fibers.

B. Ground substance is a hydrated, amorphous, extracellular material that occupies the spacesbetween cells and fibers. It is viscous and slippery and it acts as a molecular sieve that per-mits diffusion of metabolites between tissues and blood; however, it inhibits the movementand spread of larger particles such as microorganisms. It consists mainly of proteoglycansand glycoproteins.

1. Proteoglycans are a complex of glycosaminoglycans (GAGs) and core proteins.

a. GAGs are long-chained polyanionic polysaccharides with abundant acidic (sulfate andcarboxyl) groups.

b. Based on their substituted sugar residues, several GAGs have been identified:hyaluronic acid, heparan sulfate, heparin, keratan sulfate, chondroitin 4-sulfate,chondroitin 6-sulfate, and dermatan sulfate.

c. With the exception of hyaluronic acid, GAGs bind to core proteins, forming bottle-brush-like molecules with an exceptional negative charge density.

d. The most abundant GAG is hyaluronic acid, which is a large charged polyanion thatoverlaps to form dense charged networks. The abundance of negative charges in thismolecule binds water and is largely responsible for the hydrated gel properties of theground substance. Hyaluronic acid is not stained by hematorylin-eosin; but in well-preserved connective tissue, it is metachromatic with toluidine blue and can bedemonstrated with PAS stain.

2. Glycoproteins are molecules of protein with carbohydrate attached. In contrast to pro-teoglycans, the protein portion in glycoproteins is usually the most abundant.

t2


a. Several glycoproteins have been identified that are important in the binding of cells tothe extracellular matrix.

b. Fibronectin, which is synthesizedby fibroblasts, is a glycoprotein that contains bind-ing domains for cells, collagen, and GAGs. It helps mediate normal cell adhesion andmigration.

c. Thrombospondin, which is synthesizedby fibroblasts, contains binding domains forcells, collagen, heparin, and fibronectin.

CTASSIFICATION OF CONNECTIVE TISSUESA. Embryonic connective tissues

1. Mesenchymal connective tissue occurs throughout the developing body and is composedof stellate mesenchymal cells, abundant ground substance, and later, delicate reticularfibers.

2. Mucous connective tissue, found in the umbilical cord, resembles mesenchyme but con-tains more collagen fibers and a more viscous, jelly-like ground substance composedmainly of hyaluronic acid.

B. Adult connective tissues

1. Connective tissue proper

a. Loose connective tissue is composed of few fibers, an abundant ground substance, anda variety of resident cells as well as those derived from the blood. Examples of this typeare found in subcutaneous fascia, in the lamina propria of organs, and in mesenteries.

b. Dense connective tissue

( 1) Dense regular connective tissue is composed of parallel arrays of thick collagenfibers with scant ground substance and cells.It is able to withstand stress in a def-inite direction and is found in ligaments, tendons, and the cornea.

(2) Dense irregular connective tissue is composed of collagen and elastic fibersinterwoven and oriented in many different directions. Examples of this type arefound in the dermis, capsules of organs, perichondrium of the cartilage, andperiosteum of the bone.

2. Reticular connective tissue is a special loose connective tissue composed of delicate retic-ular fibers (type III collagen) and reticular cells (fibroblasts), which provide the frame-work for bone marrow liver, spleen, and lymph nodes.

3. Elastic connective tissue is composed of coarse, parallel elastic fibers or sheets interspersedwith fibroblasts and, often, delicate collagen fibers. Elastic tissue is found in yellow liga-ments of the vertebral column and in walls of hollow organs, such as the large arteries.

4. Adipose tissue is loose connective tissue in which the adipocyte predominates. It providesinsulation as well as an energy reserve.

5. Blood and hematopoietic tissue. See the Hematologic/Lymphoreticular Histologychapter of Organ Systems Book 1 (Volume III).

6. Cartilage (see below)

7. Bone (see below)

In a Nutshell

Loose Connective Tissue. Also known as areolar

tissue

. Abundant ground substanceand cells; few fibers

. Found in serosal linings ofperitoneal and pleuralcavities, and in glands andmucous memDranes

Dense Connective Tissue. Predominance of collagen

fibers; fewer cells and lessground substance

. Less flexible and moreresistant to stress thanloose connective tissue

. Found in dermis, ligaments,tendons, perichondriu mand periosteum.

t5

Musculoskeletal System, Connective Tissue, and lntegument

CARTITAGECartilage is a supportive conn€ctive tissue consisting of cells that secrete an extracellular matrix

. composed of fibers embedded in al amorphous ground substance. Cartilage is avascular and isnourished by diffi.rsion of metabolites ftom surrounding blood vessels.

A. C€ll6

1. Chondrocytes are round cartilage cells that secrete and maintain the fibers and groundsubstance that make up the extracellular matrix.

a. Chondrocftes occupy microscopic spaces within the extracellular matrix tlat arecalled lacunae.

b. Chondrocytes occur singly or in isogenous groups, resulting from the mitotic diyi-sions of a single cell.

c. Active chondroc)'tes have tle appearance oftypical protein secretory cells and containan extensive RER and prominent Golgi apparatus.

2. Chondrogenic cells are undifferentiated mesenchymal cells that are important for thedevelopment and growth of cartilage.

a. With some exceptions, cartilage is surrounded by a specialized layer of dense connec-tive tissue called the perichondriun.

b, The outer portion of the perichondrium is more fibrous, while the inner portion containsmesenchymal cells. These mesenchymal cells can differentiate into chondrogenic cellscalled drondroblasts, whidr are the immediate precursors to chondro+es.

B. Extracellular matrix of cartilage

1.. Fibers secreted by chondroc''tes consisting of collagen (mainly type II) and elastin

2. Ground substance, consisting of proteoglycans and glycoproteins

a. Proteoglycans of cartilage occur as aggregates of GAGs and are associated with coreproteins and hyaluronic acid.

(1) These aggregates associate witi cartilage fibers and bind water because of theirlarge number of negative charges.

(2) These molecular interactions provide cartilage matrix with its unique properties(resistance to compression) and its firm, yet resili€nt, consistency,

!!te " #.:,:"::ilx'to'#*'include drondronectin' a molecule that binds chondro-

The firmness of cartilage C. lpes of cartilagedepends on:. Electrostatic bonds betlveen

l' Hyaline cartilage is the most common t1rye of cartilage (Figure I-2-2)'

collagen fibers and the a. Most of the bones of the axial skeleton and all of the bones of the appendicular skele-

glycosaminoglycn side ton are first laid down in hyaline cartilage, Iater to be replaced bybone.

chains of matrix b. In the adult, hyaline cartilage is retained as tlre articular surface covering ofthe bonesproteoSlycans and the support for tlre upper r€spiratory tract.

. The binding of water (the c. Except at articular surfaces, hyzline cartilage is surrounded by a fibrous perichon-solvation of u/ater) to the drium. Perichondrium is essential for gro*th and maintenance of cartilage.

negatively charged d. The extracellular matrix of hyaline cartilage is a firm gel, consisting of a network of sub-proteoSlycn complexes microscopic t'?e II collagen fibers embedded in a hydrated matrix of ground substance.

t4


The efiracellular matrix immediately surrounding the chondrocytes, called the capsuleor territorial matrix, is highly basophilic and metachromatic because of the high con-tent of polyanionic GAGs.

Fibrous layerof perichondrium

Chondrogenic layerof perichondrium

lntercellular matrix

Chondrocyte inlacuna

Cell nest

Figure l-2-2. Hyaline cartilage.

2. Elastic cartilage is more opaque than hyaline cartilage and is yellow as a result of themany elastic fibers that it contains.

a. It is found in areas where elasticity is required, including the external ear, epiglottis,and eustachian tube.

b. Collagen fibers (tfpe II) and a perichondrium are also present.

3. Fibrocartilage is a combination of dense, regularly or irregularly arranged type I collagenfibers (dense connective tissue) and cartilage cells, which are enclosed in lacunae andsurrounded by scant amounts of hyaline matrix.

a. Fibrocartilage is found where increased tensile strength is needed, such as interverte-bral disks, pubic symphysis, and tendon insertions that are adjacent to hyaline carti-lage or articular surfaces.

b. A perichondrium is not present in fibrocartilage, but chondrocytes arise from existingfibroblasts.

D. Growth of cartilage is accomplished via two mechanisms: interstitial growth and apposi-tional growth.

1. Interstitial growth is an enlargement of the internal mass of the cartilage by mitotic divi-sions of existing chondrocytes and continued deposition of the extracellular matrix.

a. Interstitial growth, leading to the formation of isogenous groups, usually occurs insoft, young cartilage.

b. It is important in the epiphysial plates of developing long bones and accounts for theirgrowth in length.

c. It also occurs in the articular cartilages, where the perichondrium is absent.

t5


In a Nutshell

Two Mechanisms of CartilageGrowth

lnterstitial. Mitotic division of pre-

existing chondrorytes

. Occurs in epiphysial platesand articular cartilages

Appositional growth. Results from differentiation

of perichondrial cells

. Occurs on cartilage"surfaces"

Mnemonic

Osteoblasts - B for buildbone

2. Appositional growth occurs when the inner layers of perichondrium cells divide and dif-ferentiate into chondroblasts.

a. Chondroblasts surround themselves with matrix and gradually turn into chondrocytes.

b. Appositional growth increases the cartilage mass by adding to the surface.

BONEBone is a supportive connective tissue characterized by mineralization of its extracellularmatrix. Its mineral content serves as an important body reserve for calcium and phosphorus.Bone supports body tissues, protects vital organs, and contains bone marrow. It also acts as alever system whereby forces generated during skeletal muscle contraction are transformed intobody movements.

A. Cells

1. Osteoblasts are plump basophilic cells that actively secrete bone matrix.

2. Osteocftes are mature bone cells that occupy lacunae in the solid matrix and have cyto-plasmic extensions that extend through canaliculi to reach neighboring lacunae contain-ing osteocl.tes. Osteocytes are differentiated osteoblasts surrounded by newly synthesizedmatrix.

Communication between osteocytes occurs via gap junctions.

Osteocytes maintain bone matrix and, therefore, play an important role in calciumhomeostasis.

3. Osteoclasts are large, motile multinucleated cells found on bone surfaces at sites ofresorption. They are often found in shallow pits of the bone matrix called Howshiplacunae.

a. They arise by the fusion of monocytes and may contain up to 50 or more nuclei.

b. Osteoclasts erode formed bone by releasing acid and proteolytic enzymes, such as col-lagenase, which attack the inorganic and organic bone matrices, respectively.

c. These large cells have an acidophilic cytoplasm containing vacuoles and lysosomes.Their rytoplasmic bordet which abuts the surfaces of bone tissue, is elaborately fold-ed and appears as a striated or ruffled border under the light microscope.

d. Osteoclasts are stimulated by parathyroid hormone (PTH) to resorb bone tissue,thereby increasing serum calcium.

e. Osteoclasts are members of the mononuclear phagocyte system.

4. Osteogenic cells are mesenchymal-like cells in adult bone that differentiate into bone-forming osteoblasts for remodeling and repair.

a. They are located in the inner layers of the periosteum and endosteum.

b. In developing bones, they are the stem cells for bone tissue formation.

B. Extracellular matrix

1. Organic matrix consists of fibers and ground substance.

a. Fibers consist of type I collagen in the form of cross-banded fibers.

b. Ground substance consists of proteogly.ur aggregates composed of keratan sulfate,chondroitin sulfate, and hyaluronic acid.

a.

b.

t6


2. lnorganic matrix, which accounts for approximately 50o/o of the dry weight of bonematrix, consists primarily of a complex of calcium and phosphate in the form of hydroxy-apatite. Calcium carbonate, citrate, fluoride, magnesium, and sodium are also present.

C. Organization of bone tissue

1. Immature bone (i.e., nonlamellar, bundle, woven) is newly deposited bone tissue withloosely interlaced collagen fibers that contains a high density of osteocytes.

2. Mature bone is a highly structured lamellar arrangement of cells and extracellular matrixthat is organized into osteons, interstitial lamellae, and circumferential lamellae.

a. Osteons (Haversian systems) are composed of concentric lamellae around a centralneurovascular canal (Haversian canal). These rylindrical units run more or less par-allel to the long axis of compact bone.

b. Interstitial lamellae are wedges of compact bone located between the cylindricalosteons.

c. Circumferential lamellae are parallel lamellar arrays of compact bone tissue sur-rounding the osteons on the outer surface (outer circumferential lamellae) and on theinner surface (inner circumferential lamellae) of bone.

3. Periosteum is a double-layered tissue membrane bound firmly to the outer bone surface.It consists of an outer, mostly fibrous, layer and an inner, more cellular, layer that pos-sesses osteogenic potential.

4. Endosteum is a delicate membrane of osteogenic cells that lines the internal surfaces ofbones adjacent to the marrow cavities.

D. Types ofbone

l. Cancellous (spongy) bone consists of delicate anastomotic spicules or larger trabeculaeof bone tissue in the form of a porous meshwork fi.lled with marrow.

2. Compact (dense) bone consists of numerous osteons, interstitial lamellae, and circum-ferential lamellae.

E. Organization of long bones

1. Epiphyses are extremities of long bones composed of cancellous bone covered by a thinlayer of compact bone.

2. Diaphyses are cylindrical shafts of long bones composed of compact bone.

3. Metaphyses are the regions between the epiphyses and the diaphyses and consist of a shellof compact bone around a mass of cancellous bone.

F. Bone formation. Bone organs form by two distinct processes. In intramembranous ossifi-cation, bone is formed directly within layers (membranes) of mesenchyme, or primitiveconnective tissue. In endochondral ossification, a model of the bone is first laid down inhyaline cartilage, and then the cartilage is replaced by bone. In both processes of bone for-mation, a temporary, immature nonlamellar tissue appears first and is then replaced bylamellar bone.

1. Intramembranous ossification. Bones formed in this way are the membrane bones andinclude certain bones of the skull (i.e., frontal, parietal, temporal, part of the occipitalbones), facial bones, the clavicles, and part of the mandible.

a. This process begins in the primary ossification center within the connective tissuelayer.

Clinical Correlate

In Paget disease, there is adisturbance in the balance ofbone homeo$asis (anincreased rate of bonedestruction and consequentrebuilding) that leads to thecreaiion of woven orimmature bone. Peoplesuffering from Paget are pre-disposed to fractures.

Note

Primary Functions ofPeriosteum and Endosteum. Nutrition of bone tissue

. Provision of continuoussupply of new o$eoblasts

l 7


lfot,gIn endochondral ossification,there is no transformation ofcartilage into bone; bonetissue replaces the cartilagemodel.

(1) Mesenchyme cells aggregate and differentiate into osteoblasts, which depositspicules of bone matrix in the loose connective tissue.

(2) Cells of the connective tissue membrane divide to give rise to more osteoblasts,which contribute to the growth of the ossification center.

b. The matrix is calcified after it is secreted by the osteoblasts in the woven bone. Aftercalcification, the spicules of bone become coated with more osteoblasts, which trans-form the spicules into larger trabeculae. The trabeculae interconnect around the bloodvessel network in the mesenchyme to form cancellous bone.

c. The growth of bone is appositional and osteoblasts become trapped in expandingbone to become osteocftes. (Unlike cartilage, bone is able to grow appositionallyonly.) In lacunae, osteocftes rarely divide, and thus, interstitial growth is impossible.

d. The intramembranous bone has two fates:

( 1) It may remain cancellous, in which case the intertrabecular connective tissue cav-ities become filled with bone marrow or fat.

(2) It maybecome compact, in which case appositional growth continues until all of

the mesenchyme (except blood vessels) is replaced by bone. In this case, theimmature woven bone is replaced by lamellar bone through the concomitantprocess of resorption and apposition.

e. The connective tissue layer that does not undergo ossification gives rise to the perios-

teum and endosteum of the bone.

2. Endochondral ossification. Bones formed in this way are the cartilage bones and includemost of the long and short bones of the skeleton. Later in development and growth, thecartilage is resorbed and replaced by bone tissue (Figure I-2-3).

a. Hyaline cartilage models are formed by differentiated mesenchymal cells called chon-droblasts. The mesenchyme around the cartilage model condenses to form the peri-chondrium. Cartilage models increase in length by interstitial growth (i.e., division ofchondroblasts) and in width by appositional growth (i.e., new cartilage cells are con-tributed by the perichondrium).

b. Ossification of the cartilage model begins at the primary ossification center, which islocated in the diaphysis of long bones. It begins as the chondrocytes in the region ofthe primary ossification center hypertrophy, resorb some of the organic matrix, anddie, leaving large lacunae.

c. A solid mineral phase of calcium and phosphate is deposited in the remaining matrixto form a calcified cartilage. At the same time, the cells of the inner layer of perichon-drium differentiate into osteoblasts. The perichondrium is now called the periosteum.

t8


Epiphyseal bone

Resting zone

Proliferative zone

Hypertrophiccadilagezone

Calcif ied carti lage

-ugile

Ossification zone

Figure l-2-3. Endochondral ossif ication.

d. Osteoblasts secrete bone matrix on the surface of the calcifed cartilage. Capillaries,osteoclasts, and osteoblasts penetrate the periosteal bone to form the primary marrow(central) cavity.

e. Cartilage cells adjacent to the primary ossification center then begin to hypertrophyand undergo the same sequence of events: cell death, calcification of organic matrix,capillary and osteoclast invasion, and deposition of bone spicules. This process grad-ually progresses in the cartilage model, moving in a direction away from the ossifica-tion center. Thus, not all chondroblasts undergo the same changes at the same time.There are five distinct zones in the cartilage skeleton, which represent a progression ofcells from the diaphyseal primary ossification center outward.

(1) Ossification z,one consists of osteoblasts laying down bone matrix over calcifiedcartilage.

(2) Calcified cartilage zone consists of cartilage matrix becoming calcified.

(3) Hypertrophic cartilage zone consists of chondrocytes that appear large and haveabundant glycogen in their cytoplasm.

(4) Proliferative zone consists of chondrocytes dividing rapidly to form parallelrows of stacked cells along the long axis of bone.

(5) Restingr-one consists of hyaline cartilage without morphologic cell changes.

f. At later stages of development, usually after birth, secondary ossification centers arisein the epiphyses. Growth at these centers is radial rather than longitudinal.

g. All zones located between the diaphysis and epiphysis (in the metaphysis of the bone)are caught between ossification centers. The result is a transverse disk of cartilage,called the epiphyseal plate, which separates epiphyseal bone from diaphyseal bone.

Note

Growth of a Long Bone(l) Proliferation of

chondrocytes in theepiphyseal plate

(2) Chondrocytes of thediaphyseal sidehypertrophy

(3) Matrix calcifies

(a) Chondrocytes die

(5) Osteoblasts lay downlayer of primary bonealong the bone spicules

(Steps l-5, repeat)

t9


( l. ) It persists postnatally until longitudinal growth of bone is completed.

(2) When the cartilage of the epiphyseal plate stops growing (at approximately age20), it is replaced by bone tissue.

G. Growth and remodeling of bones. Bone growth is associated with concomitant resorption

NOte of preformed tissue and deposition of new tissue. Bone remodeling occurs tlroughout life.

. Endochondrar ossification = t

:rffiJffiffiffirT"lfgbonesgrowinlengthbvthecontinuedinterstitialgrowth1 in len$h a. This radial growth of cartilage tends to thicken the epiphyseal plates; however, subse-

. Appositional ossification = quent endochondral ossification keeps the Plate at about the same thickness, while

I rn girth adding to the length of the bone shaft'

b. The process of elongation does not necessarily proceed at th€ same rate in the two epi-phpeal plates of a long bone.

z. Growth in girth. The shafts of long bones increase in width by apposition of new bonesubperiosteally.

a. At the same time, bone is removed from the internal surface beneath the endosteumso that the bone marrow cavity may increase in diameter.

b. Growth in outside diameter results ftom peripheral apposition of bone. Growth incavity diameter results from central resorption of bone.

H. foints are defined as the articulation between two bones. Th€re are two tfpes of connectivetissue ioints.

l. Synarthroses are joints that permit very litde or no movement ofbones.

a. Syndesnoses are articulations where bones are joined by bands of dense connectivetissue. This type of joint forms the sutures betw€en the growing bones of the skull butis converted into a synostosis in adults.

b. Synchondrcses are ioints where bones are united by hyaline cartilage. Examples ofthis tfpe of ioint are the epiphyseal plates of growing long bones.

c. Synostoses are joints where bones are united by bone tissue. This type of joint isfound in the sutures of the adult skull.

d. Symphyses are joints where bones are united by combinations of hyaline and fibro-cartilage. The symphysis pubis and intervertebral disks are considered symphyses.

2. Diarthroses are joints that permit ftee movement. They are present in the union of longbones, such as at tle elbow and knee.

a. In a diarthrosis, a twoJayered articular capsule joins the extremities of long bones.The capsule is composed of an external fibrous layer and an internal synovial layer.

(1) The dense connective tissue frbrous layer is especially well developed in liga-ments and some of tlle tendons inserted into the bone near the ioint.

(2) The internal synovial membrane is lined by squamous or cuboidal cells of mes-enchymal origin called rynovial cclls.

b. The capsule encloses the articular cavity, which is filled with a hyaluronic acid-rich syn-ovial fluid; this fluid facilitates the sliding of the articular surfaces of the bones at thejoint.

20

Muscle Histology

Muscle is a tissue specialized for irritability and contractility. lt is composed of elongated cells calledmyofibers that contain contractile proteins arranged in rytoplasmic filaments. Muscle cells attach tobones and soft tissues and are arranged in circular sheets around tubular organs to accomplishmechanical body movements upon contraction. There are three types of muscle: skeletal, cardiac,and smooth. Skeletal and cardiac muscles are classified as striated muscles, based on theappearance of striations that run perpendicular to the long axis of the muscle fiber. The striations aredue to the highly ordered repetitive organization of the contractile filaments. Smooth muscle lacksstriations due to a less structured, looser arrangement of its contractile filaments. ln muscleterminology, the sarcolemma refers to the muscle cell membrane, the sarcoplasm refers to thecytoplasm, and the sarcoplasmic reticulum refers to the endoplasmic reticulum.

SKETETAL MUSCTESkeletal muscle is derived from mesodermal somites. Single-nucleated myoblasts fuse to formthe multinucleated skeletal muscle cells (fibers).

A. Skeletal muscle cells are long rylindrical fibers. Their multiple ovoid nuclei are locatedperipherally beneath the sarcolemma. This distinguishes skeletal muscle cells from cardiacmuscle cells, which usually have one centrally located nucleus. Each skeletal muscle fiber issurrounded by a basal lamina.

1. Light microscopy. Stained with hematorylin and eosin, the sarcoplasm appears homoge-neous or stippled in cross section and striated in longitudinal section.

a. The striations, composed of alternating dark and light bands, are contained in1-2 pm myofibrils that lie in the sarcoplasm parallel to the long axis of the musclefiber. Myofibrils are composed of a series of sarcomeres that consist of interdigitatingpolarized thin filaments and bipolar thick filaments (Figure I-3-1). The sarcomeres arethe basic units of contraction of striated muscle.

b. The dark bands of the sarcomeres are called A bands because they are anisotropic(birefringent) in polarized light. In the center of the A band, a paler region, the Hband, is seen in relaxed muscle.

c. The light bands of the sarcomere are called I bands (isotropic), and a dark transverseline, the Zline,bisects each I band.

d. A single sarcomere is bounded by two Z lines and contains one A band separating twosemi-I bands.

2 l

Muscle Histology

Muscle is a tissue specialized for irritability and contractility. lt is composed of elongated cells calledmyofibers that contain contractile proteins arranged in rytoplasmic filaments. Muscle cells attach tobones and soft tissues and are arranged in circular sheets around tubular organs to accomplishmechanical body movements upon contraction. There are three types of muscle: skeletal, cardiac,and smooth. Skeletal and cardiac muscles are classified as striated muscles, based on theappearance of striations that run perpendicular to the long axis of the muscle fiber. The striations aredue to the highly ordered repetitive organization of the contractile filaments. Smooth muscle lacksstriations due to a less structured, looser arrangement of its contractile filaments. In muscleterminolory, the sarcolemma refers to the muscle cell membrane, the sarcoplasm refers to therytoplasm, and the sarcoplasmic reticulum refers to the endoplasmic reticulum.

SKELETAT MUSCTESkeletal muscle is derived from mesodermal somites. Single-nucleated myoblasts fuse to formthe multinucleated skeletal muscle cells (fibers).

A. Skeletal muscle cells are long rylindrical fibers. Their multiple ovoid nuclei are iocatedperipherally beneath the sarcolemma. This distinguishes skeletal muscle cells from cardiacmuscle cells, which usually have one centrally located nucleus. Each skeletal muscle fiber issurrounded by a basal lamina.

t. tight microscopy. Stained with hematorylin and eosin, the sarcoplasm appears homoge-neous or stippled in cross section and striated in longitudinal section.

a. The striations, composed of alternating dark and light bands, are contained in1-2 pm myofibrils that lie in the sarcoplasm parallel to the long axis of the musclefiber. Myofibrils are composed of a series of sarcomeres that consist of interdigitatingpolarized thin filaments and bipolar thick filaments (Figure I-3-1). The sarcomeres arethe basic units of contraction of striated muscle.

b. The dark bands of the sarcomeres are called A bands because they are anisotropic(birefringent) in polarized light. In the center of the A band, a paler region, the Hband, is seen in relaxed muscle.

c. The light bands of the sarcomere are called I bands (isotropic), and a dark transverseline, the Zline,bisects each I band.

d. A single sarcomere is bounded by two Z lines and contains one A band separating twosemi-I bands.

2 l


zl ine

Myofibril

Z I b a n d , '

Sarcomere

A band . l Z l i n e

M l inelri-----tl l ' . 1

f i lament

Myosin molecule

f------ra ecules

Light Heavymeromyosin meromyosin

Figure l-3-1 . Sarcomere structure.

2. Electron microscopy. In skeletal muscle cells examined with the electron microscope, the

repeating pattern of bands and sarcomeres is due to the arrangement of the myofilaments.

a. Thin filaments are composed of the proteins actin, tropomyosin, and troponin.

( 1) Actin is a long fibrous structure (F-actin) composed of two strands of sphericalor globular G-actin monomers twisted in a double helix. The filament is polar

and contains myosin-binding sites on the G-actin monomers.

(2) Tropomyosin is a polar molecule containing two polypeptide chains in the formof an o-helix. The tropomyosin molecules lie head-to-tail to form filaments thatlie in the grooves of the actin helix.

(3) Troponin is composed of three polypeptides: TnT binds to tropomyosin atintervals along the thin filament, TnC binds calcium ions, and TnI inhibitsactin- myosin interaction.

b. Thick filaments are composed of myosin. Myosin is a molecule that contains a tailand two heads.

A I Hband band band

ocoE(g

o

Myosin

I

F-actin filament\\

\oe

f,oG-actin mol

Note

Actin and tropomyosin arelong, thin filaments, whereastroponin is a complex ofthree subunits.

22

Histology: Muscle

( 1) The tail fiber is formed from portions of two heavy chains, which are wound in a coil.

(2) The heads are globular regions formed by the association of part of one heavychain with two light chains. Myosin heads function as active sites for AIPaseactivity and as actin binding sites.

c. Actin and myosin together represent 55o/o of the total protein in striated muscle.

d. Thick filaments occupy the central portions of the sarcomere; thin filaments attach atone end to the ZIine and run parallel to, and between, the thick filaments.

(1) I bands are composed of thin filaments only.

(2) Abands .ue composed mostly of thick filaments and the thin filaments between them.

(3) H bands are composed of thick filaments only.

B. Connective tissue investments of skeletal muscles and fibers (Figure I-3-2).

Skeletal muscle

Epimysium

Perimysium

Myofibrils

Nucleus

EndomysiumSarcolemma

Figure l-3-2. Connective tissue investments of a striated skeletal muscle.

2!


Note

. Connective tissue not onlybinds muscle cells together,but also assists in thegeneration of force andmovement duringcontraction.

. Tendons attach musclesto bones.

. Ligaments attach boneto bone.

ln a Nutshell

Sliding Filament Model

Contraction is not caused bythe shortening of individualfilaments, but rather by theincrease in the amount ofoverlap between thickand thin filaments.

1. Endomysium is a connective tissue framework composed mainly of reticular fibers thatsurrounds and supports individual muscle cells.

2. Perimysium is a connective tissue septum that surrounds groups (fascicles) of muscle

cells.

3. Epimysium is a connective tissue sheath that surrounds an entire muscle.

4. Connective tissue fibers from the endomysium, perimysium, and epimysium come togeth-er at the ends of the long rylindrically shaped muscle to form a tendon.

5. Skeletal muscle is a highly vascular tissue; capillaries are located in the connective tissuesurrounding all muscle cells.

C. Muscle contraction

1. Sliding filament model has been generally accepted as the explanation of how a musclecell shortens on contraction.

a. According to this theory, the filaments maintain constant lengths during muscleshortening, with thin filaments sliding past thick filaments.

b. The sliding movement is due to cross-bridges formed between the actin monomer andthe myosin head. These cross-bridges bind the thin and thick filaments during muscle con-traction.

c. Tension development is proportional to the number of myosin heads overlapped bythin filaments.

2. Sequence of events. At the onset of muscle contraction, myosin heads move out from thethick filament backbone to interact with ATP and actin molecules.

a. The myosin head movement pulls thin and thick filaments in opposite directions. Asthe filaments slide, the sarcomeres and myofibrils shorten. The myosin heads thendetach from the actin molecules and the rycle is repeated.

b. As a consequence of this action, thin filaments slide into the A band, and the sarcom-ere and overall muscle shorten.

(1) The H band narrows and disappears.

(2) The I bands shorten.

(3) The Z lines are pulled closer together.

3. ATP provides the energy for muscle contraction in the following manner:

a. AlP-bound myosin is active and binds actin.

b. This complex is altered when AIP is split by AIPase to liberate energy.

4. Tubules formed by finger-like invaginations of the sarcolemma into the muscle cell sur-round each myofibril to form the transverse (T) tubule system (Figure I-3-3).

a. Each tubule lies between the two terminal cisternae of the sarcoplasmic reticulum toform a triad.

24

Histology: Muscle

Sarcomere

I band

Terminalcisterna Transverse tubules

Figure l-3-3. Striated muscle fiber showingsarcoplasmic reticulum and T-tubule system.

b. There are two triads in each sarcomere, which are present at the junction between theA and I bands.

c. These units serve to couple excitation of muscle cells to their contraction (excitation-contraction coupling).

5. Muscle contraction is summarizrdas follows:

a. Skeletal muscle cells are innervated by motor neurons located in the CNS.

b. The axon of the motor neuron branches in the muscle to contact several muscle cells,forming a motor unit.

c. The terminus of each branch forms a specialization at the muscle surface called amotor end plate.

d. An action potential from the motor neuron arrives at the motor end plate and causesthe release of the neurotransmitter acetylcholine onto the surface of the muscle. This,in turn, causes depolarization of the sarcolemma.

e. Electrical impulses travel into the cell via the T tubules and stimulate the sarcoplas-mic reticulum via gap junction-like bridges to release Ca2+.

f. Released Caz+ binds to the TnC unit of troponin and induces movement oftropomyosin deep into the actin helix groove.

g. As a result of this displacement, the actin filaments can bind to the myosin head, movedeeper into the A band, and the I band then shortens.

D. Muscle relaxation

1. The sarcoplasmic reticulum possesses an AlP-driven Ca2+ pumping mechanism, whichaccumulates Ca2+ within its membrane system and, thus, reduces the cytoplasmic con-centration of Ca2+ around the myofilaments.

2. At low Ca2+ concentrations, the tropomyosin falls out of the groove of the actin helix ina position where it sterically blocks the myosin-binding site on each actin molecule.

Note

Summary of ContractionMechanism

. Depolarization of nerve --+

release of neurotransmitteracetylcholine atneuromuscular junction

. Acetylcholine causesdepolarization ofsarcolemma and its Ttubules

. Increased release of Cazrfrom SR

r fsz* binds to TnC subunitof troponin, exposingactin's myosin binding site

. This allows the myosinhead to interact with theactin's myosin binding site

. Myosin head bends(ratchet-motion), pu ll in gactin past myosin

. Myosin head is releasedonly after addition of newATP molecule

2t


SMOOTH MUSCTEA, Smooth rnusde cells are derived ftorn a mesenchymal network of cells called myoblasts.

Ihey are elongated, spindle-shaped, nonstriated cells.

1. They contain a single centrally located nucleus in a homogeneous eosinophilic cytoplasm.

2. Each cell is surrounded by a basal larnina and delicate reticular fibers-

3. Lavers of smooth muscle cells are found in the walls of blood vesels and hollow viscera.Bands of smooth rnuscle cells can be found in the erector pili muscles of the skin.

{. Smooth muscle cells in a tissue are electrically coupled with each other.

a. With the electron microscope, areas of adjacent smooth muscle cells can be seen withtheir cell membranes closely apposed and forming gap junctions.

b. Similar electrical iunctions occur in cardiac muscle but not in skeletal muscle.

5. Smooth muscle cells contain actin and myosin filaments, but they are not arranged inorderly arrays like those found in skeletal muscle.

llota a. Bundles ofmyofilaments course obliquely in the cell, forming a lattice-like arrangemenl

Dense bodies in smooth b. A stding filament mechanism of contraction is tlought to occur'

muscle cells serve the function c. Thin filaments insert into dense bodies, located within smooth rnuscle cyoplasm andof Z lines in striated muscle. attached to their membranes.

B. Contraction of smooth muscle is slow and sustained. Individual cells may contract com-pletely or a wave of contraction may propagate from one end of the tissue to the other.

1 . Muscle cell contraction may be triggered by various stimuli.

a. In some structures (e.g., ductus deferens), nerve supply to smooth muscle is abundant.

b. In the smooth muscle of the intestinal wall, contraction is modulated by intrinsicrhythrnic depolarization and by neural input.

c. Hormones may also cause srnooth muscle contraction; for example, oxytocin stimu-lates uterine contraction,

2. Smooth muscle cells are able to conc€ntrate Ca2+ in their cftoplasm. This ion plays animportant role in the contraction of these cells.

a. Depolarization of the cell membrane results in an influx of Ca2+ from outside the cell.

b. Ca2+ is sequestered in either the cell membrane or in the sparse sarcoplasmic reticulum.

CARDIAC MUSCLECardiac muscle is discussed in the Cardiovascular Histology chapter of Organ Systems Book I(Volume III).

26

Histology: Muscle

SUMMARY OF MUSCLE TYPES

Thble I-3-f . Tlpes of muscle.

Muscle Type Description Cross Striations Activity

Skeletal Bundles oflong, cylindricalmultinucleatedcells

Cardiac Elongated,branchedindividual cellsthat lie parallelto each other;intercalateddisks betweenends of cells

Yes Strong, quick,discontinuous,voluntarycontraction

Yes Strong, quick,continuous,involuntarycontraction

Smooth Fusiform cells No Weak, slow,involuntarycontraction

27

Integument Histology

The integument consists of the skin (epidermis and dermis) and associated appendages (sweatglands, sebaceous glands, hairs, and nails). Considered the largest body organ, the integumentcomprises approximately 16o/o of total body weight. lt is a highly specialized organ that functions toprotect the body from injury, desiccation, and infection. lt also participates in sensory reception,excretion, thermoregulation, and maintenance of water balance.

EPIDERMISEpiderrnis is the outermost layer of tJle integument. It is a stratified squamous orthokeratinizedepithelial layer of ectoderrnal origin.

A. Layers of the epiderrnis ftom deep to superficial consist of four strata.

l. Stratum basale (stratum germinatirum) is a proliferative basal layer of columnar-likecells that contain the fibrous protein keratin.

2. stratum spinosum is a multilaminar layer of cuboidallike cells that are bound togetler illnemonic

by means of numerous cltoplasmic extensions and desmosomal junctions. BiG Stratum Basale3. Stratum granulosum consists of flat polygonal cells filled with basophilic keratohyalin (Germinativum)

granules. Viewed at the electron microscopic level, these cells also contain numerous Sta6 Stratum Spinosummembrane-coating grarules

GNe Stmtum Gnnulosum4. Stratum corneum is the superficial stratum of dead cells and consists of several to many Lots of Stratum lu.idum

layers offlat, anucleated, and cornified (keratinized) cells. In the epidermis ofthe palms -, .and soles, a thin, transitional zone of flat eosinophilic or pale-staining

"r,o.leatei ""u, charlty Stratum corneum

may occur as the stratun lucidum. This layer is found only in regions with a thick stra-tum corneum.

B. Cells of the epidermis

1. IGratinoc''tes are the most numerous and are responsible for the production oftle fam-ily of keratin proteins that provide the barrier function of the epidermis.

2. Melanocytes are derivatives of neural crest ectoderm, They are found in the dermis andare also scattered among the keratinocftes in the basal layers of the epiderrnis, These den-dritic cells produce the pigment melanin in the form of melanosomes that are trans-ferred to keratinocftes.

3. Langerhans cells are dendritic cells but are members ofthe immune system and functionas antigen-presenting cells. They have also been found in other parts of the body, includ-ing the oral cavity and lymph nodes.

29


Clinical Correlate

Psoriasis. T in number of

proliferating cells in stratumbasale + stratum spinosum.In addition, there is an 1rate of cell turnover. Thisresults in greater epidermalthickness and continousturnover of the epidermis.

Addison Disease. JACTH * tp igmentat ion

of skin

Albinism. Melanocytes are unable to

synthesize melanin (eitherby absence of tyrosinaseactivity or inability of cellsto take up tyrosine).

Vitiligo. Disorder in which

melanocytes are destroyed,thought to be secondary toautoimmu ne dysfu nction,leading to depigmentation.

Clinical Correlate

Bullous Pemphigoid. Abnormality of the dermal-

epidermal junction, leadingto a blistering disorder.

Pemphigus. Another blistering disorder;

it is caused by loss ofintercellular ju nctionsbetween keratinocvtes.

4. Merkel cells are found in the basal epidermis and appear to function in concert with nerve

fibers that are closely associated with them. They appear to have a sensory function. At the

electron microscopic level, their cytoplasm contains numerous membrane-bound granules

that resemble those of catecholamine-producing cells.

DERMISDermis is a connective tissue layer of mesodermal origin subjacent to the epidermis and its

basement membrane. The dermis-epidermal junction, especially in thick skin, is characterizedby numerous papillary interdigitations of the dermal connective tissue and epidermal epitheli-

um. This increases the surface area of attachment and brings blood vessels in closer proximity

to the epidermal cells. (The epidermis, like epithelia in general, is devoid of blood vessels.)

Histologically, dermis consists of two identifiable regions.

A. Papillary layer, associated principally with the dermal papillae, is the most superficial layer.It consists of a loosely packed, irregular meshwork of collagen fibrils that contain fine bloodvessels and nerve endings.

B. Reticular layer is the deeper dermal layer and consists of coarse collagen bundles intertwined

with elastic fibers in a gel matrix. This layer is a typical dense irregular connective tissue.

HYPODERMISThis layer of loose vascular connective tissue is infiltrated with adipocytes and corresponds tothe superficial fascia of gross anatomy. However, since it contains the deepest portions of the

cutaneous glands and hairs, it is also an important part of the skin. The hypodermis fastens theskin to underlying muscles and other structures.

CUTANEOUS APPENDAGESCutaneous appendages are all derivatives of the epidermis.

A. Eccrine (merocrine) sweat glands are simple, coiled, tubular glands that are widely

distributed over the body.

1. Secretory portions are tightly coiled and consist of a single layer of columnar-like pyra-midal cells. They extend deep within the dermis or hypodermis, where they aresurrounded by myoepithelial cells, which aid in the discharge of secretion by contraction.

2. Duct portions, composed of two cuboidal cell layers, are corkscrew-shaped and openonto the epidermal surface. The luminal diameter of the duct is less than that of the secre-tory coil.

3. These glands are important in thermal regulation. When hypotonic sweat is released

onto the body surface, heat is lost by water evaporation.

4. Control of the eccrine glands is mainly by the innervation of cholinergic fibers.

B. Apocrine sweat glands are also simple, coiled, tubular glands but are much less abundant intheir distribution than eccrine glands. They can be found in the axillary, areolar, and analregions.

1. Secretory portions of these glands are composed of a single layer of cuboidal or colum-nar cells. They are larger and have a much wider luminal diameter than eccrine sweatglands. Myoepithelial cells surround the secretory cells within the basement membraneand contract to facilitate secretion.

50

Histology: Integument

2. Duct portiom are sirnilar to those of eccrine sweat glands but generally open onto hair fol- In a NUbhellIicles instead of onto the epidermal surfaces. '

3. Functions of these glands in humans is not at all clear. In other mammals, apocrine sweat sLe ::Tlt ,.fn lff:,.|nglands are widely distributed over th€ body and serve a variety offirnctions related to olfac- [o@_ Esserrja'y Artkry,tion and behavior. Specialized apocrine glands in the ear canal (ceruminous glands) doo €v€rywnerq ar€o.r,produce a secretion in conjunction with adjacent sebaceous glands to form the protective wih some and analearwax (cerumen), Apocrine sweat is normally odorless when secreted but becomes erceplions rcsonnoticeable due to ttre activity of cutaneous bacteria, (e8,slans

4. Control of the apocrine glands is hormonal and via the innervation of adrenergic fibers. * n lil']r** Hair foricl*These glands do not begin to function until puberty. opcis

C. Sebaceous glands are sirnple, branched holocrine acinar glands. They usually discharge their ::*. il;iffil lf:tsecretions onto the hair shaft within hair follicles. These glands are found in the dermis mainty H,0 producingthroughout the skin, except on tle palrns and soles. Nacl, urea,

l. Seqetorl'portions consist ofperipherallylocat€d, flattened stem cells t}lat resemble basal NH'uricacid

keratinocftes. Toward the center of the acini, enlarged differentiated cells are engorged Inner- cholineqic Mrcneqicwith lipid. Death and ftagmentation of cells nearest the duct portion result in the trdionholocrine mechanism of secretion.

2. Duct portions of sebaceous glands are cornposed of stratified squamous epithelium that I{Oteis continuous with the hair canal and epidermal surface.

3. Functions involve the lubrication of both hairs and cornified layers of the skin, as well as Primary Contolling Factor of

resistance to desiccation. -

Sebaceous Cland Secretion

4. Control of sebaceous glands is hormonal. Enlargement of the acini occurs at puberty. MalFte$osterone

D. Ilairs are long, filamentous proiections consisting of dead keratinized epidermal cells. Each Female-combination ofhair derives ftom an epidermal invagination called the hair follide, which possesses a ter- ovarian and adrenalminal hair bulb, located in the dermis or hypodermis, from which the hair shaft grows. anorogensBundles of smooth muscle cells, called arrector pili musd€s, are attached to the hair follicleat one end and to the papillar), dermis at the other. C,ontraction of tlese muscles raise thehairs and dimple the epidermis ("goose flesh"). The follicles and associated sebaceous glandsare known as piloseboceous units.

E. Nails,like hair, are a modified stratum corneum ofthe epidermis. They contain hard keratinthat forms in a manner similar to the formation of hair. Cells continuallv proliferate andkeratinize ftom the stratum basale of the nail natrix

5 l

Musculoskeletal Anatomy

This extensive chapter covers the major bones of the skeleton as well as their associated musclesand tendons. Blood supply and innervation are reviewed for each muscle group.

SKULLBones of the skull may be classified as belonging to the neurocranium (chondrocranium) (i.e.,

the portion of the skull that surrounds and protects the brain) or the viscerocranium (i.e., the

skeleton of the face).

A. Osteology

1. Bones of the neurocranium

a. Frontal

b. Parietal

c. Temporal (squamous and petrous portions)

d. Occipital

e. Ethmoid

f. Sphenoid

2. Bones of the viscerocranium

a. Maxilla

b. Nasal

c. Zygomatic

d. Mandible

e. Vomer

f. Lacrimal

g. Palatine

h. Inferior nasal concha

t5


Clinical Correlate

The anterior fontanelle, or"soft spot," serves as a site forprenatal withdrawal of bloodsamples from the superiorsagittal sinus, The anteriorfontanelle usually closes by 18months, and the posteriorfontanelle by 6 months.

Clinical Correlate

The pterion is a landmark forthe middle meningeal artery,which grooves the bone of theskull internal to this site. Ablow to the lateral aspect, or"temple," of the skull maycause the artery to rupture,thereby causing an epiduralhemorrhage. lf blood isallowed to accumulate in theepidural space, shifting of thebrain may occur, which cancause the sharp, free edge ofthe tentorium cerebelli(tentorial incisure) to cut intobrain stem tissue on the sideopposite the in1ury. Thispressure must be relievedquickly, or death ensues.

Thble I-5-f . Muscles of facial expression.

Muscles of the scalpFrontalisOccipitalis

Muscles of the earAnterior auricularSuperior auricularPosterior auricular

Muscles of the rim of the orbitOrbicularis oculiCorrugator supercilii

Muscles of the noseProcerusNasalis

Muscle of the neckPlatvsma

Muscles surrounding the lipsLevator labii superioris alaeque nasiLevator labii superiorisZygomaticus minorZygomaticus majorLevator anguli oris (caninus)RisoriusDepressor anguli oris (triangularis)Depressor labii inferioris(quadratus labii inferioris)MentalisBuccinatorOrbicularis oris

B. Articulations. Most skull bones meet at immovable joints called sutures. The sole exception isthe temporomandibular joint (TMI), a synovial joint that has a hinge-gliding movement.

1. The coronal suture is between the frontal and the parietal bones.

2. The sagittal suture is between two parietal bones.

3. The lambdoid suture is between the parietal and the occipital bones.

4. The bregma is the point at which the coronal suture intersects the sagittal suture and isthe site of the anterior fontanelle in an infant.

5. The lambda is the point at which the sagittal suture intersects the lambdoid suture and isthe site of the posterior fontanelle in an infant.

6. The pterion is the point on the lateral aspect of the skull where the greater wing of thesphenoid, parietal, frontal, and temporal bones converge.

7. The temporomandibular joint is between the mandibular fossa of the temporal bone andthe condylar head of the mandible.

FACEA. The muscles of facial expression are derived from the second pharyngeal arch and are sup-

plied by motor branches of CN VII (Table I-5-1).

t4

Anatomy: Musculoskeletal

Superficialtemporal artery

Temporal

Facialartery

Marginal mandibular

Mandibularnerve (CN V3)

Posterior auricular

Figure l-5-1.The face and the parotid gland.

B. The parotid glurd is the largest of the salivary glands and has a dense connective tissue cap-

sule (Figure I-5-1). Structures found within the substance of this gland include the following:

1. Motor branches of the facial nerve. CN VII enters the parotid gland after emerging from

the stylomastoid foramen at the base of the skull.

2. Superficial temporal artery and vein. The artery is a terminal branch of the external

carotid artery.

3. External carotid artery

4. Retromandibularvein, which is formed from the maxillary and superficial temporal veins

5. Great auricular nerye, which is a cutaneous branch of the cervical plexus

6. Auriculotemporal nerve, which is a sensory branch of Vr. It supplies the TMJ and con-

veys postganglionic parasympathetic fibers from the otic ganglion to the parotid gland.

7. Parotid (Stensen) duct, which enters the oral cavity at the level of the maxillary second molar

8. Transverse facial artery, a branch of the superficial temporal arrery

C. The facial artery is a branch of the external carotid artery in the neck. It terminates as the

angular artery near the bridge of the nose.

D. The facial vein parallels the course of the facial artery. It terminates by joining the anterior

branch of the retromandibular vein to form the common facial vein.

Clinical Correlate

Bell palsy is caused by anidiopathic paralysis of thefacial nerve. Patients presentwith an inability to close theeye, sagging of the corner ofthe mouth, an inability tosmile voluntarily, drooling, andan inability to move food fromthe vestibule to the oral cavityproper. The condition usuallyresolves spo nta neously.

Note

The facial vein has manytributaries that com mu nicatewith the cavernous sinus.Because the veins have novalves, extracranial infectionsarising within a triangular areabounded by the bridge of thenose, and the angles of themouth may moveintracranially to reach thecavernous sinus. This area issometimes referred to as the"danger triangle."

55


NECKA. Osteology

Superior sagittal

Corpus ca

Frontal sinus

Cribiform plateof ethmoid bone

Torustubarius

Hard palate

Tongue

Epiglottis

MandibleGeniohyoid

Mylohyoid

Thyroid cartilage

Larynx

Oricoid cartilage, arch Trachea

Thalamus

Tentor iumcerebel l i

Cerebel lum

Pons

Externaloccipitalprotuberance

Internaloccipitalprotuberance

Falx cerebell i

Atlas

Dens of axis

Posterior wall ofpharynx

Retropharyngealspace

Lamina ofcricoid cartilage

Note

Movement at the atlanto-occipital joint causes flexionand extension, or nodding ofthe head (e.g., saying "yes").Movement at the atlantoaxialjoint causes lateral rotation(e.g., saying "no"),

Note

The hyoid is the only bone inthe human body that does notdirectly articulate with at leastone other bone. lt is stabilizedby the attachment of variousmuscles and ligaments.

56

Figure l-5-2. Sagittal section of the head and neck.

1. Cervical vertebrae. There are seven cervical vertebrae of which the first two are atypical.All cervical vertebrae have openings in their transverse processes, the foramina transver-saria, which, when aligned, produce a canal that transmits the vertebral artery and vein.

a. Atlas. This is the first cervical vertebra (Cl). It has no body and leaves a space toaccommodate the dens of the second cervical vertebra.

b. Axis. This is the second cervical vertebra (C2).It has a tooth-shaped process, the dens(odontoid process), which articulates with the atlas as a pivot joint. Movement at thisjoint allows lateral rotation of the head.

Hyoid bone is a small U-shaped bone, which is suspended by muscles and ligaments atthe level of vertebraC3.It occupies the angle of the throat that separates the neck fromthe floor of the oral cavity.

Laryngeal prominence is formed by the lamina of the thyroid cartilage. It is more promi-nent in men than in women and children.

Cricoid cartilage. The arch of the cricoid, another laryngeal cartilage, is palpable belowthe thyroid cartilage and superior to the first tracheal ring (vertebral level C6).

2 .

3.

4.


B. Triangles of the neck. The neck is divided into a posterior and an anterior triangle by thesternocleidomastoid muscle. These triangles are subdivided by smaller muscles into six

smaller triangles (Figure I-5-3).

Submandibulartriangle

Mastoid process

Sternocleidomastoidmuscle

Occipital triangle

CN XI

Submental triangle

Carotid triangle

Muscular triangle Subclavian triangle

Figure l-5-3.Triangles of the neck.

1. Posterior triangle is bound by the sternocleidomastoid, the clavicle, and the trapezius.The floor of the posterior triangle is formed by the splenius capitis, the levator scapulae,

and the medial and posterior scalene muscles.

a. Occipital triangle is located above the inferior belly of the omohyoid muscle. Its con-tents include the following:

(1) CN XI is the cranial nerve that supplies motor innervation to the trapezius andsternocleidomastoid muscles.

(2) Cutaneous branches of the cervical plexus are the lesser occipital, great auricular,transverse cervical, and supraclavicular nerves.

b. Subclavian (omoclavicular, supraclavicular) triangle is located below the inferior

belly of the omohyoid. Its contents include the following:

(1) Brachial plexus (supraclavicular portion-roots, trunks), the branches of whichenter this region from behind the scalenus anterior muscle. The branches include

the dorsal scapular, long thoracic, subclavius, and suprascapular nerves.

(2) The third part of the subclavian artery enters the subclavian triangle from behindthe scalenus anterior muscle anterior to the brachial plexus. Branches mayinclude the transverse cervical and/or suprascapular arteries.

(3) The subclavian vein passes superficid to scalenus anterior muscle. It receives the

external jogol"t vein, a superficial vein that crosses the sternocleidomastoid muscle.

Cliniol Conelate

The occasional presence of acervical rib may exert pressureon the lower trunk of thebrachial plexus or on thesubclavian artery. Cervical ribsyndrome is a particular typeof thoracic outlet syndrome.

t7


Clinical Correlate

An unusually prominentexternal jugular vein (knownas jugular venous distension

[JVDI) may be a sign of heartfailure when accompanied bya rise in venous pressure inthe superior vena cava and itstributaries. lt may also be asign of obstruction of thesuperior vena cava by a tumor.

Bridge to Cardiovascular

A chemoreceptor (the carotidbody) and a baroreceptor (thecarotid sinus) are located inthe wall of the carotid artery ator near its point of bifurcation.The former is sensitive tooxygen levels in the blood,whereas the latter responds toincreases in blood pressure.Visceral afferent impulses fromeach of these receptors areconveyed by CN lX.

Baroreceptors andchemoreceptors are discussedin the Cardiovascular andRespiratory Physiologychapters in Organ SystemsBook t (Volume lll).

2. Anterior triangle is bound by the sternocleidomastoid muscle, the midline of the neck,and the inferior border of the body of the mandible.

a. Muscular triangle is bound by the sternocleidomastoid muscle, the superior belly ofthe omohyoid muscle, and the midline of the neck.Its contents include the infrahyoid(strap) muscles, which function to control movements of the hyoid bone and larynxduring speech and deglutition (swallowing).

b. Carotid (vascular) triangle is bound by the sternocleidomastoid muscle, the superiorbelly of the omohyoid muscle, and the posterior belly of the digastric muscle. Thecarotid triangle contains the following:

(1) Internal jugular vein

(2) Common carotid arterf, bifurcates at the upper border of the thyroid cartilage(i.e., vertebral level C3) to form the internal and external carotid arteries. Theexternal carotid artery has six branches (i.e., the superior thyroid, the ascendingpharyngeal, the lingual, the facial, the occipital, and the posterior auricular arter-ies). These supply structures of the neck and face (Figure I-5-4).

(3) Vagus nerve (CN X)

(a) Hypoglossal nerve (CN XII)

(5) Internal and external laryngeal branches of the superior laryngeal branch of thevagus nerve. The internal larygeal nerve conveys sensory information from thelaryngeal mucosa above the level of the vocal folds, and the external laryngealnerye supplies motor fibers to the cricothyroid, an intrinsic muscle of the larynx.

c. Digastric (submandibular) triangle is bound by the anterior and posterior bellies ofthe digastric muscle and the inferior border of the body of the mandible. The floor ofthis triangle is formed by the hyoglossus and mylohyoid muscles. It contains the sub-mandibular salivary gland.

d. Submental triangle is bound by the anterior belly of the digastric muscle, the hyoidbone, and the midline of the neck. The floor of this triangle is formed by the mylohy-oid muscle. It contains the submental ly-ph nodes.

C. Root of neck This area communicates with the superior mediastinum through the thoracicinlet. Structures of the region include the following:

1. Subclavian artery and vein. The subclavian artery passes posterior to the scalenus ante-rior muscle, and the vein passes anterior to it. Branches of the artery include:

a. Vertebral artery

b. Thyrocervical trunk, which gives rise to the inferior thyroid, the transverse cervical,and the suprascapular arteries.

c. Internal thoracic artery

d. Corticocervical trunk

58


Superficial temPoral arterY

Transversefacial artery

Maxillaryartery

Facial artery

External carotidartery

Lingual artery

Superior thyroid artery

Inferior thyroid artery

Common carotid artery

Internal carotidartery

Vertebralartery

Costocervicaltrunk

Note

Mnemonic for Branchesof External Carotid Artery"Salfops Max"

Superior thyroid

Ascending pharyngeal

Lingual

Occipital

Posterior auricular

Superficial temporal I terminal

Maxillary Jbranches

Clinical Correlate

The recurrent laryngeal nervesare vulnerable during thyroidsurgery. lf one of these nervesis damaged, the quality of thevoice may be changed, resultingin extreme hoarseness.

Clinical Correlate

Infection within the potentialspaces between the fascialplanes responds poorly toantibiotic treatment because thespaces are essentially avascular.Treatment therefore usuallyinvolves the e$ablishment ofexternal drainage of the affectedarea. The space between thealar and prevertebral fasciallayers (danger space') iscontinuous with themediastinum; infection cantherefore pass into themedia$inum, potentiallyresulting in a fatal pericarditis.

artery

Descendingbranch

First

Internal thoracic artery

Thyrocervical trunk Subclavian artery

Figure I-5-4. Arteries of the neck.

2. Phrenic nerve is a branch of the cervical plexus, which arises from C3, C4, and C5. It is

the sole motor nerve to the diaphragm. It crosses the anterior scalene muscle from later-

al to medial to enter the thoracic inlet.

3. Recurrent laryngeal nerve is a branch of the vagus nerve. This mixed nerve conveys sen-

sory information from the laryngeal mucosa below the level of the vocal folds and pro-

vides motor innervation to all the intrinsic muscles of the larynx except the cricothyroid

muscle.

4. Thoracic duct terminates at the junction of the left subclavian and the left internal j,tgn-

lar veins. On the right side of the body, the right lymphatic duct terminates in a similar

fashion.

D. Fascias of the neck

1. Superficial investing fascia encloses the platysma, a muscle of facial expression, which

has migrated to the neck.

2. Superficial layer of deep investing fascia surrounds the trapezius and sternocleidomas-

toid muscles.

3. Pharyngeal (visceral) fascia surrounds the pharynx.

59


In a NutshellMuscleGroup Innervation

Tongue CNXII

Larynx Recunentlaryngealbranch ofvaSus

Pharynx CNX andCN XI

Soft palate CN X andCN XI

lnfrahyoid Ansa cervicalisof cervicalplexus (Cl,O, C3)

Exception

Palatoglossus(cN x)

Cricothyroid(externallaryngealbranch ofvagus)

Stylopharyn-geus (CN lX)

Tensor velipalatini(cN v3)

Thyrohyoid(branch of Cl)

4. Prevertebral fascia invests the prevertebral muscles of the neck (i.e., longus colli, longuscapitis). This layer gives rise to a derivative known as the alar fascia.

E. The major muscle groups and their innervations. A simple method of organizing the mus-cles of the neck is based on two basic principles: (1) The muscles may be arranged in groups,according to their functions; and (2) all muscles in a group share a common innervationwith one exception in each group.

1. Group l: Muscles of the tongue. All intrinsic muscles plus all but one of the extrinsicmuscles (i.e., those containing the suffix, glossus) of the tongue are supplied by CN XII.The one exception is palatoglossus, which is supplied by CN X.

2. Group 2: Muscles of the larynx. All but one of the intrinsic muscles of the larynx are sup-plied by the recurrent laryngeal branch of the vagus nerve. The sole exception is thecricothyroid muscle, which is supplied by the external laryngeal branch of the vagus.

3. Group 3: Muscles of the pharyruc All but one of the longitudinal and circular muscles ofthe pharynx are supplied by CNs X and XI (cranial portion). The sole exception is the sty-lopharyngeus muscle, which is supplied by CN IX.

4. Group 4: Muscles of the soft palate. AII but one of the muscles of the palate are suppliedby CNs X and XI (cranial portion). The sole exception is the tensor veli palatini, which issupplied by CN Vr.

5. Group 5: Infrahyoid muscles. All but one of the infrahyoid muscles are supplied by the ansacervicalis of the cervical plexus (Cl,Cz,and C3). The exception is the thyrohyoid, which issupplied by a branch of Cl. (This branch of Cl also supplies the geniohyoid muscle).

THORACIC WAttA. Osteology

1. There are l2thoracic vertebrae.

a. The vertebrae have facets on their bodies to articulate with the heads of ribs; each ribhead articulates with the body of the numerically corresponding vertebra and the onebelow it.

b. The thoracic vertebrae have facets on their transverse processes to articulate with thetubercles of the numerically corresponding ribs.

2. Sternum

a. The manubrium articulates with the clavicle and the first rib. It meets the bodv of thesternum at the sternal angle, an important clinical landmark.

b. The body articulates directly with ribs 2-7; it articulates inferiorly with the xiphoidprocess at the xiphisternal junction.

c. The xiphoid process is cartilaginous at birth and usually ossifies and unites with thebody of the sternum around age 40.

3. Ribs and costal cartilages. There are 12 pairs of ribs, which are attached posteriorly tothoracic vertebrae.

Note

The sternal angle is a usefullandmark for many thoracicstructures and events:

. The second pair of costalcartilages attaches here, andthe ribs are counted fromthis point.

. Bifurcation of the tracheaforms the primary bronchi.

. The superior vena cava isformed from the right andleft brachiocephalic veins.

. The sternal angle marks thebeginning and end of theaortic arch.

40


First rib

Clavicle

Second rib

Scapula

Manubrium of sternum

Sternal angle

Body of sternum

Costochondraljunction

Figure l-5-5. Thoracic wall.

a. Ribs l-7 are termed "true ribs," and attach directly to the sternum by costal cartilages.

b. Ribs 8-10 are termed "false ribs," and attach to the costal cartilage of the rib above.

c. Ribs 11 and 12 have no anterior attachments, and are therefore classified as both"floating ribs" and false ribs.

d. The costal groove is located along the inferior border of each rib and provides protec-tion for the intercostal nerve, artery, and vein. Ribs 1, 2, L0,11, and 12 are atypical.

B. Muscles

1. External intercostal muscles

a. There are 11 pairs of external intercostal muscles. Their fibers run anteriorly and infe-riorly in the intercostal spaces from the rib above to the rib below.

b. These muscles fill the intercostal spaces from the tubercles of ribs posteriorly to thecostochondral junctions anteriorly; they are replaced anteriorly by external intercostalmembranes.

2. Internal intercostal muscles

a. There are 11 pairs of internal intercostal muscles. Their fibers run posteriorly and infe-riorly in the intercostal spaces deep to the external layer.

b. These muscles filI the intercostal spaces anteriorly from the sternum to the angles ofthe ribs posteriorly; they are replaced posteriorly by internal intercostal membranes.

Clinical Correlate

Rib fractures represent themost common chest injuriesand usually result from directblows such as steering wheelimpact, falls, and crushinginjuries to the chest. Since thefirst 2 ribs are protected by theclavicle and pectoralis majormuscle, and the last 2 ribs are"mobile," they are the leastcommonly injured. The middleones are the most commonlyfractured. In some cases,fractured ribs may causedamage to the heart, lungs,trachea, bronchi, esophagus,spleen, liver, and kidneys.

Note

The fibers of the externalintercostal muscles run in the"ha nds-i n-pockets" d irection;those of the internalintercostal layer run at rightangles to the externals.

4l


3. Innermost intercostrl muscles

a. The deep layers of th€ intemal int€rcostal muscles are the innermost intercostal rnuscles'

b. These muscles are separated ftom the internal intercostal musdes by intercastal nervesand vesels.

. 4. Subcostalis muscles

(1) Fibers extend from the inner surface of the angle of one rib to the rib t}rat isinferior to it.

(2) Fibers may cross more than one intercostal space.

5. Tranwersus thoracis muscle

(1) Fibers attadr postedorly to the sternum.

(2) Fibers cross more than one intercostal space.

(3) Intemal thoracic vessels, branches of the subclavian arteries, run anterior tothese fibers.

C. Intercostal structrf€s

' 1 lntercostal nerves

a. There are 12 pairs of thoracic nerves: 11 intercostal pairs, and 1 subcostal pair.

b. Intercostal n€rves are the ventral primary rami of thoracic spinal nerves. These nervessupply the skin and musculature of the thoracic and abdominal walls.

2. Int€rcostal arteries

a. There are 12 pairs of posterior and anterior arteries, 11 intercostal pairs, and 1 sub-costal pair.

b. Anterior intercostal arteries

(l) Pairs 1-{ are derived ftom the internal thoracic arteries.

(2) Pairs 7-9 are derived fiorn the muscr:lophrenic arteries.

(3) There are no anterior intercostal arteries in the last two sPaces; these spaces aresupplied by branches of the posterior intercostal arteries.

c. Posterior intercostal arteries

( I ) The first two pairs arise ftom the superior intercostal artery a branch of the cos-tocervicd trunk of the subclavian artery.

(2) Nine pairs of intercostal and one pair of subcostal arteries arise from the tloracicaorta.

' 3. Intercostrl veins

F"I1!g|-Cf,g-.-* " ffi'f;:n'jfifts of the intercostd veins drain to the internal thoracic and muscu-

A chest tube is placed iust i b. Post€rior branches drain to the azygos rystem of veins.above the lower rib of theintenpace so as not to disrupt 4' Lymphatic drainage of intercostal spaces

the nerve, artery, and vein that a. Anterior drainage is to the internal thoracic (parasternal) nod€s.lie in the coshl groove behindthe inferior margin Of each rib.

b. Posterior drainage is to the para-aortic nodes of the posterior mediastinurn'

42


ANTERIOR ABDOMINAT WAtt

Sacrum

Coccyx

Pubiccrest

Pubictubercle

Figure l-5€. The abdominopelvic cavity.

A. Osteology. Unlike the thoracic wall, the bony support of the abdomen is minimal, consist-ing only of the lumbar vertebrae and portions of the pelvis (the ilium and the pubis).

1. There are five lumbar vertebrae, Ll through L5.

2. The ilium is part of the hip bone or os coxae. The osteology of this bone is presented indetail in the section on the pelvis. Only the landmarks pertinent to the anterior abdomi-nal wall are listed here.

a. Anterior superior iliac spine (ASIS)

b. Iliac fossa

c. Iliac crest

d. Iliac tubercle

3. Pubis (part of os coxae)

a. Pubic tubercle

b. Pubic crest

c. Pubic symphysis

Lumbarvertebrae

45


B. Surface anatomy

1. Linea alba is a shallow groove that runs vertically in the median plane from the xiphoid

to the pubis. It separates the right and left rectus abdominis muscles.

2. Lineasemilunaris is a curved line defining the lateral border of the rectus abdominis, a

bilateral feature.

3. Inguinal groove indicates the site of the inguinal ligament, the rolled-over, free border of

the external oblique aponeurosis. It separates the abdomen superiorly from the lower

extremity inferiorly. The inguinal ligament extends from the ASIS to the pubic tubercle.

C. Planes and regions. There are four planes to define nine regions of the abdomen (Figure l-5-7).

Figure l-5-7. Regions of the abdomen. RH = right hypochondrium;LH = left hypochondrium; RL - right lumbar; LL = left lumbar;

Rl = right inguinal;Ll = left inguinal.

1. Subcostalplane (horizontal) passes through the inferior margins of the 10th costal carti-lages.

2. Tianstubercular plane (horizontal) passes through the iliac tubercles (body of L5).

3. Midclavicular lines (vertical) are the two planes that pass from the midpoint of the clav-icle to the midpoint of the inguinal ligament.

M


D. Fascial layers

1. Superficial fascia

a. Camper fascia is subcutaneous and variable in thickness due to the presence of fat.

b. Scarpa fascia is a deeper membranous layer devoid of fat and is continuous with thefascia lata of the thigh below the inguinal ligament, the dartos fascia of the scrotumor the labia majora, and Colles fascia of the perineum.

2. Deep (innominate) fascia is the investing fascia of the abdominal musculature and iscontinuous with the external oblique aponeurosis.

E. Muscles

1. External oblique

a. The fibers run anteriorly and inferiorly (i.e., the hands-in-pockets direction like theexternal intercostal layer in the thorax).

b. As fibers pass medially, they become aponeurotic and contribute to the anterior layerof the rectus sheath.

c. Inferiorly, the free border of the external oblique aponeurosis forms the inguinalligament.

d. The superficial inguinal ring is an opening in the external oblique aponeurosis justsuperior and lateral to the pubic tubercle.

e. In men, this layer (external oblique aponeurosis) gives rise to the external spermaticfascia of the spermatic cord.

2. Internal oblique

a. The fibers run posteriorly and inferiorly at right angles to those of the external obliquelike those of the internal intercostal layer in the thorax.

b. As the fibers pass medially, they become aponeurotic and split to contribute to theanterior and posterior layers of rectus sheath.

c. Inferiorly, these fibers contribute to the formation of the conjoint tendon.

d. In men, this layer (internal oblique aponeurosis) gives rise to the middle spermaticfascia and the cremaster muscle of the spermatic cord.

3. Transversus abdominis

a. The muscle fibers run horizontally. As the fibers pass medially, they contribute to theposterior layer of the rectus sheath.

b. Inferiorly, the fibers join with those of the internal oblique to form the conjoint tendon.

4. Rectus abdominis

a. The fibers run vertically between the pubic symphysis and the xiphoid process.

b. The right and left recti muscles are separated medially by the linea alba.

c. The rectus sheath is formed by aponeurotic fibers of three lateral muscle layers.

(1) The arcuate line is located one-third of the distance between the umbilicus andpubis. It is a landmark for the change in disposition of the aponeurotic fibers. Abovethe arcuate line, posterior and anterior layers of the rectus sheath have equal thick-ness;below it, all aponeurotic fibers run anterior to the rectus abdominis.

Clinical Correlate

A potential space existsbetween Scarpa fascia and thedeep innominate fascia whereblood or urine extravasatedfrom a ruptured membranousurethra may accumulate in amale patient. The spread offluid is limhed along a lineapproximately one inch belowthe inguinal ligament, whereScarpa fascia blends with thefascia lata.

45


Clinical Correlate

lndirect inguinal hernias areoften congenital and involvean outpouching of peritoneumor viscera through the deepinguinal ring, beginning justlateral to the point where theinferior epigastric vessels crossthe inguinal ligament. Directinguinal hernias are acquiredas a result of abdominalstraining. They bypass thedeep inguinal ring and godirectly to the superficial ring.They begin medial to theinferior epigastric vessels andburgeon through the inguinal(Hesselbach) triangle, whichis bound by the inferiorepigastric vessels, the inguinalligament, and the lateralborder of the rectusabdominis.

Note

The iliopsoas muscle is theonly muscle that insertson the lesser trochanter.(Filet mignon comes fromthe psoas muscle in cows.)

(2) Superior and inferior epigastric vessels travel in the posterior layer of the rectussheath.

F. Transversalisfascia

1. The transversalis fascia lines the abdominal cavity. It forms the posterior layer of the rec-tus sheath below the arcuate line and the internal spermatic fascia of the spermatic cord.

2. The deep inguinal ring begins as an outpouching of transversalis fascia just lateral towhere the inferior epigastric vessels intersect the inguinal ligament.

3. The transversalis fascia is separated from the peritoneum by a layer of fatty areolarextraperitoneal connective tissue.

G. Nerves, blood vessels, and lymphatics

1. Innervation of the skin and musculature of the anterior abdominal wall is via branches ofthe ventral primary rami of the lower six thoracic spinal nerves (includes subcostal nerve),plus the iliohypogastric and ilioinguinal branches of the ventral primary ramus of Ll.

2. The major arterial blood supply to the anterior wall is derived from the superior epigas-tric branch of the internal thoracic artery as well as the inferior epigastric and the deep

circumflex iliac branches of the external iliac artery.

3. Venous drainage from the anterior wall is to the superficial epigastric, the lateral thoracicveins superiorly, and the great saphenous vein inferiorly.

a. Lymph from tissues of the anterior wall drains to axillary nodes superiorly and to super-ficial inguinal nodes inferiorly.

POSTERIOR ABDOMINAT WAttThe posterior abdominal wall is located behind the posterior layer of the parietal peritoneum.

A. Osteology. The bony structure of the posterior wall includes many of the same features asthe anterior wall of the abdomen and bony landmarks from the thorax and the inferiorextremity.

1. Five lumbar vertebrae (L1 through L5)

2. Iliac crest

3. Iliac fossa

4. Twelfth pair of ribs

5. Lesser trochanter of femur

B. Muscles

1. The quadratus lumborum extends upward from the iliac crest to the inferior border ofthe 12th rib. It stabilizes the 12th rib during inspiration.

2. The psoas major arises from the transverse processes of the lumbar vertebrae.

a. Insertion, along with iliacus, is on the lesser trochanter of the femur.

b. It is the chief flexor of the hip.

3. The iliacus originates from the iliac fossa.

a. It joins with the psoas major to insert on the lesser trochanter.

b. Together with psoas major, it is known as the iliopsoas.

46


PEwTSA. Osteology

1. Pelvic girdle is formed anterolaterally by the paired hip bones (os coxae) and is completedposteriorly by the sacrum and cocc''n

a. The os coxae is composed of the ilium, the pubis, and the ischium, including the ischialspine and the ischial tuberosity

b. Greater and lesser sciatic notches (foramina)

c. Sacrospinous and sacrotuberous ligaments

2. Pelvic cavity

a. Pelvis major (false pelvis) lies above the pelvic brim between the iliac fossae. Oinkal GOrrelab

b. Pelvis minor (true pelvis) is th€ spac€ between the pelvic inlet (pelvic brim) and the ;" "*rne splne of the ischium is anouuet. obstetric landmark in the

B. Pelvic diaphragn is the muscular floor ofthe pelvic cavity. administration of anesthesia

1 Levator eni has openings to transmit the urethra and the anus in both sexes and the vagi- for a pudendal nerve block tona in women. " eliminate sensation in the

a. pubococcygeus : r:ff:T:::'.1{elivery lhe

puoenoat nerye passesb. Puboreaalis through the pudendal (Alcock)

c . I l i o c o c c y g e u s c n a l i n t h e v i c i n i t y o f t h e

2. coccygeus is the posterior portion of the pelvic diaphragm ischial spine'

UPPER IIMBA. Pectoral region, axilla, and shoulder

1. Osteology (Figure I-5-S)

Note

The clavicle is the first bone toossify in fetal life and is themo$ frequently fracturedbone in the body.

47


Acromion

Coracoid processLesser tubercleGreater tubercle

Intertubercular groove

Surgical neck

Deltoid tuberosity

Lateral

CapitulumHead of radius

Tuberosity of radi

Radius

Styloid processof radius

Proximalphalanx

Distalphalanx

Anterior view

Medial epicondyle

Trochlea

Coronoid process

Figure l-5-8. Osteology of the upper limb.

Carpal bones

Metacarpal bones

48


Pectoralis major

Serratus Pectoralis minoranterior

Latissimus Intertuberculargroovedorsi

Teres major

Subscapularis

Rib

Scapula

Figure l-5-9.Transverse section through the axilla.

a. Sternum has three parts: the manubrium, the body, and the xiphoid process.

b. Clavicle is an S-shaped bone, which articulates with the manubrium of the sternummedially and with the acromion process of the scapula laterally.

c. Scapula landmarks include the acromion process, or point of the shoulder, and thecoracoid process, which is an anteriorly projecting "crow's beak." The glenoid fossa ofthe scapula articulates with the head of the humerus. The subscapular fossa formsthe major portion of the anterior surface of the scapula. The spine of the scapula, orshoulder blade, is located posteriorly and separates the supraspinous fossa abovefrom the infraspinous fossa below.

d. Humerus is the bone of the arm. In addition to the head of the humerus, landmarksinclude the bicipital groove (intertubercular sulcus) and the lateral and medial lips ofthe bicipital groove. The greater and lesser tuberosities are located inferior to thehead of the humerus. The deltoid tuberosity is an elongated, roughened area of theshaft of the humerus.

2. The axilla is a space shaped like a truncated pyramid, which serves as a passagewaybetween the neck and the upper limb. Its apex is formed by the cervicoaxillary canal andis bounded by the clavicle, scapula, and first rib. The base is formed by the fascia and hair-covered skin of the armpit.

a. Walls of the axilla (Figure I-5-9)

(1) The anteriorwall is formed by the pectoralis major and pectoralis minor. Thepectoralis major forms the anterior axillary fold.

(2) The posterior wall is formed by the subscapularis, teres major, and the latissimusdorsi muscles. The latissimus dorsi forms the posterior axillary fold.

(3) The medial wall is formed by the serratus anterior muscle and the underlying ribsand intercostal spaces.

( ) The lateral wall is formed by the bicipital groove of the humerus.

Nole

The surgical neck of thehumerus is a frequentsite of fractures. Theaxillary nerve is at risk.

49


Clinical Correlate

Damage to the upper trunk ofthe brachial plexus may resultin an inability to flex, abduct,and laterally rotate theshoulder due to a weakness ofthe dehoid and rotator cuffmuscles. (When this occursfrom birth, it is known as Erbpalsy.) Lower brachial plexusinjuries involve the ulnar nerveand result in reducedsensation of the medial arm,forearm, and hand, as well asweakness in the forearm andhand. (When this occurs fromtrauma, ifs known as Klumpkepalsy.)

Thble I-5-2. Major Branches of the brachial plexus.

Roots

SUPRACI.AVICUI.A,R

Trunl$

b. Contents of the axilla

( 1) The axillar'' arter'' is a continuation of the subclavian artery as it passes over theouter border of the first rib. It becomes the brachial artery at the outer border ofthe teres major. The axillary artery has six branches. Of these, the most clinical-ly significant are the thoracoacromial, the lateral thoracic, the subscapular, andthe posterior humeral circumflex arteries.

(2) The axillaryvein follows the same pattern as the artery.It receives the basilic andcephalic veins.

(3) The axillary ly-ph nodes drain ly-ph from the upper extremiry the lateralbreast, and the superficial portions of the thoracic and upper abdominal wall.The axillary nodes are divided into five groups: apical, central, humeral, pectoral,subscapular. Efferent lymphatics from the last four groups drain to the apicalnodes, which then drain to the subclavian ly-ph trunk.

(a) The bradrialplexus is the somatic nerve plexus of the upper limb. It is formed fromthe ventral primary rami of cervical nerves 5-8 and the ventral primary ramus ofthe first thoracic nerve. The roots of the plexus emerge from between the middle

and anterior scalene muscles in the neck. Th.y combine to form trunks, whichdivide into anterior and posterior divisions. The divisions pass through thecervicoaxillary canal to reach the axilla and reunite to form lateral, medial, and pos-

terior cords in relation to the second part of the axillary artery.Each trunk dividesinto nryo terminal branches, which comprise the major nerves of the arm, forearm,and hand (Table l-5-2).

INFRACIAVICUTAR

Cords Branches (Terminal)

C5: Dorsal scapular nerve;supplies rhomboids

C5, C6, C7 : Longthoracicnerve; supplies serratus

C8, T1

Upper trunkSuprascapular nerve;

supplies supraspinatusand infraspinatus

Lateral cord1. Lateral pectoral nerve; supplies

pectoralis major

Medial cord1. Medial pectoral nerve; supplies

pectoralis major and minor

2. Medial brachial cutaneousnerve; supplies skin of themedial arm

3. Medial antebrachial cutaneousnerve; supplies skin of themedial forearm

Posterior cord1. Upper subscapular nerve;

supplies subscapularis

2. Middle subscapular nerve(thoracodorsal nerve); supplieslatissimus dorsi

3. Lower subscapular nerve;supplies teres major

1. Musculocutaneous nerve2.Lateral head of median

nerve

1. Medial head of anteriormedian nerve

2. Ulnar nerve

1. Radial nerve

2. Axillary nerve

50


Thble I-5-3. Nerve supply of shoulder muscles.

Muscles Acting on the Shoulder Nerve Supply

FlexorsCoracobrachialisDeltoid (anterior segment)Pectoralis major

ExtensorsTeres majorLatissimus dorsi

Musculocutaneous nerveAxillary nerveMedial and lateral pectoral

nerves

Lower subscapular nerveThoracodorsal nerve

Lower subscapular nerveThoracodorsal nerveMedial and lateral pectoral

nervesAxillary nerve

Subscapular nerves (upper &lower)

Lower subscapular nerveThoracodorsal nerveMedial and lateral pectoral nerves

Suprascapular nerveAxillary nerve

Mnemonic

With a rotator cuff injury, thepitcher SITS on the bench:su praspinatus, lhfraspinatus,feres minor, subscapularis.

Deltoid (posterior segment) Axillary nerve

AbductorsDeltoid (middle segment) Axillary nerveSupraspinatus (initial abductor) Suprascapular nerve

AdductorsTeres majorLatissimus dorsiPectoralis major

Teres minor

Medial rotatorsSubscapularis

Teres majorLatissimus dorsiPectoralis major

Lateral rotatorsInfraspinatusTeres minor

3. Shoulder. The shoulder joint is a shallow ball-and-socket joint. The head of the humerus isheld against the glenoid fossa by ligaments and muscles (Table I-5-3).

B. Arm. The portion of the upper extremity between the shoulder and elbow joint is the arm.It is enclosed in alayer of deep fascia. Two septa originate from this fascia and divide the arminto an anterior (preaxial) and a posterior (postaxial) compartment. Flexor muscles occu-py the anterior compartment, and extensors are found in the posterior compartment (FigureI-s- 10).

1. Osteology. The bone of the arm is the humerus.

a. Radial (spiral) groove is located posteriorly; this shallow depression is occupied bythe radial nerve and the deep brachial (profunda brachii) artery.

b. Trochlea is a pulley-shaped feature of the distal humerus, which articulates with thetrochlear notch of the ulna.

5 l


2.

CoracoidAcromion

SuprasPinatus

Glenoid cavitY

Infraspinatus

SubscaPularis

Teres minor

Inferior angle

Figure l-5-10. Muscles of the rotator cuff (lateral view).

c. Capitulum is a rounded process located lateral to the trochlea and articulating withthe head of the radius.

d. Medial and lateral epicondyles are subcutaneous projections from the distalhumerus, and give rise to the muscles of the forearm.

Anterior (flexor) compartment of the arm

a. Muscles

(1) The coracobrachialis is a small muscle arising from the coracoid process.

(2) The biceps brachii is the principal flexor of the forearm at the elbow joint. Thebiceps is also a powerfi.rl supinator of the forearm.

(3) Brachialis lies deep to biceps brachii.

b. Innervation. All muscles of the flexor compartment of the arm are supplied by themusculocutaneous nerve.

Posterior (extensor) compartment of the arm

a. Muscles. The long head of the triceps arises from the scapula; lateral and medial headsof the triceps arise from the posterior surface of the humerus.

b. Innervation. The three heads of the triceps are supplied by the radial nerve.

The cubital fossa is a triangular area anterior to the elbow. The roof of the cubital fossais formed by deep fascia and by the bicipital aponeurosis, which is part of the insertion ofthe biceps brachii. Contents of the cubital fossa include the following:

Clinical Correlate

"Colfer's elbovV" (medialepicondylitis) results from aninflammation of the flexortendons on the medialepicondyle of the humerus(imagine the standard golfingswing, flexing the elbow).

"Tennis elbow" (lateral

epicondylitis) results from aninflammation of the extensortendons on the lateralepicondyle of the humerus(imagine the backhand swing,extending the elbow).

3 .

4.

52


a. The median cubital vein is a superficial vein, which communicates between the basficand cephalic veins. It lies superficial to the bicipital aponeurosis.

b. The biceps tendon inserts on the radial tuberosity.

c. The brachial artery lies medial to the biceps tendon and terminates by dividing intoradial and ulnar arteries.

d. The median nerve supplies no muscles in the arm but is responsible for motor inner-vation of many muscles of the flexor forearm.

5. Elbow joint. This joint is a hinge joint that includes three articulations. The articulationbetween the humerus and the bones of the forearm allows flexion and extension at theelbow. The articulation between the radius and the ulna is a pivot, which allows rotationof the radius around the ulna (i.e., supination and pronation).

C. Forearm is the portion of the upper limb between the elbow and the wrist joint. The fore-arm is enclosed in a layer of deep fascia. The two bones of the forearm, the radius and ulna,as well as an interosseous membrane and two fibrous septa, divide the forearm into an ante-rior (preaxial) compartment and a posterior (postaxial) compartment.

1. Osteology

a. Radius

(l ) The head articulates with the capitulum of the humerus.

(2) The radial tuberosity is the site of insertion of the biceps brachii.

(3) The dorsal (Lister) tubercle is located on the posterior surface of the distal aspectof the radius. The tendon of the extensor pollicus longus passes medial to thisprominence.

(a) The styloid process is the prominent subcutaneous distal expansion of theradius.

b. Ulna

(1) The olecranon, coronoid process, and trochlear notch form the articular surfaceof the ulna with the humerus.

(2) The radial notch is the articular surface for the radius.

(3) The tuberosity is the site of insertion of the brachialis muscle.

(a) The sryloid process is the prominent subcutaneous distal expansion of the ulna.

2. Anterior (flexor) compartment of the forearm

a. Muscles. The eight muscles of the flexor forearm are arranged in three layers, fromsuperficial to deep.

(1) First layer includes four muscles, which arise from the medial epicondyle of thehumerus. From lateral to medial, they are the pronator teres, the flexor carpiradialis, the palmaris longus, and the flexor carpi ulnaris ('PFPF" muscles).

(2) Second layer has only one muscle, the flexor digitorum superficialis (sublimus).

(3) Third layer has three muscles: the flexor digitorum profundus, the flexor pollicislongus, and the pronator quadratus.

b. Innervation. The median nerve supplies all the muscles of the anterior compartmentof the forearm, except for the flexor carpi ulnaris and the medial (ulnar) half of theflexor digitorum profundus, which are supplied by the ulnar nerve.

Clinical Correlate

Subluxation of the head of theradius occurs in young childrenwho are "pulled along" bythe upper limb. The annularligament, which surrounds thehead of the radius, stretchesor tears. This is known as"nursemaid's elbow"

Clinical Correlate

Damage to the anteriorinterosseous nerve, alsoknown as the deep branch ofthe median nerve, results inthe inability to form a round"0" with the thumb and indexfinger. The "flat pinch" iscaused by impaired functionof the flexor pollicis longusand lateral two tendons offlexor digitorum profundus.

55


Clinical Correlate

Carpal tunnel syndrome iscaused by compression of themedian nerve within thetunnel formed by the carpalbones and flexor retinaculum.In severe cases, the muscles ofthenar eminence atrophy, andthe patient is unable tooppose the thumb to thedigits. The disorder iscommon in people whosework necessitates repetitivemovements of the wrist, e.g.,keyboard operators.

Clinical Correlate

Scaphoid bone-mostfrequently fractured ofcarpal bones

Lunate bone-mostfrequ ently dislocated.

3. Posterior (extensor) compartment of the forearm

a. Muscles. There are 11 muscles in the posterior compartment. They can be classifiedin three groups according to function.

(1) Extensors of the hand at the wrist include the extensor carpi radialis longus,extensor carpi radialis brevis, and extensor carpi ulnaris.

(2) Extensors of the digits are the extensor digitorum, extensor indicis, and exten-sor digiti minimi.

(3) Extensors of the thumb are the abductor pollicis longus, extensor pollicis brevis,and extensor pollicis longus.

(4) Additional muscles of the extensor compartment include the brachioradialis andthe supinator.

b. Innervation. All muscles of the posterior compartment of the forearm are supplied bythe radial nerve.

4. Wrist

a. Osteology. The eight bones of the wrist, or carpus, are arranged in two rows of four.

(1) The distal row, medial-to-lateral: hamate, capitate, trapezoid, and trapezium.

(2) The proximal row, lateral-to-medial scaphoid, lunate, triquetrum, and pisiform.

b. Flexor retinaculum (transverse carpal ligament) is a band of deep fascia, whichextends anteriorly across the carpal bones. It forms a passageway through which thetendons of the flexor muscles and the median nerve enter the palm of the hand.

D. Hand

1. Osteology (Figure I-5-11)

a. Metacarpals. Five metacarpal bones articulate proximally with the carpal bones anddistally with the proximal phalanges. They form the support for the palm of the hand.

b. Phalanges. The thumb has two phalanges, proximal and distal. The remaining fourdigits each have three phalanges: proximal, middle, and distal.

2. Intrinsic muscles

a. Thenar muscles

(1) Abductor pollicis brevis

(2) Flexor pollicis brevis

(3) Opponens pollicis

b. Hypothenar muscles

(1) Abductor digiti minimi

(2) Flexor digiti minimi

(3) Opponens digiti minimi

c. Lumbrical muscles. There are four lumbrical muscles. They flex the digits at themetacarpophalangeal joints and extend at the interphalangeal joints.

54


d. Interosseous muscles. There are seven interosseous muscles. The three palmarinterossei adduct the digits, and the four dorsal interossei are responsible for abduc-tion of the digits.

Distalphalanx

Middlephalanx

Proximalphalanx

Head

Fifthmetacarpal

Hook of h Trapezoid

Pisiform

TriTrapezium

Lunate Tubercleof scaphoid

Right palmar view

Figure l-5-11. Osteology of the right hand (palmar view).

3. Innervation

a. Motor innervation of intrinsic muscles (Figure I-5-12)

(1) The median nerye supplies the muscles of the thenar eminence, via the recurrentbranch, as well as the first and second lumbrical muscles.

(2) The ulnar nerve supplies the remaining intrinsic muscles of the hand.

55


Note

The ulnar nerve and arteryenter the palm throughthe Cuyon canal.

Clinical Correlate

Allen Test

This test is used to determineanastomoses between theradial and ulnar arteries.

Palmar digital nerves

Branches to first andsecond lumbricals

Palmar digital nerves

'Recurrent branchof median nerve

Thenar muscles

Median nerveUlnar nerve

Figure l-5-12. Innervation of the palm.

Palmar view

Figure l-5-13. Distribution of cutaneous nerves to thepalm and dorsum of the hand.

56


b. Sensory innervation of the hand. The median, ulnar, and radial nerves provide specificareas of the palm and dorsum of the hand with sensory innervation (Figure I-5- 13).

4. Blood supply

a. The superficial palmar arch is derived mainly from the ulnar artery.

b. The deep palmar arch is derived mainly from the radial artery.

TOWER IIMBA. The thigh is the region extending from the inguinal ligament to the knee. The thigh is sur-

rounded by a dense layer of deep investing fascia, called the fascia lata. Fibrous septa dividethe thigh into three compartments: anterior, medial, and posterior.

l l iac crestAnteriorsuperioriliac spine

Anterior inferior

lliac fossaSuperior ramusof pubis

i l iac spine

Head of femurGreatertrochanter Body of

pubis

lntefirochantericl ine Pubic symphysis

Obturator foramen

lschial tuberosityFemur

Lessertrochanter

Adductor tubercleLateralepicondyle Medial epicondyle

PatellaHead off ibula

Neck off ibula Tibial tuberosity

Pubic tubercleCrest of pubis

Pectenpubis

Figure l-5-14. Osteology of the lower limb: hip, thigh, and knee.

57


Note

Postaxial muscles in the lowerlimb are anterior in location;postaxial muscles in the upperlimb are posterior in location.This is due to the rotation ofthe lower limb, which beginsduring the fetal period and iscompleted during the fir$ year.

Clinical Correlate

A femoral hernia, which entersthe thigh by passing throughthe femoral ring and femoralcanal, may appear as aswelling over the femoraltriangle. Unlike an inguinalhernia, it protrudes inferiorand lateral to the pubictubercle.

I. Osteology (Figure I-5-14)

a. The anterior-superior iliac spine is the superolateral attachment of the inguinal ligament.

b. The pubic tubercle is the inferomedial attachment of the inguinal ligament.

c. The ischial tuberosity is the site of origin of the hamstring muscles.

d. The greater and lesser trochanters of the femur and the intertrochanteric line are sites

of muscle and ligamentous attachments.

e. The linea aspera of the femur is the site of insertion for the adductor muscles.

f. The adductor tubercle of the femur is the site of insertion for the ischiocondylar por-

tion of the adductor magnus.

2. Anterior thigh muscles. The anterior compartment of the thigh contains postaxial mus-

cles, which are supplied by the femoral nerve:

a. The quadriceps femoris is comprised of the vastus lateralis, vastus medialis, vastus

intermedius, and the rectus femoris. The rectus femoris crosses both the hip and the

knee joints. It has a weak flexor action at the hip and a strong extensor function at the

knee. The three other components of the quadriceps arise from the shaft of the femur.

b. The sartorius muscle acts on both the hip and knee joints, primarily as a flexor.

c. The iliopsoas is the chief flexor of the hip.

d. The pectineus maybe innervated by the obturator nerve as well as by the femoral nerve.

3. Femoral triangle (Figure I-5-15)

a. Boundaries. The femoral triangle is bounded by the inguinal ligament superiorly, themedial border of the sartorius laterally, and the medial border of the adductor longus

medially.

b. Contents

(1) The femoral nerve, a mixed branch of the lumbar plexus, contains fibers fromL2,L3,and L4; a postaxial nerve, it supplies the extensor muscles of the thigh and

cutaneous areas of the thigh. The femoral nerve has a long sensory branch, the

saphenous nerve, which supplies the knee joint and the skin on the medial aspectof the foot.

(2) The femoral artery, also known as the superficial femoral artery,has three main

branches: the profunda femoris, the medial femoral circumflex, and the lateral

femoral circumflex arteries. The MFCA and the LFGA are more often branchesof the profunda femoris.

(3) The deep inguinal lyrtph node (of Cloquet) is located in the most medial com-partment of the femoral sheath. This compartment is known as the femoral

canal, and it communicates with the abdomen via a small opening, called thefemoral ring.

a. Inguinal lymph nodes

a. Superficial nodes

(1) Horizontal group. These nodes lie along the inguinal ligament. They drain theanterior abdominal wall below the umbilicus; the perineum, including the exter-nal genitalia; and the lower one-third of the anal canal.

58


Anterior superioriliac spine

Inguinal l igament Pubic tubercle

Sartorius

Femoral artery

Adductorlongus

Adductortubercle

Figure l-5-15. Anterior thigh and femoraltriangle.

(2) Vertical group. These nodes follow the great saphenous vein and drain most ofthe superficial lymphatics of the lower limb.

b. Deep nodes. These nodes receive ly-ph from the superficial nodes and from the deepcompartment of the leg. Efferent vessels from the deep nodes drain to the external iliacnodes.

5. Medial thigh, or medial compartment, contains muscles responsible for adduction of thethigh. These are preaxial muscles, which are innervated by the anterior and posterior divi-sions of the obturator nerve. They arise from the pubic bone and the ischium.

a. Muscles

(l) Adductor longus

(2) Adductor brevis

(3) Adductor magnus

(4) Gracilis

b. Nerves

(1) The anterior division of the obturator nerve, which is a preaxial nerve derivedfrom L2,L3, and L4, supplies the pectineus, the hip joint, the adductor longus,the gracilis, and part of the adductor brevis.

59

Musculoskeletal Sy$em, Connective Tissue, and Integument

(2) The posterior division of the obturator nerve supplies the obturator externus, the

knee joint, the adductor magnus, and part of the adductor brevis.

c. Blood supply

(1) Profunda femoris

(2) Obturator artery

6. Posterior thigh, or posterior compartment, contains muscles that extend the thigh at the

hip and flex the leg at the knee. These preaxial muscles are known as the "hamstrings."

They arise from the ischial tuberosity and are supplied by the tibial division of the sciaticnerve (Figure I-5-16).

a. Muscles

(1) Semitendinosus

(2) Semimembranosus

Rectusfemorismuscle

Femur

Adductormagnusmuscle

Figure l-5-16. Gompartments of the left thigh (transverse section).

(3) Long head of the biceps femoris. The short head of the biceps arises from the shaftof the femur. It is a postaxial muscle and is, therefore, supplied by the commonperoneal division of the sciatic nerve. The ischiocondylar portion of adductormagnus arises from the ischial tuberosity. It inserts on the adductor tubercle andnot on the linea aspera with the remaining fibers of adductor magnus. Hence, theischiocondylar portion of adductor magnus acts as a hamstring. It is, therefore,supplied by the tibial portion of sciatic and not by the obturator nerve.

Yi'nitirioi

MeSU_aliaj)

Hamstrings

60


b. Nerves. The sciatic nerve is actually two nerves: the tibial nerve, which is preaxial andsupplies the hamstrings as well as the muscles of the calf and the sole of the foot, andthe common peroneal nerve, which is postaxial and supplies the short head of bicepsfemoris and the muscles of the lateral and anterior compartments of the leg.

c. Blood supply. The muscles of the posterior compartment receive arterial supply fromthe perforating branches of the profunda femoris.

B . H i p

1. Gluteal region. The muscles of this region extend, abduct, and rotate the thigh.

a. Muscles

(1) Gluteus maximus is the extensor of the thigh

(2) Gluteus medius

(3) Gluteus minimus

(4) Tensor fascia lata

(5) Piriformis

(6) Small gluteal muscles include the obturator internus, superior and inferiorgemelli, and quadratus femoris.

b. Nerves

The sciatic nerve is derived from ventral rami L4-S3.

The superior gluteal nerve supplies the gluteus medius, gluteus minimus, andtensor fascia lata.

(3) The inferior gluteal nerve supplies the gluteus maximus.

( ) The pudendal nerve is a branch of the sacral plexus (S2, 53, S4). It enters thegluteal region through the greater sciatic foramen, arches over the sacrospinousligament, and leaves through the lesser sciatic foramen en route to the ischiorec-tal fossa and perineum. It travels with the internal pudendal nerve and artery.

c. Blood supply

( 1) Superior gluteal vessels

(2) Inferior gluteal vessels

(3) Internal pudendal vessels

2. Hip joint. This joint is a ball-and-socket joint. Located at the point at which the headof the femur articulates with the acetabulum of the os coxae, the hip joint is more sta-ble than the shoulder joint. This stabiliry however, is gained at the expense of rangeof motion. The upper limb has a 360" range (i.e., circumduction), whereas motion atthe hip is limited by the range of medial and lateral rotation.

a. Ligaments

(1) Iliofemoral ligament (Y ligament of Bigelow)

(2) Ischiofemoral ligament

(3) Pubofemoral ligament

(a) Ligamentum capitis femoris

( 1 )

(2 )

Clinical Correlate

An early separation of thesciatic nerve into tibial andcommon peroneal nerves mayresuh in the "piriformissyndrome," in which thecommon peroneal nerveenters the gluteal region bypassing over or emerging fromthe substance of the piriformismuscle. In its most extremeform, piriformis syndrome canresult in "foot drop" ("slapfoot").

Clinical Correlate

The prognosis for healing ahip fracture depends onwhether the fracture is intra-or extracapsular. With ani ntracapsular f ractu re, chancesare greater that the head ofthe femur will undergonecrosis as a result ofinterruption of its bloodsupply. An extracapsularfracture (i.e., one nearer thegreater trochanter) has abetter chance of healingbecause much of the bloodsupply will be preserved.

6l


Clinical Correlate

Because of the presence of alarge amount of fat in thepopliteal fossa and therelatively deep location of theartery, a popliteal pulse maybe difficult to detect. lt isimportant to e$ablish theexistence of this pulse becauseits absence may indicateproximal obstruction of theartery due to atherosclerosis.

b. Blood supply. The hip is the central axis of an arterial supply, which arrives from four

directions and is known as the cruciate anastomosis.

(1) Medial femoral circumflex artery

(2) Transverse branch of lateral femoral cutaneous artery

(3) Inferior gluteal artery

(4) First perforating branch of profunda femoris artery

C. Knee

1. Poplitealfossa. This is the diamond-shaped space at the back of the knee. Contents of thepopliteal fossa include the following:

a. Poptteal artery and vein. As the superficial femoral vessels pass through the adduc-

tor hiatus, they become the popliteal vessels. The femoral artery lies superficial to the

femoral vein in the subsartorial (adductor) canal; however, in the popliteal fossa therelationship is reversed and the artery lies deep to the vein.

b. Genicular anastomosis is a network of arteries surrounding the knee joint, which

may provide alternate pathways for blood flow if there is a blockage of the main artery.

c. Tibial nerve enters the posterior compartment of the leg.

d. Common peroneal nerve follows the medial border of the biceps femoris to pass later-

ally around the neck of the fibula.

2. Knee joint is a hinge-Vpe, synovial joint.

a. Osteology

(1) Patella is a sesamoid bone located within the quadriceps tendon, which inserts

on the tibial tuberosity.

(2) Tibia is the bone of the shin. It is the weight-bearing bone of the leg. Its medialand lateral condyles articulate with the femur, and its lateral condyle has adepression for articulation with the fibula.

(3) Fibula. The head of the fibula articulates with the tibia. A groove in the neck ofthe fibula indicates the path of the common peroneal nerve.

b. Ligamentous and cartilaginous structures

(1) The medial collateral ligament is a wide, flat ligament that attaches the medialcondyle of the femur to the shaft of the tibia. It is also firmly attached to themedial meniscus.

(2) The lateral collateral ligament is a discrete cord-like structure that attaches thelateral condyle of the femur to the head of the fibula.

(3) The oblique popliteal ligament is an extension of the semimembranosus insertion.

(a) The anterior cruciate ligament runs from the anterior intercondylar surface ofthe tibia to the lateral femoral condyle. It prevents hyperextension of the knee.

(5) The posterior cruciate ligament runs from the posterior intercondylar surface ofthe tibia to the medial femoral condyle. It prevents hlperflexion of the knee.

(6) The medial semilunar cartilage (medial meniscus) is a nearly circular disk offibrocartilage that lines the articular surface of the medial tibial condyle. It isattached to the medial collateral ligament.

62


(7) The lateral semilunar cartilage (lateral meniscus) is a C-shaped disk of fibrocar-tilage that lines the articular surface of the lateral tibial condyle. It is not attachedto the lateral collateral ligament.

c. Muscles related to the knee joint

(1) The popliteus is a small muscle located posterior to the knee joint. Its tendoninserts on the femur deep to the lateral collateral ligament. It initiates flexion ofthe knee joint by medially rotating the femur on the tibia.

(2) The quadriceps femoris is an extensor of the knee.

(3) The sartorius, gracilis, and semitendinosus muscles insert on the medial aspectof the knee as the "pes anserinus."

D. The leg is the portion of the lower extremity between the knee and the ankle. Like the thigh,the leg is encased in a dense layer of deep fascia, the crural fascia. The nvo bones of the leg,the interosseous membrane between them, and two fibrous septa divide the leg into threecompartments.

1. Osteology (Figure I-5-17)

a. Tibia. The anterior surface of the tibia is devoid of muscular attachments and is pal-pable throughout its length as the shin. The lower end of the tibia articulates with thetalus and forms a subcutaneous projection, the medial malleolus.

b. Fibula is covered throughout its length by muscle. It is palpable only at its head andmost distal projection, the lateral malleolus, which articulates with the talus.

2. Posterior compartment

a. Muscles. The preaxial muscles of the posterior compartment are arranged in twogroups, superficial and deep. They plantar flex the foot.

(1) Superficial

. Gastrocnemius

. Soleus

. Plantaris

Clinical Correlate

A fracture of the neck of thefibula may cause commonperoneal nerve damage,resulting in "foot drop"-a lossof function in the muscles ofthe anterior compartment ofthe leg that are supplied bythe deep peroneal branch ofthe common peroneal nerve.Therefore, there would bedifficulty in dorsiflexing thefoot. Also affected would bethe muscles supplied by thesuperficial peroneal nerve:peroneus longus and brevis,which evert the foot.

Clinical Correlate

The anterior compartment islimited by the presence ofthree features: the two bonesof the leg, the interosseousmembrane, and the cruralfascia. Fluid buildup within thiscompartment may occur as aresult of direct trauma, otherserious injury, or infection.This fluid, which may bebloody, will exert pressure onthe deep peroneal nerve andthe anterior tibial bloodvessels, resulting in "anteriorcompartment syndrome." Thiscondition warrants immediatefasciotomy.

65


Neck of fibulaTuberosity

Lateral malleolus Medial malleolus

Calcaneus Talus

NavicularCuboid

Cuneiforms

Metatarsals

Proximal phalanx

Distal phalanx

Figure l-5-17. Osteology of the lower limb: leg and foot.

(2) Deep

. Tibialis posterior

. Flexor digitorum longus

. Flexor hallucis longus

b. Nerves. The flexor muscles are supplied by the tibial nerve, which also supplies mus-cles of the plantar surface of the foot.

c. Blood supply. The posterior tibial artery supplies the posterior compartment of theleg and terminates by dividing into the medial and lateral plantar arteries.

3. Anterior compartment

a. Muscles. The postaxial muscles of theextend) the foot.

il

anterior compartment act to dorsiflex (i.e.,


(1) Tibialis anterior

(2) Extensor hallucis longus

(3) Extensor digitorum longus

(4) Peroneus tertius

b. Nerves. Motor branches of the deep peroneal nerve supply the muscles of the anteri-or compartment. The terminal sensory branch of the nerve conveys sensory informa-tion from tlle dorsum of the foot in the area between tlle great and second toes (i.e.,fust web space).

c. Blood supply, The anterior tibial branch of the posterior tibial artery supptes theanterior compartment. The artery terminates on the dorsum of the foot lateral to thetendon of extensor hallucis longus as the dorsalis pedis artery.

4. Lateral compartment In a NUbhell

a. Muscles. The major function of the peroneus longus and the peroneus brevis, the compart- Nerve Aderypostaxial muscles of the lateral compartment, is to eyert the foot. r.d

b, Nerves. The peroneal muscles of the lateral comPartment are supplied by the superfi- Anterior Deep Anteriorcial peroneal nerve, which also conveys sensory information ftom most of the dorsal peroneal tibial bnnchsurface of the foot. il,trff::i

c. Blood supply. The p€ron€al artery a branch ofthe posterior tibial, supplies the later- Lateral Superficial peronealal compartm€nt of the leg. This artery does not enter the lateral compartment itself peronealbut gives of branches that pierce tlle lateral intermuscu.lar septum to supply the per- pone;or Tibial posterioroneal muscles. tibial

E. Anlle. The anHe joint is a rynovial hinge-type joint located between the tibia, the fibula,and the body of the talus.

1. Osteologf

a. The talus is the weight-bearing bone of the foot.

b. The calcaneus is the bone of the heel.

c. The tuberosity ofthe navicular bone is palpable anterior to the medial malleolus andserves as part of the attachm€nt of the tibialis posterior muscle.

d. The cuboid bone is the most lateral of the small bones of the foot.

e. The cuneiform bones are three wedge-shaped bones that articulate proximally with Cliniol Correlatethe navicular bone and distally with the metatarsals of the foot. They are primarilyresponsible for the formation of the transverse arch of the foot. Evenion sprains of the ankle

2. Lisamenrs :fiilf:lTn'Ji',#"**'a. Medial The deltoid ligament is the strong, medially located, reinforcement of the ligam-enq inversion sprains are

anHe ioint. It attaches the medial malleolus to the talus. more common beouse *n

b. Irteral lateral lisamenb are subiect to

(1) Anteriortaronburar *:Tiif,il1ff:iltJH.,(2) Posterior talofibular rrgamern is tire interior

talofibular, followed bY the(J'' LiucaneonDuar calcaneofibular Repeated injury

(4) Anterior and posterior tibiofibular to these ligamenb results ininstability of the ankle joint.

65


F. Foot

1. Osteology

a. There are five metatarsal bones.

b. Phalanges. The great toe, or hallux, has two phalanges, a proximal and a distal phalanxEach of the remaining toes (i.e., digits) has three phalanges: proximal, middle, and distal.

2. Ligaments. The plantar calcaneonavicular, or "spring" ligament, supports the head of thetalus, which forms much of the medial arch of the foot.

3. Muscles. The muscles of the sole of the foot are arranged in four layers. These muscles aresimilar to those of the palm of the hand.

4. Nerves. The intrinsic muscles of the sole are supplied by the medial and lateral plantarnerves, which are branches of the posterior tibial nerve.

5. Blood supply. The arterial supply of the sole of the foot is derived from the medial andlateral plantar branches of the posterior tibial artery.

66

Musculoskeletal Physiology

Muscle cells are specialized for contraction. An action potential is transmitted along the sarcolemma(muscle cell membrane) that, in turn, activates the contractile mechanism. There are three majortypes of muscles. skeletal muscle, which is striated (striped under the liSht microscope), is undervoluntary control, and is rapid acting; smooth muscle, which is not striated, is located in blood vesselwalls and internal organs, is involuntary (having inherent rhythmic contractile activity), and is slowacting; and cardiac muscle, which is striated like skeletal muscle but has some characteristis of bothsmooth and skeletal muscle. This chapter will discuss the contraction mechanisms of skeletal andsmooth muscle; cardiac muscle is discussed separately in the Cardiovascular Physiology chapter ofOrgan Systems Book 1 S/olume lll),

SKEIETAI MUSCTESkeletal muscle is typically composed of many parallel muscle fibers (myofibers) that run thelength of the muscle and terminate in tendons that attach the fiber to the skeletal system. Each

myofiber is a multinucleated structure surrounded by the sarcolemma.

A. Structural changes during contraction

1. The shortening of a muscle results from an increase in the extent of thin-thick filamentoverlap, owing to the sliding of the former over the latter toward the center of the sar-

comere. This method of contraction is therefore termed the sliding filament mechanism

of muscle contraction. Although the sarcomere length decreases, the lengths of both thick

and thin filaments essentially remain constant (Figure I-6-1).

l-sarcomere++l |+1tz tband 1/z t oand+l l*

Contraction.'...'.''.''.'.'''''''.''''''''''''''''''''''''''''*

H a n d lbands

shorten

F--+lH band

Relaxed state

i t -H band

Contracted state

Figure l-6-1. Contraction of the sarcomere.

67


Clinical Correlate

Rigor MortisThe absence of ATP results inthe inability of myosin heads tobe released. The actin-myosincomplex becomes stable,leading to muscular rigidity.

2. Molecular aspects of contraction (Figure I-6-2).

a. Upon stimulation of a myofiber, myosin heads can make connections with neigh-boring thin filaments.

b. Once an actomyosin complex is formed, the head undergoes a conformationalchange (state 3), displacing the thin filament toward the center of the sarcomere.

c. The actin-myosin bond is subsequently broken (state 6) and the cycle may be repeat-ed as long as the muscle remains stimulated.

d. The molecular events in the rycle are driven by the hydrolysis of AIP. The myosinheads in state 1 contain ADP and inorganic phosphate (P,) that remain bound duringthe binding of the head to the thin filament. Dissociation of the phosphate is thoughtto accelerate the tilting step (or power stroke) from state 2 to state 3. Finally, the ADPdissociates from the attached tilted state (state 4). ATP in the cytoplasm replaces thepreviously bound ADR resulting in the dissociation of the head.

e. The final step involves the hydrolysis of the bound AIP with the liberated energy repo-sitioning the myosin head for another rycle. The head in the resting position (state 1),therefore, is considered to contain stored potential energy, which is expended duringthe power stroke. If ATP supplies were to run out, all the heads would be trapped instate 4, the so called rigor state. The complex equilibrium involving the actomyosinATPase shows all of the coexisting chemical species.

f. Although a single contraction results only in an extremely small movement and littleforce generation, the combination of continuous asynchronous cycling of many headsand the multiplicity of interprotein connections in the myofibriis greatly amplifr themolecular events.

thin fi lament

Jtoo,

Figure l-6-2.The contractile cycle (mechanochemical coupling).

g. There have been recent developments involving the precise mechanism of contractionat the level of the actin-myosin interaction. There is some evidence that a single crossbridge cycle involving the motion of a myosin head may slide the actin and myosin fil-ament more than the distance between two adjacent active sites on the actin filament.

B. Excitation-contraction coupling (EC coupling) refers to the mechanism by which an actionpotential generated by a motor neuron in the muscle initiates the mechanical eventsdescribed above.

1. An action potential generated in a muscle fiber is transmitted along the surface mem-

Pi

4

68

Physiology: Musculoskeletal

brane and down the T tubule to the sarcoplasmic reticulum, resulting in a release of thesequestered Caz+ into the cytoplasm. Cytoplasmic Ca2+ rises to approximately 10-s M(Figure I-6-3).

T tubule

Figure l-6-3.The transverse tubule system.

2. Ca2+ released from the sarcoplasmic reticulum diffuses into the myofibrils, where it comesinto contact with the thick and thin filaments.

3. When Ca2+ binds to the TnC subunit of troponin, it initiates a conformational change inTnC that is transmitted to the other thin-filament proteins, ultimately causing a shift inthe position of tropomyosin with respect to the actin surface. The movement oftropomyosin exposes a site on actin that is the binding site for cycling myosin heads.

4. In the absence of further stimuli, the Ca2+-AIPase of the sarcoplasmic reticulum rapidlydepletes the cytoplasmic Ca2* concentration, causing a return to the inactivated state ofthe thin filament.

C. Summary of the contraction sequence

1. Release of ACh at the neuromuscular junction occurs when an action potential reaches

the end of the axon; ACh difuses across the gap.

2. The nicotinic acetylcholine receptor at the muscle end plates reacts with ACh, which, inturn, depolarizes the muscle cell membrane at the motor end plate from the -90 mV rest-ing potential.

3. The threshold is reached when the membrane is sufficiently depolarized, initiating anaction potential along the muscle cell membrane that propagates bidirectionally from theend plate and extends into the T tubules.

4. T tubule depolarization influences the sarcoplasmic reticulum of the triads, and the sar-

coplasmic reticulum releases Ca2* into the cytoplasm.

5. Ca2+ binds to troponin-tropomyosin. Myosin heads are now able to bind, and myosinATPase is activated. Cross-bridges attach and detach cyclically at the expense of AIR andthe "rowing motion" causes thick and thin filaments to slide past each other.

6. After a time lag, the sarcoplasmic reticulum actively pumps Ca2+ back into the lumen,decreasing available Ca2+ and removing Ca2* from the troponin-tropomyosin complex.The regulatory proteins then rebind to the actin outside the groove, and the actin-myosininteraction is inhibited. A single action potential thus results in a muscle twitch, a brief

contraction followed by relaxation. The twitch starts approxim ately 2 msec after the depo-

larization of the membrane begins, i.e., during repolarization (Figure I-6-4).

69


Clinical Correlate

The Ca2* re-uptake mechanismof the sarcoplasmic reticulum iscalled the ryanodine receptor.ln some people, this receptor isblocked by general anesthetissuch as succinylcholine. Whenthese drugs are given to suchpatients, Ca2* is not taken upquickly enough and themuscles "overcontracf' andgenerate enormous amounts ofheat. This condition is calledmalignant hyperthermia andcan be fatal if not treated withdantrolene.

In a Nutshell

Types of Contraction

lsometric: Change in forcebut no changein lengh

lsotonic: Change inlengh but nochange in force

Dynamic: Change in bothlengh and force

ffi {Beginnin.g electrical responsetime to peak of contraction)

Figure l-6-4. Relative timing of action potential and muscle contraction.

D. Muscle mechanics

1. Definitions. An isometric contraction occurs when both ends of a muscle are fixed andno change in length occurs during the contraction, but tension increases. An isotoniccontraction occurs when a muscle shortens during contraction while tension remainsconstant (Figure I-6-5). When both the muscle length and force change during the con-traction, it is referred to as a dynamic contraction. In a dynamic contraction, the musclemay shorten (concentric contraction) or be pulled out by the load (eccentric contrac-tion). Most physical activity includes both isometric and isotonic contractions.

Figure l-6-5. lsotonic contraction.

2. tength-tension relationship. The tension developed by an intact muscle in an isometriccontraction varies with the initial length of the muscle fiber; there is an optimal length atwhich the muscle is able to develop maximum tension (Figure I-6-6). Figure I-6-7 plotsthe isometric tension developed by a single muscle fiber at different sarcomere lengths.Active tension refers to the difference between the total tension measured on stimulationand the passive tension (resistance to stretch) of an unstimulated muscle fiber, i.e., theresting tension. Thus, active tension refers to the tension produced by the active contrac-tion alone.

70


c.oocoF

a.

Figure l-6-6. Length-tension relationship.

In part A of the curve in Figure l-6-7, active tension is not developed by the fiberbecause the sarcomeres are stretched past their usual maximum length and there is no

overlap between thin and thick filaments (Figure I-6-84); no cross-bridges can formto generate force.

1.27 1.65 2.0 2.25Sarcomere length (p)

Figure l-6-7. Active tension generated as a function of sarcomere length.

b. In part B, the sarcomeres begin to overlap, and the increase in tension is proportional to

the extent of overlap, i.e., to the number of cross-bridges that form (Figure I-6-88).

c. Part C of the curve is the plateau tension; no further increase in tension is observedwith further shortening because the thin filaments overlap the thick filaments up to the

bare areas in the central region, in which no cross-bridges are present (Figure I-6-8C).

Increased shortening only overlaps the thin filaments with more bare area; hence, no

further increase in active tension is generated. The sarcomere length is optimal forgenerating tension at approximately 2 mm, the length that corresponds to the in situresting length of the sarcomeres in the fiber.

d. Part D of the curve shows a linear decline in active tension because the thin filaments

have moved past the bare areas of the thick filaments and begin to overlap one another;thin filaments from opposite halves then interfere with each other (Figure I-6-8D).

e. Part E of the curve shows further decline in tension at a faster rate until zero tensionis reached. The thick filaments have reached the Z lines and begin to crumple as the Z

lines compress them (Figure I-6-8E).

c.oU'coo

o

7 l

Lop,

Length (for an intact muscle)


A

B

-I r-tFH{.|HH{lH{I H-fi-t+{H.|{{{{{J-I r+#.|flf-fi.|fl#{

D

I r-Fl-Fl-FHFFtIHi

I Fl-BFr-Hr-r-H-H{

I nnnr+lnnnc

Figure l-6-8. A, No overlap of thick and thin filaments; B, initial overlap andtension increase; C, plateau tension; D, initial relaxation of tension;

and E, rapid relaxation and thick filament crumbling.

3. Sarcomeres acting in series do not generate additional force, since the forces act in oppo-site directions on the two sides of the Z line and thereby cancel each other (Figure I-6-9).The total force generated by many sarcomeres in series is thus the same as that of one sar-comere.

a. The displacement provided by the sarcomeres increases with more sarcomeres inseries, since each sarcomere shortens by a given amount.

b. Because the sarcomeres in series contract nearly simultaneously, the speed of shorteningis increased by the arrangement of sarcomeres in series, proportionally to the number soarranged.

:

I r{++++{H+t+fl+{I r{{.|{.t{H{+il+{.|

72


4.

...--->

t -t -----r----

---T--------r---

F- -+-----t--------T--------+-------l--

Figure l-6-9. Opposing forces in sarcomeres in series.

Sarcomeres acting in parallel generate additional force proportional to the number inthis arrangement because the amount of force that is generated is proportional to thenumber of cross-links acting in parallel simultaneously (Figure I-6-10). Thus, the forcethat a muscle generates is proportional to the cross-sectional area of the contractile mate-rial. The tension provided by a muscle can therefore increase by increasing the cross-sec-tional area of each fibril (adding more filaments in parallel), by increasing the number offibrils per muscle fiber (cell), thereby increasing the number of cross-links (force-gener-ating attachments) acting in parallel.

Figure l-6-10. Sarcomeres in parallel.

Isotonic contraction. If a muscle contracts isotonically, it is found that the velocity atwhich the muscle contracts varies inversely with the load it lifts (Figure I-6-11). At zeroload, a muscle exhibits a rapid but finite velocity of shortening, which corresponds to themaximum velocity for unloaded cross-bridge rycling. With increasing load, the velocityasymptomatically approaches a value of zero. At zero velociry the contraction becomesisometric. This point represents the maximum active force of the muscle.

Note

Sarcomeres of the samemyofibril do not generateadditive force. Therefore, togenerate more force, moremuscle fibers must be recruited.

5.

E(do

o()L

oTL

lsometric contraction maximum force

Initial velocity of contraction

Figure l-6-11. Force-velocity relationship in skeletal muscle.

73


E. Tlpes of skeletal muscle fibers. TWo types of fibers occur interspersed in most muscles,although one type usually predominates in any given muscle. Their properties are summarizedin Thble I-6-1.

Thble I-6-f . Properties of fast-twitch and slow-twitch fibers.

Propertyand Type Fast TWitch Slow TWitch

Red (myoglobin)Few

LowMany (sustained

contractions)

1. Fast-twitch fibers are white in appearance (hence the term "white muscle"), large indiameter, and usually arranged with relatively few muscle fibers per motor unit. The lightcolor is due to the absence of red myoglobin.

a. Fast-twitch fibers use glycolysis to generate energy; thus, they usually function underanaerobic conditions.

b. These muscle fibers are adapted for rapid contraction: the sarcoplasmic reticulumsystem and T tubules are extensive and regularly arranged, and the myosin AIPaseactivity is high.

c. These fibers enable fine, careful movements, for example, contraction of the extraoc-ular muscles of the eye.

2. Slow-twitch fibers (or red muscle) are red because of the presence of myoglobin.

a. The fibers are smaller in diameter than white muscle fibers, there is less sarcoplasmicreticulum and fewer T tubules than in white muscle, and the motor end plates aresmaller than those of white muscle.

b. Red muscle, such as back muscle, is slower to contract and is adapted for long, sus-tained contractions; oxidative metabolism is used for energy. Large numbers of mito-chondria permit sustained contractions, and there is a greater blood supply.

c. Muscle with little sarcoplasmic reticulum contracts slowly, since less Ca2* is released ata slow rate, and contraction takes longer because of the slower removal of Ca2*.

Motor units

1. Motor units consist of all the muscle fibers innervated by a single nerve axon (alphamotor neuron). Excitation of the motor neuron of the unit results in contraction of all thefibers in the motor unit.

a. Each of the muscle fibers of a given motor unit is of the same muscle type. The nerveexerts a tropic influence on the muscle fibers.

b. If the pattern of neural firing is experimentally changed, the muscle changes in type tothat determined by the motor nerve. Thus, the firing of any given axon results in eitherslow or fast contraction.

c. If the motor nerve is destroyed, all muscle fibers innervated by that neuron atrophy.

ColorSarcoplasmic reticulum

and T tubulesMyosin AIPaseMitochondria

WhiteMany

HighFew, (short, rapid

movements)

In a Nutshell

Fast Twitch VersusSlow Twitch

Think of a chicken:

. White meat (white muscle)is in the breast and is usedfor intermittent flapping ofthe wings.

. Dark meat (red muscle) isin the thighs, which areused for sustainedmaintenance of posture.

74


2. Length and tension developed by skeletal muscle is determined by the rate of firing of themotor neuron. Each muscle fiber has one end plate and is innervated by one motorneuron.

No activiry occurs in the absence of motor nerve stimulation (i.e., relaxation).

All motor neuron inputs are excitatory, and all reach threshold; i.e., they all generatethe action potential necessary to initiate contraction.

c. Skeletal muscle motor neuron cell bodies are located in the ventral horn of the spinalcord gray matter.

(1) A single, rapidly conducting myelinated axon directly connects with the musclefiber motor end plate.

(2) Initiation and coordination of the control occurs in the cerebral cortex, cerebel-lum, specific brain stem nuclei, and basal ganglia, and via reflexes.

G. Tr,nitch and tetanus

l. Single twitches. Elastic elements (tendons, connective tissue) within muscle and betweenthe muscle and its attachments represent slack that must be stretched before the activetension generated by the muscle can be exerted.

a. When contraction is initiated, the active tension first stretches the elastic elements.This time delay for elastic stretch is sufficient for the active twitch to begin to decline.Thus, the peak tension is never exerted by a single twitch (Figure I-6-12A).

100

75

1Time (sec)

Figure I-6-12. A, twitch amplitude and relative timing and amplitude forforce generated (for frog sartorius muscle at 0"C); B, tetanus.

a.

b.

E.9th

b" ,lz(uo(L

25

Unfused tetanus(colonus)

Response to two stimuli

75


ln a Nutshell

Tetanus results from highfrequency neural stimulationover short periods of time.

In a Nutshell

Muscle spindles (intrafusalfibers) contain a contractileelement innervated by gammamotor neurons, and anoncontractile element that isenveloped by stretch-sensitiveafferent neurons.

b. The force exerted increases with the frequenry of twitches, since the slack is exhaust-ed at the beginning and the firll energy of the twitch is then made available.

c. The elastic elements recoil at the end of one or more twitches, returning the energy inputduring initiation; this smooths out the decline of tension at the end of contraction.

2. Tetanus is the summation (fusion) of contractions that occurs when the fiber is stimu-lated repetitively within a short time, resulting in greater contractions (development ofmore tension) than from a single twitch.

a. Tetanus is caused partly because the elastic elements have been frrlly stretched from theearly contractions so that the maximum tension can be developed by the muscle fiber,assuming it is not allowed to relax (Figure I-6-12B).

b. Another reason for the occurrence of tetanus involves the increased availabiliw of Ca2+over repeated contractions.

c. Tetanus can be maintained until fatigue sets in due to an accumulation of lactic acidfrom anaerobic glycolysis.

3. Graded forces are generated through increasing the number of motor units (recruitment)and increasing the firing rate to increase muscle tension (rate coding).

H. Muscle receptors. TWo tfpes of specialized receptors exist in skeletal muscle: muscle spin-dles, which are embedded within groups of muscle fibers, and Golgi tendon organs,arranged in tendons in series with the myofibers.

1. Muscle spindles

a. Intrafusal fibers are small muscle fibers that are innervated bv small motor neuronscalled gamma motor neurons.

b. Primary, or annulospiral, terminals in muscle spindles are rapidly conducting tfpeIa fibers that innervate the centers of both the nuclear bag and nuclear chain fibers(the two types of intrafusal muscle fibers, named after the arrangement of nuclei intheir equatorial region).

c. The secondary, or flower-spray, terminals are slightly slower conducting tfpe II fibersthat innervate only the nuclear chain fibers.

d. Motor innervation of intrafusal fibers is through small, slowly conducting gammafibers (Figure I-6-13). These primarily terminate at the poles of the spindle on thenuclear bag fibers.

la afferent

ll afferent

Nuclear bag

Nuclear chain fiber

Gamma efferents

76

Figure l-6-13. Intrafusal fiber and innervation.


2.

e. Stretching of a muscle causes stretching and deformation of the muscle spindle,which results in a volley of impulses in the primary endings that synapse directly onthe alpha motor neurons innervating the extrafusal fibers of the muscle in which thespindle is embedded. For example, a contraction of the quadriceps muscle is elicitedwhen the patellar tendon is tapped and the familiar knee-jerk reflex occurs.

f. Primary endings discharge rapidly during the actual lengthening of the muscle andless rapidly when this increased length is maintained (Figure I-6-14). Primary endingsthus respond to length as well as velocity of stretch of the muscle.

Muscle length

la response

ll response

Figure l-6-14. Muscle length changes and responses from la and ll fibers.

g. Secondary endings discharge rapidly during the entire period of stretch of the mus-cle; thus secondary fibers respond primarily to length.

Golgi tendon organs

a. The Golgi tendon organ is a receptor in series with a discrete number of skeletal mus-cle fibers. When a skeletal muscle contracts, the tendon in which the muscle insertslengthens and stretches the nerve endings of the afferent fibers, causing them to fire.

b. Golgi tendon organs are arranged in series with extrafusal fibers and are supplied byIb afferent fibers. Excessive stretch of a muscle causes firing of Ib fibers, which synapseon inhibitory interneurons, which, in turn, synapse on alpha motor neurons. Excessivestretch thus inhibits muscle contraction, resulting in the inverse stretch reflex. This isa protection against the possible damage that may be caused by excessive stretching ofa muscle.

Golgi tendon organs and the muscle spindles work in concert during muscle stretching,but function somewhat differently from each other.

a.If a muscle is stretched, both afferents fire.

b. If the stretched muscle is made to contract actively, the tendon organ further increas-es its discharge, but the muscle spindle decreases or ceases its rate of discharge; this isbecause spindle organs are arranged in parallel and tendon organs are arranged inseries with the muscle.

c. Tendon organs are more sensitive to muscle tension, and muscle spindles are moresensitive to muscle length.

d. Extrafusal muscle fibers are controlled by alpha motor neurons, whereas the controlof intrafusal muscle fibers is by smaller gamma motor neurons. Gamma motor neu-rons regulate the sensitivity of the spindle afferents to dynamic and static phases ofstretch. Input through the CNS via gamma motor neurons can thus regulate muscletone and contraction.

Note

Muscle stretch causes anincreased rate of firing fromspindle afferents. This resultsin increased firing of alpham0t0r neurons to causemuscle contraction.

ln a Nutshell

. Muscle spindles sensemuscle length.

. Colgi tendon organssense muscle tension.

3 .

77


SMOOTH MUSCTESmooth muscle is involved in regulating the internal environment of the body. Smooth musclesare generally smaller than skeletal muscles and are usually uninucleated.

A. Structure of smooth muscle fibers. Smooth muscle fibers have fewer myofibrils per cell andare less morphologically organized than are skeletal muscle fibers.

1. Dense bodies on the cell membrane and in the cytoplasm, analogousto Z lines, act as sitesof thin filament insertion.

2. Smooth muscle fibers have much less myosin than skeletal muscle cells and no thick fila-ments. Only small aggregates of myosin bridge the actin filaments.

3. Theyhave no T-tubule system and only sparse sarcoplasmic reticulum; most Ca2* appearsto enter from the extracellular fluid.

4. Unlike skeletal and cardiac muscle, smooth muscle does not have troponin. Ca2+ isnecessary for activation of myosin kinases, which in turn mediate excitation-contractioncoupling.

B. Contraction and relaxation, which occur slowly, probably involve overlap of actin andmyosin. Thin filaments inserted into dense bodies are pulled closer together by bridgingmyosin units. Dense bodies on the cell surface are pulled so that the cell is deformed.

1. Myosin molecules consist of two heavy chains and four light chains; the light chains con-tain the regulatory subunits.

a. After an appropriate signal, intracellular calcium concentrations rise, and calcium willbind to calmodulin (Figure I-6-15).

t tcq2*l

calmodulin Ca2{catmodulin

myosin l ightchain kinase(inactive)

II

* ,Ca2*-calmodulin-myosin l ight chainkinase (active)

ln a Nutshell

In skeletal muscle, Ca2+binding to troponin allowsactin-myosin interaction.

In smooth muscle, thephosphorylation of themyosin light chain allowsactin-myosin interaction.

ATP I ADPr l l

. \ * - /myosin(inactive) (active)

Figure l-6-15. Contraction and relaxation.

b. Ca2+-calmodulin will activate myosin light chain kinase (MLCK).

c. MLCK phosphorylates the myosin light chain, which allows the myosin head to inter-act with actin.

C. Pharmacological considerations. Knowledge of the mechanism of smooth muscle contrac-tion easily explains why autonomic drugs have their effects. Arteriolar regulation will be usedfor this example.

1. Neutrotransmitters (e.g., norepinephrine) or drugs (e.g., phenylephrine) cause vasocon-striction by activating clr-receptors. These receptors increase levels of inositol triphosphate

78


(IP3), which in turn, increases intracellular Ca2+. This Ca2+ will lead to the cascade ofevents described culminating in vasoconstriction.

2. Neurotransmitters (e.g., epinephrine) or drugs (e.g., isoproterenol) activate Br-receptorsthat produce vasodilatation by increasing the level of cAMP. cAMP activates cAMP-dependent protein kinase, which phophorylates MLCK. This inactivates the enzyme; themyosin light chain cannot be phosphorylated, and vasodilatation occurs.

D. Types of smooth muscle

1. Multiunit smooth muscle is characterized by individual muscle fibers having separateinnervation for initiation of activity. Muscle fibers are not interconnected by g"p junc-tions. There is little spontaneous activity or response to stretch. This type of muscle allowsfine, graded contractions to occur, such as those that occur in the iris of the eye.

2. Unitary (visceral) smooth muscle has many separate fibers that operate as a unit(functional syncytium) because of gap junctions (nexus), which are regions of electricalcoupling (low electrical resistance and good current flow). Their fibers are sparsely inner-vated by the ANS.

a. Muscle fibers exhibit spontaneous activity. The resting potential is close to thresholdand is unstable. Oscillations of the resting potential, known as slow waves, bring themembrane potential to threshold repeatedly and rhythmically. These changes are prob-ably due to high Na* permeability.

b. Stretch activation occurs, where deformation initiates activity by depolarizingthe cellsmore rapidly. Muscle fibers are also frequently responsive to circulating hormones.

c. The ANS innervation to some fibers enables regulation (but not initiation) of con-tractile activity.

d. Contractions in unitary muscle are very slow, sustained, and rhythmic (e.g., the gas-trointestinal tract). They are initiated by action potentials that fire at the end of theslow waves.

Bridge to Pharmacolry

. NE producesvasoconstriction byactivating cr,l -receptors. Thisincreases lP, and thereforeCa2* levels. This leads tothe activation of MLCK.

. EPI produces vasodilatationby activating pr-receptors.This increases cAMP, whichleads to the inactivationof MLCK.

79

M uscu loskeletal, Con nectiveTissue, and Integument Pathology

Musculoskeletal and skin pathology encompass a broad range of congenital anomalies, autoimmunediseases, and neoplastic disorders. This chapter will discuss the characteristis of each disease state,their clinical presentations, and, when identifiable, their causes and treatments.

BONEA. Congenital anomalies

1. Osteogenesis imp€rfecta is a term used to describe several clinical phenotypes of hered-itar)' bone ftagilit)'.

a. Four types are generally recognized. All are rare.

(i) Type I shows autosomal dominant inheritance and causes mild-to-rnoderatelong bone disease, blue sclerae, deaftress, and litde progression after puberty.

(2) Type II is autosonal recessive and often produces a stillborn infart, or death afterbirth, with generalized crumpled bones.

(3) Tfpe III is autosomal recessive and produces progressive severe deformity.Patients have white sclerae.

(4) Type IV is autosomal dominant with variable severiry normal sclerae, and frac-tures of the long bones and spine.

b. Etiology. The caus€ in all cases of osteogenesis imperfecta seems to be a d€f€ct it n" !!!!!!91-e!!*!:synthesis of type I collagen. Genes for the peptide chains of collagen are located onchromosomes 17 and 7. Many different typei of lesions have bee'n described, from

;:::$:::;ffi:T*chain termination to amino acid substirution' co agen synth*rs.

c. Pathology Heritability varis among( I ) In bones, woven bone instead of trabecular bone and abnormal arrangements 61 : the types; blue sderae

collagen fibers are seen. Joints show tigametrtous laxitl' as a resr. t of abnormal and lax ligamenb arecollagen. : common features.

(2) In the eye, some patients have an abnormally thin sclera with a blue hue.

(3) In the ears, there may be fractured ossicles, producing deaftress.

(4) Teeth may be smali and discolored (dentinogenesis imperfecta), there may bemitral valve prolapse, and the dermis may be abnormally thin

8t


Nole

The defect in osteopetrosisseems to be an inability ofo$eoclasts to resorb bone.

Clinical Correlate

Achondroplasia is the be$known form of dwarfism,characterized by short limbs,large body, frontal bossing,and "saddle nose."

Ngte

In o$eoporosis, the bone isformed normally but indecreased amounts.

ln a Mbhefl

O$eoporosis may lead to easyfracturing, especially of hipsand vertebrae.

2. Osteopetrosis is a group of hereditary disorders characterized by increased density andthickening of bone cortex with narrowing of medullary cavities. Bones are brittle andfracture easily. Membranous bones are not affected (e.g., cranium). It may be associatedwith anemia, blindness, deafness, hydrocephalus, and cranial nerve palsies. There are twoforms of inheritance.

a. Autosomal recessive disease affects children and produces early death due to anemiaas the bones grow and squeeze out the marrow space.

b. Autosomal dominant disease affects adults and does not cause death but may causeincreased fractures and encroach upon cranial nerves as they exit from the skull.

3. Achondroplasia is an autosomal dominant disease characterized by abnormal cartilagesynthesis with subsequent decreased epiphyseal bone formation. It spares the craniumand vertebral bones. Clinically, achondroplasia is characterized by dwarfism with shortextremities and a large body and head.

4. Osteochondromatosis is a hereditary disorder characterized by the formation of multi-ple exostoses.

a. Clinical features

(1) Exostoses may be asymptomatic or produce deformity and compromise theblood supply.

(2) Gardner syndrome is a rare genetic disorder in which there is an association ofexostoses with sebaceous cysts, desmoid tumors, and colonic polyps, which maybecome carcinomas.

b. Pathology. Exostoses are bony metaphyseal projections capped with cartilage. Theyare multiple, often symmetric, and originate from epiphyseal cartilage.

5. Enchondromatosis (Ollier disease) is a nonhereditary syndrome characterized by multiplecartilaginous masses within the medullary cavit'' of bone, most commonly in the handsand feet. It often presents with pain and fractures. These masses may undergo malignanttransformation; half of all chondrosarcomas arise from enchondromas. Maffrrccisyndromeis a tamilial association of enchondromas and hemangiomas of the skin.

B. Osteoporosis is a decrease in bone mass, causing fragility of bone. Osteoporosis most com-monly occurs in postmenopausal women.

1. Pathogenesis

a. Primarycauses include estrogen deficienry,low density of original bone,lack of exer-cise, and nutritional factors associated with accelerated bone loss.

b. Secondary causes include immobilization, endocrinopathies (e.g., Cushing, thyrotoxi-cosis), and malnutrition (e.g., deficiencies of calcium, vitamins C and D, protein).

2. Clinical features

a. Patients may experience pain and fractures without obvious trauma.

b. X-rays show generalized radiolucenc)'of bone.

c. Laboratory tests reveal normal serum calcium, phosphorus, and alkaline phosphatase.

3. Pathology. Thinned cortical bone and an enlarged medullary cavity are seen. All bonesare affected. Weight-bearing bones (vertebrae, femoral neck) are predisposed to fractures.There is otherwise normal bone histology and a normal ratio of mineraUorganic bonyelements (Figure l-7 -I).

82

Pathology

,&%.e

....k.,J V' "".:7,:

w ""r',&,&.' '' . 4 :

F * ' i 1,i* #'w;#ii+

rati ign't r r l ' . * 1 . ! '

Figure l-7-1. Osteoporosis of vertebra (microscopic).

C. Osteomalacia and rickets

l. Etiology. Both diseases are caused by vitamin D deficiency from chronic renal insuffi-cienry, intestinal malabsorption, or dietary deficiency.


a. Rickets occurs in children prior to closure of the epiphyses, leading to bone deformi-ties and pain. Patients show the "rachitic rosary" (deformity of the chest wall as a resultof swelling at osteochondral junctions of ribs), bowing of legs, and fractures.

b. Osteomalacia is an impaired mineralization of the osteoid matrix. It causes fracturesand bending of bones and widening of osteoid seams.

(1) Laboratory tests show low serum calcium and phosphorous and high alkalinephosphatase, which distinguishes this syndrome from osteoporosis.

(2) X-rays show diffuse radiolucency of bone.

D. Paget disease (osteitis deformans) is due to excessive bone resorption with replacement bysoft, poorly mineralized matrix in a disorganized array.

1. Ctinical features

a. Paget disease may present with pain, deformity, and fractures. It is usually polyostotic(affecting many bones), involving the skull, pelvis, femur, and vertebrae. When theskull is involved, impingment of cranial nerves often causes deafness. Involvementmay cause bone hypervascularity with increased warmth of the overlying skin.

b. X-ray shows enlarged, radiolucent bones.

c. Laboratory tests show an extremely elevated alkaline phosphatase.

2. Pathology. The disease progresses from an osteolytic to an osteoblastic process. Resorbedbone is replaced by a vascular connective tissue, which later becomes mineralized. Thereis a mosaic rather than trabecular pattern from persistent osteoid seams at the margin ofnew bone.

E. Fibrous dysplasia causes focal areas of fibrous replacement of bone. Incidence is higher inteenagers, with men more frequently affected than women.

, t . rW. i ;

*

Note

Rickets and osteomalaciaare disorders of o$eoidmineralization; osteoid isproduced in normal amountsbut is not calcified properly.

*r'r,&u#;&'il,A;. .,H

8T


Note

Brown tumors are classic signsof hyperparathyroid ism.

1. Clinical features. Monostotic fibrous dysplasia is often asymptomatic or may lead topathologic fracture. Albright syndrome is an association of polyostotic fibrous dysplasia,caf6-au-lait spots, and sexual precocity in women.

2. Pathology. Fibrous dysplasia is usually monostotic, affecting the long bones, ribs, skull, andfacial bones. Fibrosis starts within the medullary cavity and remains encased in cortical bone.

F. Bone abnormalities in hlperparathyroidism (osteitis fibrosa cystica)

1. Pathogenesis. Excess parathyroid hormone activates osteoclasts to resorb bone and caus-es the kidney to waste calcium.

2. Clinical features. Osteitis fibrosa cystica occurs more comrnonly in primary hyper-parathyroidism, causing bone pain and fractures.

3. Pathology

a. Microscopically, there is an increased number of osteoclasts with excess bone resorp-tion and fibrous replacement of marrow causing cystic spaces in trabecular bone and"brown tumors" (areas of organized hemorrhage).

b. Grossly, brown tumors may produce rystic enlargements of bones.

G. Hypertrophic osteoarthropathy


a. Clinically, hypertrophic osteoarthropathy presents with painfirl swelling of wrists, fin-gers, ankles, knees, or elbows. The pathogenesis is unknown.

b. This is a periosteal inflammation, and new bone forms at the ends of long bones,metacarpals, and metatarsals.

c. Arthritis of adjacent joints is commonly seen, often with digital clubbing.

2. Etiology. Causes include intrathoracic carcinoma (a paraneoplastic syndrome), sepsis,endocarditis, ryanotic congenital heart disease, and inflammatory bowel disease. The syn-drome regresses when the underlying disease is treated.

H. Fibrous cortical defect (nonossifring fibroma) is a common developmental abnormalityseen in bones of the lower extremities in children. They are non-neoplastic lesions of bonecortex that are composed of fibrous connective tissue.

1. Clinical features. Fibrous cortical defect is usually asymptomatic, non-neoplastic, andusually resolves spontaneously.

2. Pathology. There are irregular, well-demarcated, radiolucent defects in the bony cortex,with an intact subperiosteal shell of bone. In the metaphysis, there are whorls of connec-tive tissue. Occasionally, multinucleated giant cells are seen. This entity must be differen-tiated from giant cell tumors of bone, which may cross the epiphysis (fibrous corticaldefect does not do this). The stromal cells of giant cell tumors are also more atypical, withlarger, darker nuclei and less cytoplasm than seen in fibrous cortical defect.

I. Osteomyelitis

1. Pyogenic osteomylitis

a. Etiology. Caused by direct innoculation of bone or by seeding of bone after bac-teremia. Organisms include Staphylococcus flnreus, Streptococcas, gonococci, andHaemophilus influenzae. Salmonella may be seen in patients with sickle cell disease.Pseudomonas is common in intravenous drug users and diabetics.

84

Pathology

b. Clinical features include fever,localized pain, erythema, and swelling. The x-ray maybe normal for up to 2 weeks, then may initially show periosteal elevation.

c. Pathology. Suppuration begins within the metaphyseal medullary cavity and pene-trates the cortex. Compression by exudate leads to vascular insufficiency and ischemicnecrosis. Specific findings include:

(1) Sequestrum, a necrotic bone fragment

(2) Involucrum, new bone that surrounds the area of inflammation

(3) Brodie abscess, localized abscess formation in the bone

2. Tuberculous osteomyelitis occurs in 1olo of cases of TB, causing caseating granulomas inthe bones. The term "Pott disease" refers to spinal involvement.

L Tumors

1. Osteoblastic tumors

a. Osteoma is a benign growth that frequently involves the skull.

( 1) "Hlperostosis frontalis interna" describes an osteoma that extends into the orbitor sinuses.

(2) Pathology shows dense normal bone.

b. Osteoid osteoma is a benign growth of the diaphysis of long bones, often the tibia or femur.

(1) Clinical features include pain that is worse at night and relieved by aspirin.X-rays show a central radiolucency surrounded by a sclerotic rim.

(2) Pathology shows a l-cm brown nodule surrounded by dense sclerotic corticalbone. Microscopically, the nodule is formed of vascular, woven bone withpartially mineralized osteoid.

c. Osteoblastoma is similar to a large osteoid osteoma, but is large, painless, ofteninvolves vertebrae, and may be malignant.

d. Osteosarcoma is a malignant bone tumor that produces osteoid and bone.

(1) Incidence. Men are affected more often than women, and the tumor usuallyoccurs in the second and third decade of life.It is the most common bone tumorin older people and is often associated with Paget's disease. Over one-third ofpatients with retinoblastoma also develop osteosarcoma.

(2) Pathogenesis is unclear. There is an increased incidence with irradiation, Pagetdisease, and other previous bone pathology.

(3) Clinical features. Patients present with localized pain and swelling, weight loss,and anemia. Classic x-ray findings include Codman triangle (periosteal eleva-tion) and bone destruction.

(4) Pathology. Grossly, osteosarcoma, particularly in teenagers, often affects themetaphyseal ends of long bones, usually around the knee, producing largenecrotic and hemorrhagic mass. Microscopically, the tumor may be sclerotic(with mineralized osteoid) or osteolytic (with little osteoid). It also may containcollagen or cartilage. The classic finding is anaplastic cells with osteoid, pink,amorphous material that is variably mineralized (Figures I-7-2 andl-7-3).

(5) Prognosis is poor. Patients are treated with amputation and chemotherapy.Metastasis to the lungs is common. Prognosis is improved with aggressive man-agement, such as resecting single pulmonary metastases.

85


Fi gu re l-7 -2. Osteogenic sarcoma (m icroscopic).

Figure l-7-3. Osteogenic sarcoma with vertebral collapse (gross).

2. Chondromatous tumors

a. Osteochondroma is an exostosis that forms benign metaphyseal growths. They maybe solitary. Lesions are identical to those in multiple form (osteochondromatosis).

b. Enchondroma is a solitary cartilaginous growth within the spongiosa of bone.Solitary growths are similar to those in multiple form (Ollier disease).

c. Chondromyxoid fibroma is a benign,rare tumor affecting young men. It forms a firmmass within the metaphyseal marrow cavity of the tibia or femur. The tumor containsfibrous and mlxomatous tissue, which must be differentiated from a malignant lesion.

d. Chondrosarcoma is a malignant tumor of chondroblasts. The age range is from 30-60years. Men are more often affected than women.

86

Pathology

(1) Etiology. The tumor may arise de novo or secondary to a pre-existing enchon-droma or exostosis.

(2) Clinical features. Chondrosarcomas are slower growing than osteosarcomas.They typically present with pain and swelling.

(3) Pathology. Tumors typically involve the spine, pelvic bones, and upper extremi-ties. Microscopically, they are characterizedby atypical chondrocytes and chon-droblasts, often with multiple nuclei in a lacuna.

3. Giant cell tumor is a malignant neoplasm containing multinucleated giant cells and aqrq7-ical stromal cells. This is an uncommon tumor, affecting patients from age 2G-50 years.


(1) Tumors present as a bulky mass with pain and tenderness.

(2) X-rays show an expanding area of radiolucency without a sclerotic rim.

b. Pathology

(1) Grossly, tumors arise in the epiphyseal region of long bones, forming a club-likedeformity at the end of the bone.

(2) Microscopically, multiple giant cells, resembling osteoclasts within a matrix offibroblast-like cells with large, atypical nuclei, occur.

a. Ewing sarcoma is a malignant neoplasm of undifferentiated cells arising within the marrowcavity. It is rare, usually affecting adolescents. Men are affected more often than women.

a. Etiology. The tumor arises from mesenchymal cells that have been shown to have someexpression of neural antigens.

b. Clinical features are pain, tenderness and early widespread dissemination.

c. Pathology

(1) Grossly, the tumor commonly affects the pelvis and metaphyses of long tubularbones. Cells erode through the cortex and invade surrounding tissues. Half of thecases have "onion skin" or concentric layering of new bone.

(2) Microscopically, undifferentiated small cells resembling lymphocytes occur.Surface antigens make the diagnosis.

forNTsA. Arthritis

1. Suppurative arthritis

a. Pathogenesis. The primary mechanism of suppurative arthritis is hematogenousseeding of joints during bacteremia, which is more common than direct invasion.Organisms include gonococci, Staphylococcus, Streptococcns, H. inlluenzae, and Gram-negative bacilli.

b. Clinical features include tender, swollen, and erythematous joints that require rapidintervention to prevent permanent joint damage.

ln a NuBhell

OsteochondromaExo$osis from misdirectedgrowth of growth plate

EnchondromaSolitary benign growth ofcartilage inside bone

ChondrosarcomaMal i gnant cartilage-producin gtumor

Nole

System ic I upus erythematosustypically includes joint pain.Because it is a multisystemicimmune disorder, it isdiscussed in the Clinicallmmunology chapter ofCeneral Principles Book I(Volume l).

87


ln a Nutshell

Suppurative Arthritis. Manife$ed by a tender, red,

sruollen joint (e.g., "a hotknee").

. Usually monoarticular, highneutrophil count in jointfluid, and often due to staph,strep, and gonococci.

Note

Tuberculosis of the spine iscalled Pott's disease. lt may beconfused with brucellosis ofthe spine.

In a Nutshell

0steoarthritis. Due to aging or wear and

tear on joints.

. Erosion of articular cartilageleads to bone eburnationand chipping.

. X-rays show the loss of jointspace.

. Heberden nodes are foundat the DIP joint.

c. Pathology. This disease is usually monoarticular, affecting a large joint.Characteristics of typical suppurative infection are cloudy synovial fluid with a highneutrophil count that clots readily. If the organism is very virulent or if it is leftuntreated, the synovium may ulcerate and infection may erode articular cartilage.

2. Tirberculous arthritis

a. Incidence. This form occurs more commonly in children.

b. Clinical features include an insidious onset and joint destruction.

c. Pathology. It occurs most often in the spine and hip. The synovial lining is coveredwith tubercles and granulation tissue. Pannus develops over the articular cartilage andmay erode it. Destruction of joint space ensues with fibrosis and calcification, eventu-ally leading to ankylosis.

3. Osteoarthritis (degenerative joint disease)

a. Incidence. Osteoarthritis increases with age, affecting women more than men. Itaffects 80o/o of people over 70 years old in at least one joint.

b. Pathogenesis

( 1) Aging or wear and tear (biomechanical) is the most important mechanism. Also,chondrocyte injury and abnormal collagen activity (biochemical) contribute;usually, both act together.

(2) Predisposing factors include obesity, previous joint injury, and synovial disease.Most retired football players have at least some osteoarthritis in the knees andankles.

c. Clinical features. There is an insidious onset with joint stiffness, decreased range ofmotion, effrrsions, crepitus, and bony swelling. Symptoms of nerve compression maydevelop secondary to compression by osteophytes.

(1) Heberden nodes (nodules at the base of terminal phalanges) occur more fre-quently in women.

(2) X-ray shows narrowing of the joint space due to loss of cartilage and osteoscle-rosis.

(3) foint fluid shows few cells and normal mucin.

d. Pathology

(1) The most commonly affected joints include vertebrae, hips, knees, and distalinterphalangeal (DIP) joints of fingers.

(2) Ioint mice are flakes of cartilage in the joint space from erosion.

(3) Osteophytes and bone spurs develop. Denuded, sclerotic, subchondral bonemay become exposed in areas (eburnation).

4. Rheumatoid arthritis is a systemic chronic inflammatory disease characterized by pro-gressive arthritis. There are many clinical variants.

a. Incidence. Women are affected three times more frequently than men. There is afamilial predisposition, and the disease commonly presents from ages 2G-60 years.

b. Pathogenesis involves an autoimmune reaction with the formation of circulatingantibodies (rheumatoid factor) against the Fc fragment of autologous IgG, leading toimmune complexes.

88

Pathology

c. Clinical features

(1) Symptoms include low-grade fever, malaise, fatigue, and morning stiffness.

(2) Physical examination shows joint swelling, redness, and warmth. In late stages,ankylosis may develop.

(3) Synovial fluid shows increased cells (usually neutrophils) and poor mucin.

(4) There is an elevated sedimentation rate and hlpergammaglobulinemia. The levelof rheumatoid factor may correlate with the severity of the arthritis.

(5) X-rays show erosions and osteoporosis.

(6) Systemic features include subcutaneous nodules (20o/o patients), Sj6gren sFndrome(l5o/o), glaucoma, pericarditis, vasculitis, hepatosplenomegaly, and adenopathy.

d. Pathology

(1) The disease usually starts in the small joints of the hands and feet but mayinvolve any joint. There is usually symmetric involvement. Patients develop adiffirse proliferative synovitis in which the synovium becomes replaced bypannus, a vascularized mass packed with lymphocytes, macrophages, andplasma cells. Pannus erodes articular surfaces, bone, joint capsule, and ligaments.Adhesions and ankylosis may result.

(2) Rheumatoid nodules are composed of proliferative connective tissue with areasof central necrosis. They may be seen in skin, heart valves, lung, pleura,pericardium, and spleen. Skin nodules are usually on extensor surfaces.

(3) Arteries may show acute necrotizing vasculitis due to circulating antigen-antibody complexes.

e. Other types of rheumatoid arthritis

(1) Juvenile rheumatoid arthritis (Still disease) has a peak incidence from1-3 years. Girls are affected more frequently than boys. It is often preceded byacute febrile illness. There is periarticular swelling, lymphadenopathy, hep-atosplenomegaly, and absence of rheumatoid factor. The course is variable andmay resolve.

(2) Ank/osing spondylitis occurs predominately in young men with HLA-B27.Itis also associated with inflammatory bowel disease and usually involves thesacroiliac joints and spine.

(3) Arthritis associated with ulcerative colitis occurs in 25o/o of patients with ulcer-ative colitis. It is not progressive and resolves spontaneously or with treatment ofthe ulcerative colitis. There is no pannus formation.

(4) Psoriatic arthritis has pathology similar to rheumatoid arthritis but an absenceof rheumatoid factor. It is also associated with HLA-B27.

(5) Felty syndrome is a polyarticular rheumatoid arthritis associated withsplenomegaly,leukopenia, and leg ulcers. Neutropenia is related to splenomegaly,antineutrophil antibodies, and bone marrow failure.

5. Gout. In gout, there is hlperuricemia associated with recurrent bouts of acute arthritis,resulting from deposition of monosodium urate in joint tissues.

Note

Ankylosing spondylitis occursmainly in H LA-B27-positivepatients. Note that psoriaticarthritis and Reiter syndromeare also more common in thepresence of HLA-827.

89


ln a Nutshell

Gout. Cout is the deposition of

urate crystals leading toacute, painful attacks ofarthritis. The big toe isclassically affected.

. Cout may result fromoverproduction orunderexcretion of uric acid.

. Tophi are pathognomonic.

. Urate crystals are needle-shaped and negativelybirefringent,

In a Nutshell

Pseudogout. Calcium pyrophosphate

deposition

Reiter syndrome. Arthritis, uveitis, and

conjunctivitis

. Possibly due to Chlamydia

a. Types

(1) In primarygout (90olo of cases), there is an inborn error of purine metabolism.The metabolic defect is usually not known. Specific enzfme defects account for

only about l0o/o of cases (e.g., Lesch-Nyhan syndrome).

(2) Secondary gout is hyperuricemia resulting from a disorder unrelated to purinemetabolism (e.g., excessive cell breakdown as in leukemia and polycythemia).

b. Incidence. Most cases are in men, but it occasionally affects postmenopausal women.

It is familial (primary gout) in about 20o/o of cases.

c. Pathogenesis is an overproduction of uric acid (under 10o/o) or underexcretion of uricacid (over 90o/o).

d. Clinical features. There is an asymptomatic period of hyperuricemia (>7 mgldl) fol-

lowed by acute episodes of joint pain and swelling. After approximately 10 years of

recurrent attacks, chronic disabilities ensue (i.e., decreased range of motion; joint

deformities). Uric acid kidney stones develop in up to 25o/o of patients.

e. Pathology. Precipitation of urate crystals in joint fluid causes an acute inflam-matory synovitis with synovial edema and leukocytic infiltrate. It usually affects thejoints of the lower extremities, particularly of the large toe. Formation of tophi (urate

deposits surrounded by inflammatory cells, including foreign body giant cells) ispathognomonic. Tophi may form in the helix of ear, bursae, ligaments, and kidney.Chronic changes include urate deposition along articular surfaces, pannus formation,

erosion of cartilage and bone, adhesions, and anlcylosis. Uric acid crystals are best pre-

served in tissue samples by fixing in ethanol rather than formalin.

6. Pseudogout (chondrocalcinosis) is arthritis secondary to deposition of calciumpyrophosphate crystals in joint fluid. It is associated with many metabolic diseases (e.g.,

Wilson disease, hypothyroidism, diabetes mellitus). The crystals are recognizably differ-

ent from urate on light microscopy.

7. Reiter syndrome is an association of arthritis, urethritis, conjunctivitis and mucocuta-neous lesions, possibly secondary to Chlamydia infection. The relative risk of this syn-drome is raised approximately 40 times by the presence of HLA-827.

B. Tirmors

1. Synoviosarcoma

a. Incidence. This is a rare tumor with a peak incidence in early adulthood, affectingboys and girls equally.

b. Clinical features. These tumors form slow-growing, painless masses. They are veryaggressive with early metastases to the lung and pleura.

c. Pathology. Two-thirds of synoviosarcoma form in the lower extremities and one-thirdform in the upper extremities. They arise from synovial lining cells of bursae and ten-don sheaths. The picture is often biphasic with a spindle cell fibrosarcoma elementenclosing an epitheloid (glandular) component.

2. Matignant fibrous histiocytoma

a. Incidence. This is a relatively common soft tissue malignancy, affecting adult menmore than women.

b. Pathology. Ttrmors arise in soft tissue or bones. They are located in the lower extrem-ities more often than in the upper extremities and in the abdominal cavity.Microscopically, tumors are pleomorphic, composed of fibroblasts, histiocytes, andtumor giant cells.

90

Pathology

C. Other lesions

1. Ganglions are small cysts of tendon sheath or joint capsule, often in the wrist.

2. Tenosynovitis is an inflammation of tendon sheaths and tendons, often secondary toexcess stress or trauma. Rare forms include suppurative or tuberculous tenosynovitis.

3. Bursitis is an inflammation of the bursa, often caused by excessive stress or trauma andoccasionally bacterial invasion.

4. Pigmented villonodular synovitis is a villous proliferation of synovium colored brownby hemosiderin deposition. It is probably a reactive response to recurrent trauma andpossibly a neoplastic process that does not metastasize.

SKELETAI MUSCLE PATHOTOGYA. Clinical features. Signs and physical findings of muscle disease include myotonia (continu-

ous tonic contraction), weakness, muscle atrophy (wasting), fasciculations (twitching), andpseudohypertrophy. The symptoms and history of muscle disease include various combina-tions of the following:

1. Tripping, clumsiness (distal weakness especially)

2. Difficulty climbing stairs or rising from chairs (proximal weakness)

3. Family history, which includes three common patterns of inheritance: sex-linked (X-linked) inheritance, autosomal recessive inheritance, and autosomal dominant inheri-tance.

B. Diagnosis. Laboratory findings that may help differentiate muscle diseases include:

1. Creatine kinase is elevated in myositis and some dystrophies.

2. The erythrocyte sed.imentation rate (ESR) may be elevated in myositis or any otherinflammation.

3. Serum potassium may be abnormal in periodic paralysis and raised whenever there is cellnecrosis.

4. Pyruvate or lactate may be abnormal in metabolic, particularly mitochondrial, musclediseases.

5. Urinarymyoglobin is elevated if there is acute muscle destruction (e.9., rhabdomyolysis).

6. Electromyography (EMG) and peripheral nerve conduction velocities (NCVs) may helpdifferentiate neurogenic from myopathic disorders; in general, proximal weakness is oftenmyopathic, while distal weakness is often neurogenic.

7. Muscle biopsy is often the definitive diagnostic procedure in myopathic disorders.Diagnosis is made by the presence or absence of certain histologic features or by stainingwith enzymatic stains.

C. Neurogenic muscle atrophy covers a large class of disorders secondary to loss of normalnerve supply; muscle is lost secondarily.

1. Features of denervated muscle include fiber shrinkage and angulation with nuclearpyknosis.

2. Initially, the histologic picture is of scattered atrophic fibers, but, since a nerve typicallysupplies many fibers, a picture of group fiber atrophy eventually becomes apparent.

3. Types I and II fibers show atrophy.

9 l


ln a Nutshell

Myasthenia gravis is anautoimmune disease in whichantibodies are made again$NMJ acetylcholine receptors.Clinically, it presents withmuscle weakness thatworsens with use. ftosis iscommonly seen.

In a Nutshell

The myositides are disordersthat probably have anautoimmune etiology.They are characterized bymuscle fascicle atrophy,edema, and necrosis.

E.

4. Intact neighboring axons may sprout and reinnervate fibers, which results in a single fibertfpe, regardless of the initial fiber rype. This is known as "fiber-type grouping." Fibersbecome heterogeneously grouped together according to the "fiber tFpe" (white or red) ofthe innervating neuron.

5. Ultimately, denervated muscle is replaced by connective and adipose tissue.

6. Polyarteritis nodosa (PAN) may show muscle vascular infiltration and infarction of mus-cle and nerve; PAN is particularly notorious for causing mononeuritis multiplex byinfarction of multiple peripheral nerves,leading to neurogenic atrophy.

D. Myasthenia gravis typically affects young women.

1. Pathogenesis. This is an autoimmune disorder caused by IgG directed against the acetyl-choline (ACh) receptor.

2. Clinical features include fluctuating weakness. This weakness involves muscles suppliedby cranial and peripheral nerves with no sensory abnormalities, and it is especially pro-found late in the day.

3. Diagnosis is established by a decremental response to repetitive electrical stimulation onEMG or by clinical improvement when a cholinesterase inhibitor (e.g., edrophonium) isadministered. Muscle biopsy shows group atrophy and, occasionally, mononuclear cellinfiltrates. Patients may have thymic abnormalities, including thymoma (10-20o/o) orthymic hyperplasia (70-80o/o). In these patients, thymectomy is often curative.

Myositides include both polymyositis and dermatomyositis. Both polymyositis and der-matomyositis are classified as autoimmune or collagen vascular diseases.

1. Incidence. Polymyositis is more common in females.

2. Pathogenesis. These disorders are associated with autoantibodies, with a cell-mediatedimmune response, C2 deficienry, and HLA-DR3.


a. Neck and proximal limb muscle weakness, dysphagia and muscle pain, tenderness andswelling are all common in polymyositis and in dermatomyositis.

b. Dusky erythema of the skin with plaques over the joints or purple discoloration of theeyelids (heliotrope rash) is also a feature of dermatomyositis.

c. Adults with dermatomyositis are at increased risk of having internal malignancies,particularly stomach, colon, lung, and breast.

d. Laboratory studies show elevated creatine kinase and ESR. Creatinuria can resultfrom breakdown of muscle proteins.

e. Electromyographic abnormalities reflect abnormal muscle function.

4. Pathology. There is variation in fiber size, peripheral atrophy in fascicles, necrosis,myofiber vacuolation, edema, and perivascular mononuclear cell infiltration.

Muscular dystrophies are a heterogeneous group of disorders that have a common featureof muscle degeneration. Dystrophic muscles are shrunken, flabby, and pale. Microscopically,there may be vacuolization, cytoplasmic fragmentation, hyalinization, and necrosis.

1. Duchenne muscular dystrophy is the most severe fype of muscular dystrophy.

a. Pathogenesis. This disorder shows X-linked recessive inheritance. The dystrophinprotein, encoded on the X chromosome and normally present in muscle cell mem-branes, is usually absent.

b. Clinical features

92

Pathology

2.

( 1) Elevation of creatine kinase and histologic degeneration precedes clinical features.

(2) The classic presentation is with pelvic girdle weakness and ataxia. The course isprogressive, and children are unable to walk by the age of 10.

(3) Pseudohypertrophy of the calves is characteristic.

(4) Myocardial muscle involvement accompanies other muscle degeneration andmay cause death.

(5) Mental retardation is also an associated feature.

c. Diagnosis

(1) Muscle biopsy reveals fiber degeneration with connective tissue proliferation andmyophagocytosis; eventually, muscle is replaced by connective tissue and fat.

(2) DNA tests are available for the detection of mutations in the dystrophin gene.

(3) Heterozygous female carriers may have elevated creatine kinase and subclinicaldegeneration, which is detected by biopsy.

Becker muscular dystrophy

a. Pathogenesis. This disease shows both X-linked recessive inheritance or spontaneousmutations in the same gene as Duchenne dystrophy.

b. Clinical features. Patients may walk until age 20 or 25. Cardiac lesions are mild orabsent.

c. Diagnosis. Creatine kinase is elevated. Muscle biopsy changes are similar to those inDuchenne's but less severe.

Facioscapulohumeral muscular dystrophy (FMD)

a. Pathogenesis. Inheritance is autosomal dominant, but spontaneous mutation iscommon.

b. Clinical features. Presenting symptoms usually involve the face, neck, and shouldermuscles. Pelvic muscles may be involved at later stages.

c. Diagnosis. Muscle biopsy reveals degenerative changes with fibrosis and inflammatorycell infiltration.

Limb-girdle muscular dystrophy (tGD)

a. Pathogenesis. Inheritance is autosomal recessive.

b. Clinical features. Weakness begins in either the pelvic or shoulder girdle and spreadsto involve other muscles. Affected individuals may retain ambulation for 25 years ormore.

c. Diagnosis. Muscle biopsy reveals striking myofiber size variation with atrophy andhypertrophy.

Myotonic dystrophy

a. Pathogenesis. This disorder arises with an autosomal dominant pattern or throughspontaneous mutations. The genetic defect for myotonic dystrophy is a trinucleotiderepeat in a protein kinase encoded on chromosome 19.

b. Clinical features.It is clinically unique from other dystrophies. Characteristics includeweakness, atrophy, and myotonia (tonic contraction of an affected muscle with inabil-ity to voluntarily relax it). Head and neck muscles are frequently weak and atrophic,

Clinical Correlate

Calf pseudohypertrophy(replacement of muscle tissuewith adipose and fibroustissue) is characteristic ofDuchenne musculardystrophy.

Note

Becker muscular dystrophy isessentially a less severe formof Duchenne. In Becker,dystrophin is usually presentbut is of abnormal size.

3.

4.

5 .

95


while limb involvement is usually distal (hands and feet). Patients may have cardiacarrhythmias, cataracts, ftontal baldnes, hlryogonadism, and idiosyncratic reactions inanesthesia. Muscle enzymes and biopsies may be normal.

c. Characteristic pathologic Endings on light microscopy (ring fibers and sarcoplasmicmasses) distinguish this syndrorne ftom other forms of muscular dystrophy.

Bridge- !o Biochemktry G. Glycogenoses are diseases caused by defects in glycogen-cleaving enzfmes that result inglycogen accumulation in various tissues, including rnuscle,

Certain glycogen storagediseases affect the muscular

t ' Tlpe II (Pornpe disease)

svstem because the a. Pathogenesis, This disease is due to acid maltase deficiency (a-1,4-glucosidase).

accumulation of glycogen Glycogen accumulates in the brain, liver, and muscles (including the heart).

impedes normal cellular b. Clinical features include h€patom€galy, cardiomegaly, macroglossia, weakness, andprocesses. h ?otonia. Presentation is within 3 months of birth, and death occurs by 8 months.

Serum lipid, glucose, and ketones are normal. An adult form exists, which is milderand presents as weakness without organomegaly.

c. Diagnosis is made by enzymatic assay of acid maltase in leukocytes or fibroblasts.

2. Type III (Cori disease; limit dentrinosis)

a. Pathogenesis. This disease is due to a deficiency in a debranching enzyme (amylo-1,5-glucosidase) .

b. Clinical features. Hepatomegaly and growth failure are early features. There may befasting hypoglycemia, ketosis, and elevated lipids.

c. Tleatment. Response to glucagon or epinephrine is blunted because of inability tocleave glycogen past branching points.

3. Type IV (Andersen disease)

ln a Nutshell a. Pathogenesis. This disease is due to a deficiency of the branching enzyme involved inglycogen synthesis.

Muscle weakness and exercisetmoterance are common b. Pathology. A polysaccharide similar to amylopectin accumulates in th€ h€art, liv€r,

features of $ycogen storage muscle, and brain. Hepatomegaly is followed by cirrhosis and liver failure.

mvooathies. 4. Tlpe V (McArdle disease)

a. Pathogenesis, This disease is due to myophosphorylase deficiency. Glycogen accumu-lates in vesicles within muscles.

b. Clinical features. Muscle cramping and myoglobinuria are usual. There is no lacticacidosis during exercise, and the glucagon response is normal.

5. Type VII is due to phosphofructokinase deficiency and is clinically similar to McArdledisease.

H. Congenital nyopathies typically present early in life. Clinical features include hypotoniaand slowly progressive weakness. They may be distinguished primarily by histopathologicfeatures.

l. In central core disease, dense ryIindrical cores extend ttle entire length of the fibers.

2. In nemaline myopathy, nemaline bodies appear to be derived from Z discs and possesscross striations.

3. Centronuclear myopathy (myotubular myopathy) usually involves facial and extraocu-lar muscles. Onset may be in infancy, adolescence, or adulthood. The syndrome is

94

Pathology

genetically heterogeneous. Nuclei are characteristically located in a central chain, sur-rounded by vacuoles.

I. Werdnig-Hoffrnann disease is not a myopathy but an autosomal recessive degeneration ofthe brain stem and spinal cord motor neurons.

1. Clinical features. It may present as neonatal hlpotonia (floppy baby) or decreasedintrauterine fetal movement. Intercostal weakness is frequent.

2. Complications. Respiratory complications are the usual cause of death.

3. Pathology. There is neuronal loss in anterior horns of the spinal cord as well as the cra-nial nerve nuclei.

L Myositis ossificans causes ossification at the site of traumatic hemorrhage. It presents withpain, swelling, and tenderness. Differentiation from neoplasms can be made by biopsy.

K. Desmoid tumor (aggressive fibromatosis) is an infiltrative, fibrous proliferation, arisingfrom the aponeuroses of skeletal muscle. They are histologically benign and do not metasta-size but can become large, locally invasive masses. They frequently occur in young women,often in the abdominal wall. There is a possible association with multiple pregnancies andprevious trauma. Differentiation from sarcomas is made histologicully by the absence ofatypical cells.

L. Rhabdomyosarcoma is a malignant neoplasm arising from striated muscle. It is the mostcommon soft tissue sarcoma in children. Prognosis depends on the site of origin. Up to 40olohave metastases at the time of diagnosis.

1. Embryonal rhabdomyosarcoma

a. In infanry or childhood, it is most often located in head and neck tissues and is lessaggressive than other forms.

b. Sarcoma botryoids is an embryonal rhabdomyosarcoma with a grape-like, soft, poly-poid gross appearance. It is usually located in the genitourinary, upper respiratory, orbiliary tract. It is extremely aggressive.

M.Skeletal muscle abnormalities in AIDS

1. Incidence. Up to 50olo of HlV-positive individuals have some form of muscular abnor-mality.

2. The most common fiodirg is similar to polymyositis (i.e., inflammatory infiltrates withmacrophages and muscle fibers showing coagulative or segmental necrosis). The muscle isnot directly HlV-positive. Clinically, the picture is also similar to non-HlV-relatedpolymyositis with weakness (primarily proximal in distribution) and EMG and laboratoryfindings typical of myopathy (increased serum creatine kinase).

3. Nemaline rod myopathy with atrophy of tfpe I fibers is similar to congenital nemalinemyopathy. Weakness is predominantly proximal in distribution, and the EMG is myo-pathic.

4. Zidovudine (AZT)-induced myopathy is characterized by multinucleated cells associatedwith myositis and by focal infection.

Clinical Correlate

Werdnig-Hoffman disease isknown as "floppy babysyndrome" due to the loss ofneurons innervating bothbodily and facial muscles.

Bridge to Reproductive

Sarcoma botryoids isdiscussed in theReproductive Pathologychapter in this volume.

In a Nusthell

A myositis-like syndrome mayoccur in AIDS as a result ofinfection or AZT treatment.

95


Note

Scleroderma presentswith sclerosis of the skin.It is discussed in detail inthe Clinical lmmunologysection of Ceneral PrinciplesBook t 0/olume l).

ln a Nutshell

Seborrheic keratoses are gray,scaly, greasy lesions withhyperkeratosis, epidermalpapillary hyperplasia, andoccasional keratin pseudocystformation. They are benign.

Clinical Correlate

Skin tags are normal findingson most people; highnumbers of them mayindicate diabetes.

SKINA. Epidermal lesions

1. Seborrheickeratoses are benign neoplasms that usually arise in areas exposed to the sun.They are very common in late adulthood.

a. Clinical features. Although they are usually left untreated, they may be removed ifthey become irritated, or for cosmetic purposes. Sudden development of multiplelesions may follow an inflammatory dermatitis, hormonal therapy, or may accompa-ny an underlying malignanry.

b. Pathology

(1) Grossly, lesions are typically located on the face, back, or trunk. They are typi-cally brown to gray scaly, and greasy.

(2) Microscopically, seborrheic keratosis is a squamoproliferative disorder charac-terized by hyperkeratosis, papillary epidermal hyperplasia, and occasionally,development of pseudo horn cysts (epidermal pseudorysts filled with keratin).These are invaginations created between the papillae of keratin-producing cells.

2. Keratoacanthoma is also a benign squamous lesion, arising in sun-exposed areas. It ismost common in middle age.

a. Clinical features. Keratoacanthoma is a rapidly growing papule that must be distin-guished from squamous cell carcinoma.

b. Pathology

(1) Grossly, lesions are located on the head and arms. They start as a round pinkpapule that grows within weeks up to 2 cm with a central depression filled withkeratin.

(2) Microscopically, the squamous cells are well organized and not anaplastic,although mitoses are present during the rapid growth phase. A key feature of thisneoplasm is a lip of normal, nondysplastic epidermis on both sides of thekeratin-filled crater. Keratoacanthomas are said to be composed of large squa-mous cells with a hyaline, "ground-glass" cytoplasm.

3. Fibroepithelial polyps are benign. Also known as skin tags, these lesions are common inmiddle age but may also develop during pregnancy. They are also associated with diabetesor intestinal polyposis. They usually occur in intertriginous regions and on the neck. Skintags are composed of benign squamous epithelium covering a fibrovascular core.

4. Basal cell carcinoma is invasive, but it rarely metastasizes.

a. Incidence. It is most common in middle-aged or elderly individuals and those whohave fair complexions. They occur on sun-exposed areas.

b. Clinical features. Basal cell carcinomas are locally aggressive and rarely metastasize.Complete excision is usually curative, but there is approximately a50o/o recurrence ratefrom shave biopsies.

c. Pathology

(1) Grossly, basal cell carcinoma lesions are located on sun-exposed regions or areascontaining pilosebaceous follicles. Most lesions are on the face. They form pearlygrey papules with heaped up borders and a central depression (Figure I-7-4).

96

Pathology

5.

Figure l-7-4. Basal cell carcinoma (gross).

(2) Microscopically, there are nests of tumor cells surrounded by a fibrous stroma.

Pallisading of tumor cells and retraction from the stroma at the edges of nests is

a particularly useful microscopic characteristic (Figure I-7-5).

Actinic keratoses are premalignant and may develop into squamous cell carcinoma.

a. Incidence is highest in fair-skinned people of middle age. It is associated with chronic

sun exposure.

Figure l-7-5. Basal cell carcinoma (microscopic).

Pathology

(1) Grossly, there are rough, crusty, red papules up to 1 cm in diameter.

ln a Nutshell

Basal Cell Carcinoma. Due to sun exposure

. Most commonly occur onthe face

. Rare metastases

. Nests of tumor cells indesmoplastictissue

. Pallisading of cells ischaracteristic

,i&,b:tV.*'#

b.

,."w*,#; {:'.

;fi.fu{";i

97


6.

(2) Microscopically, there are focal regions of atypical epidermis cells that do notinvade the basement membrane and do not occupy the full thickness of the epi-dermis. Disruption of the granular layer and formation of parakeratosis arecommon.

Squamous cell carcinoma is a malignant tumor that is also found most frequently insun-exposed areas.

a. Incidence. The tumor peaks at 60 years of age with a preponderance among women.

b. Etiology. Chronic sun exposure and fair complexion are the greatest risk factors.Chronic skin ulcers or sinus tracts, longterm exposure to hydrocarbons, burns, andradiation also contribute to risk. Papilloma viruses are associated with squamous cellcarcinomas of the anogenital region.

c. Clinical features. When squamous carcinoma occurs on sun-exposed regions, it rarelymetastasizes. When it occurs on nonexposed skin, up to 50olo metastasize, indicating afundamentally different biology in the two systems.

d. Pathology

(1) Grossly, the appearance is variable, depending on location and invasiveness.Squamous carcinomas may be firm, erythematous, scaly nodules or oozing ulcerswith raised borders. On mucosal surfaces, th.y may be associated with leukoplakia(white plaques), made white by the keratin produced (Figure I-7-6).

Figure l-7-6. Squamous cell carcinoma (gross).

Microscopic findings include atypical cells restricted to the epidermis (Bowendisease or squamous cell carcinoma in situ) and atypical keratinocytes invadingthe dermis (invasive cancer). Arypical keratinocytes may form squamous pearls,i.e.,laminated squamous cells with central keratinization in an "onion skin" con-figuration (Figure l-7 -7).

In a Nutshell

Squamous cell carcinomaarises in sun-exposed areas,skin ulcers, sinus tracts, orthe anogenital region.

Crossly, squamous cellcarcinoma may appear inmany forms.M icroscopically, "squamouspearls" (formed by atypicalkeratinocytes) help makethe diagnosis.

(2)

98

Pathology

#

,W'uffi *.#i!::

, * ' t

,ii"' '4i..* ffiW,:

3Mna;:.:

Figure a-7-7.Well-differentiated squamous cell carcinomawith keratin pearls (microscopic).

B. Dermal lesions

l. Xanthomas

a. Incidence. Xanthomas may be idiopathic, or they may be associated with hyperlipi-

demia or malignancies.

b. Pathology. They are yellownodules, composed of foamy histiocytes with eosinophilic

cytoplasm. The cells contain cholesterol, triglycerides, and phospholipids.

2. Capillary hemangiomas ( strawberry heman gio mas )

a. Clinical features. These lesions usually arise within the first weeks of life and usually

resolve spontaneously, starting at 1-3 years of age; most are completely gone by age 5.

b. Pathology. Capillary hemangiomas form a soft, red,lobulated mass, l-6 cm in diam-

eter, composed of thick-walled capillaries.

3. Nevus flammeus (port wine stain) is a common congenital lesion, composed of telang-

iectatic vessels. Usually located on the neck or face, it appears as a large, flat, irregular pink

patch that tends to resolve spontaneously.

4. Kaposi sarcoma is a malignant mesenchymal tumor (an angiosarcoma), characterizedby

an aggressive course in patients with AIDS and by a slower course in elderly men.

C. Pigmentary disorders

l. Freckles are areas of increased melanin deposition in the basal cell layer of the epidermis.

2. Vitiligo is irregular, completely depigmented patches.

a. Incidence is common and may affect any race. Risk is increased with a positive family

history.

b. Etiology is unknown, but it is possibly autoimmune or related to stress.

c. Pathology. Microscopically, the skin is devoid of melanocftes in affected areas.

3. Melasma is irregular patches of hyperpigmentation on the face. It most commonly

appears during pregnancy and does not completely regress.

ln a Nutshell

Xanthomas are collectionsof lipid-laden histiorytesand are often associatedwith hyperlipidemia.

ln a Nutshell

Kaposi sarcoma is anangiosarcoma found on skinand mucous membranes. lt isassociated with AIDS andcaused by human herpesvirustype B (HHVB).

ln a Nutshell

Vitiligo is characterized byirregular patchy depigmentationof unknown origin due tomela nocyte def iciency.

99


Note

Melanomas tend to growhorizontally before spreadingvertically. Prognosis relates todepth of invasion.

D. Melanocfte tumors

l. Nevocellular nevus is a benign tumor of nevus cells and melanocftes.

a. Types of common nevi include junctional, compound, and intradermal. Although thedifferent types may have distinguishing clinical features, histologic examination isneeded for accurate diagnosis.

(1) Junctional nevi are recognized histologically by the presence of nests and indi-vidual nevus cells in the lower epidermis, close to the dermal-epidermal junction.

(2) Compound nevi have both epidermal and dermal components.

(3) Dermal nevi are characterized by the presence of mature nevus cells within thedermis. In time, the nevus cells are surrounded by dense fibrosis and mav even-tually regress altogether.

b. Clinical features

(1) The relationship between nevi and melanoma is largely unknown except thatboth are clearly related to sun exposure. Although malignant transformation ofnevi is not common, approximately 30o/o of cases of melanoma are associatedwith nevi. There is also increased incidence of melanoma associated with eiantcongenital pigmented nevi.

(2) In most cases, one can distinguish a benign nevus from melanoma on clinicalgrounds (i.e., colot contour). A nevus is tan to brown and has sharp, well-cir-cumscribed borders. Color is usually uniform, and the lesions are stable in shapeand size.

2. Lentigo maligna (Hutchinson freckle)

a. This is a premalignant lesion, occurring on sun-exposed surfaces in the elderly.

b. It is characterizedby intraepidermal proliferation of atypical melanocytes. Up to 50%progress to invasive melanoma over the course of several years.

3. Malignant melanoma

a. Incidence. Melanoma peaks by ages 40-60.

b. Pathology (Figures I-7-8 and I-7-9)

( 1) tentigo maligna melanoma arises from lentigo maligna with a peak incidence atage 70.It grows horizontally first (radial growth), followed by vertical dermalinvasion (nodular growth) and forms a large brown-black patch with an irregu-lar border up to 6 cm in diameter, usually on the face or neck. Small, raisedlesions within the patch represent regions of dermal invasion. This form ofmelanoma has the best prognosis.

(2) Superficial spreading melanoma shows extensive horizontal growth with theradiating cells more atypical than those of lentigo maligna. The tumors mayform a plaque up to 3 cm with varied coloration and irregular borders. Lesionsare most commonly on legs, chest, and back; peak incidence is by age 60.

r00

Pathology

'ffi,!jq'

Figure l-7-8. Melanoma (gross).

Figure l-7-9. Melanoma (microscopic).

(3) Nodular melanoma shows extensive dermal invasion and rapid growth. Raisedbrown-black lesions may be found anywhere on the skin or mucosa. Peak inci-dence is by age 50 and has the worst prognosis of the melanomas.

c. Diagnosis. Staging is by depth of invasion, through the layers of the epidermis and

dermis. Five-year survival rates range from 10% for the deepest invasion to 100o/o forthe most superficial invasion. There seems to be a prognostic cut off at a total thick-ness of 0.7 mm. Greater than 0.7 mm causes a greater likelihood of metastasis.

t0 l


ln a Nutshell

. Bullous pemphigoid iscaused by autoantibodies todermoepidermal ju nctionantigens.

. Pemphigus vulgaris is dueto autoantibodies tokeratinocyte i ntercellu la rjunction antigens.

. Dermatitis herpetiformis is avesicular, pruritic diseaseoften associated with celiacsprue. lgA is found at thedermoepidermal junction.

d. Treatment is complete excision. Systemic disease is treated with chemotherapy orimmunotherapy with poor but variable results. Some metastic melanomas resolvespontaneously, and some relapse as internal metastases more than a decade after aseeming "cure."

E. Primary bullous disease

1. Bullous pemphigoid

a. Incidence. This disorder is uncommon; however, it occurs more frequently than otherprimary bullous disease and tends to occur after age 60.

b. Clinical features. Bullous pemphigoid causes large, tense, pruritic bullae, usually onthe lower abdomen, groin, inner thighs, and mouth. Most patients have circulatingautoantibodies against the dermoepidermal junction. The disease follows a chronicrelapsing course and is self-limited.

c. Pathology. Subepidermal bullae and a linear deposition of IgG and complement at thedermoepidermal junction on immunofluorescence is seen.

2. Pemphigus vulgaris

a. Incidence is most common from ages 40-60.

b. Pathogenesis. Autoantibodies against the intercellular junctions between ker-atinocytes cause acantholysis. The loss of intercellular connections causes an alteredcell configuration.


(1) Pemphigus starts with small vesicles, usually on the oral or nasal mucosa, thenspreads to other parts of the body. Bullae are delicate and flaccid.

(2) Nikoltky tigt is the development of bullae, caused by rubbing the skin with afinger. Pemphigus may result in erosions; secondary infections may lead to 40olomortdity. Lesions are treated with corticosteroids.

d. Pathology.Intraepidermal bullae, acantholysis, intraepidermal IgG, and complementdeposition occur.

F. Dermatitis herpetiformis

1. Incidence is most common from ages 25-30 and is often associated with gluten-sensitiveenteropathy and specific human HLA haplotypes.

2. Pathogenesis.IgA antibodyis found at the dermoepidermal junction, specifically at thedermal papillae and in the upper dermis. Some patients have circulating IgA-gluten com-plexes, which may be trapped in the skin.

3. Clinical features. There is a symmetrical distribution of grouped vesicles, often overlyingan urticarial lesion. Vesicles are intensely pruritic. Patients experience a relapsing course.

4. Pathology. Subepidermal bullae and a granular deposition of IgA and complement at thedermoepidermal junction occur.

G. Infectious diseases

1. Impetigo is a superficial skin infection, usually caused by group A p-hemolytic strepto-cocci or staphylococci. It is characterized by eroded pustules, covered by honey-coloredcrusts. Impetigo may lead to poststreptococcal glomerulonephritis.

t02

Pathology

2. Molluscum contagiosum is a poxvirus infection, causing development of multiple small,firm, umbilicated papules with a characteristic microscopic aPPearance in which viralclusters cause eosinophilic inclusions in keratinocfes.

3. Verrucre. Warts are caused by papillomaviruses, which cause epidermal hlperplasia in acharacteristic papillary configuration with hlperkeratosis and parakeratosis.

4. Superffcial fungal infections rnay be caused by Trichophyton, Microsporum, and Noh

Malassezia-lnfeaion is limited to the cornified layer of the epidermis. Tinea corooris is also known

a. Tines capitis ("cradle cap") affects the scalp in children. as tingworm', and is

b. Tinea corporis infests the trunl and extremities of children. It usually presents as actually a tunSal infeclion.

expanding round lesions with erythematous circinate borders.

c. Tinea vesicolor causes hlao- or hyperpigmented groups of macules'

d. Tinea pedis causes 'athlete's foot."

e. Tinea cruris causes 'jock itch."

f. Tinea unguium (onychomycosis) causes thickening and discoloration of the nail bed.

5. Scalded skin syndrome is a pediatric condition caused by an exfoliative toxin producedby S. aureus. The toxin splits the epidermis at the level of the stratum granulosum, caus-ing a global denudation of the skin.

H. Hnrersensitivity reactions

1. Urticaria, or hives, are usually transient, raised, pruritic, pinl wheals, charact€rized bydermal edema.

2. Rrzena is a class of very common pruritic skin disorders, characterized by distinctiveclinical and pathologic features.

a. Clinical forms

( 1 ) Atopic dermatitis is of variable and often unknown etiology; usually, there is afamily history of atopy (allergy).

(2) Contact dermatitis may result ftom allergic or irritant exposure.

(3) Lichen simplex chronicus causes chronic, lichenified plaques, probably causedby rubbing.

(4) Polymorphous light eruption is seen after ultraviolet light exposure.

(5) Drug reactions resolve when t}re offending drug is discontinued.

(6) Edoliative dermatitis describes scaling and erythema of the entle skin'

b. Pathologic types

( 1) Acute e€zema (i.e., contact dermatitis) describes edematous, oozing, red plaques,often witl vesicles and dermal inflammation.

(2) Subacute eczema (i.e., childhood atopic dermatitis) is associated with moist, redpapules and plaques with epidermal hyperplasia and derrnal inflammation'

(3) Chronic eczema. Dry, scaly plaques are present for months. Lichenification caus-es accentuated skin creases and thickened skin.

c. Tleatment. Moisturizers can be used to control the itching; oral antihistamines andtopical steroids may also be used.

t05


3. Erythema rnultiforrne

a. Pathogenesis. This may be a hnrersensitivity response to drugs (e.g., sulfonamides,penicillins), infections (e.g., herpes, mycoplasma), collagen vascular diseases, ormalignancies.

In a llubhell b. clinical features. Erythema multiforme is uncommon. There is often symmetrical

Erythema muhiforme is a involvement of the lirnbs'

hypersensitivity reaclion to ( l ) In the minor form, tlere are few lesions, no s),st€mic symptoms; and the diseasedrugs. StevensJohnson is selflirnited.syndrome is the severe form (2) In the major form (st€vels-Johnson syndrorne), there is fever, r€spiratory

difficulty, widespread skin involvement (including mucous membranes), a highrisk of sepsis, and a risk of fatality.

c. Pathology. A large erythematous papule that dwelops central vesiculation; erosion isclassic. ksions are also characterized bv edema and inflammatorv infiltration.

I. Psoriasis

I . Incidence. One percent of the population of the United States is affected. The peak inci-dence is 30 years of age, and the most common form is psoriasis vulgaris.

2. Pathogeresis. The etiology is urrknown, but there is a clear genetic component.

!1 I Nubhell Precipitants include hormonal changes, infection, and trauma. Psoriasis may also be asso-

psoriasis ciated with arthritis, enteropathy, and myopathy.

. A silvery scaly plaque that 3' clinical features of psoriasis vulgaris

primarily affecb knees , a. ksions are located throughout the body, especially on the nails, knees, elbows, andelbows, and the scalp. scalp' They usually do not involve mucous membranes-

. Hinologically, it is b. lesions are well-demarcated, coral-colored plaques with white or silver scale.

characterized by epidermal c. The Auspitz sign is seen when removal of scale results in pinpoint areas of bleeding.hyperplasia and hyper- This is characteristic of psoriasis.keratinization 4. pathologic features ofpsoriasis vulgaris

a. Hlperkeratinization with parakeratosis appears in a patc\ distribution.

b. Epidermal hyperplasia causes thickening and lengthening ofthe rete ridges, usually toa uniform depth.

c. Thinning ofthe surface epidermis, particularly over the dermal papillae, is character-istic.

5. Treatment is usually with topical steroids and ultraviolet irradiatioL Severe, systemicdisease may be treated with methotrexate.

I. Inflammatorvdisorders

l. Acne vulgaris causes comedones, papules, and c)'sts. It may be related to hormones,drugs, diet, irritants, and genetic factors. An all€rgy to Propionbacterium acnes is clearlyinvolved.

2' Pitl'riasis rosea

a. Incidence. This disorder is common, from ages 1G.-40.

b. Pathogenesis, There is a possible viral etiology.

t04

Pathology

c. Clinical features. Pityriasis rosea presents first with a "Herald patch," an approxi-mately 4-cm, red, scaling patch, followed within days by eruption in "turtle neck-shortsleeve" distribution. Lesions are small, pink, oval patches along flexural lines (fir treepattern), appearing in crops. The disease is usually self-limited (1-4 months).

3. Rosacea

a. Incidence. Rosacea is common from ages 30-50. Women are affected three times morecommonly than men, but the syndrome is more severe in men.

b. Clinical features. The lesions affect the central face. Erythema and telangiectasias,acneform lesions (i.e., papules, rysts, pustules), and rhinophyma (teleangiectasiasand hyperplasia of nasal soft tissue) are all seen in various combinations, sometimescausing a severe distortion of the face, particularly the nose.

r05

Musculoskeletal, Connective Tissu€,and lntegument Pharmacology

The nonsteroidal analgesig antipyretic, and anti-inflammatory drugs are a heterogeneous group oforganic acids, the prototype being aspirin. All aspirin-like drugs share certain therapeutic actions andside effects, but there are some distinct differences in their activities. These drugs are mild analgesisthat are effective against pain of low-to-moderate intensity, particularly in association withinflammation. They are used clinically as anti-inflammatory agents in the treatment of rheumaticdisorders and gout.

Cout results from an inflammatory response to the deposition of sodium urate crystals in the jointsand periarticular tissues. Drugs used in the treatment of gout act to inhibit synthesis of uric acid,increase the urinary excretion of uric acid, inhibit granulocyte chemotaxis to the inflammatory site, orrelieve symptoms of pain and inflammation.

SALICYTATESA. Aspirin (acerylsalicylic acid)

1. Pharmacologic properties

a. Pharmacokinetics. Oral preparations are absorbed rapidly in the stomach and smallintestine. The half-life of aspirin is approximately 3 hours.

b. Metabolism. Aspirin is hydrolyzed to salicylic acid, which binds tightly to plasma pro-teins. Seventy-five percent undergoes hepatic conjugation with glycine.

c. Preparations. Aspirin is available in buffered effervescent preparations, enteric-coat-ed preparations, and rectal suppositories.

d. Action. Aspirin relieves pain of low intensity (..g., headache, myalgias, arthralgias) byboth peripheral and central effects. Unlike opioids, no tolerance or addiction develops.It lowers elevated body temperature by inhibition of pyrogen-induced prostaglandinbiosynthesis in the CNS. It inhibits the inflammatory response by blocking the actionof cyclooxygenase (COX) and inhibiting prostaglandin synthesis. Aspirin also pro-longs bleeding time as a result of altered platelet ryclooxygenase function and inhibi-tion of thromboxane production.

2. Indications for use

a. Aspirin is used for both rheumatoid arthritis and osteoarthritis.

b. Aspirin suppresses the acute inflammatory process of acute rheumatic fever but hasno effect on disease progression.

c. Aspirin is used as an analgesic for headache, arthritis, dysmenorrhea, neuralgia, andmyalgia. It is not as effective as narcotic analgesics.

Nole

PhospholipidsI

Cortico$eroido I PhosPholiPase'&Y

Arachidonic Acid

NSAtDso i--1 \/ Cyclooxygenases \ Lipory-

/ COX-I and C0X-2 \ genases

l l \ \o| / \ lZilentonl e o I

,^glr l coxibs steroidsr/

TXA2' /

Pro$aglandins LeukotrienesReceptorsO by

-lukasls

Note

There are two types of COX.COX-I is expressed in mosttissues; C0X-2 is expressed atthe sites of inflammation.

t07


Bridge to Biochemistry

Acute toxicity of aspirin resultsin uncoupling the electrontransport chain from oxidativephosphorylation.

Note

Platelets are irreversiblyinhibited by aspirin (otherNSAIDs are reversible). Theanticoagulant effects of aspirinare thus longer lasting.

Clinical Correlate

Aspirin should not beadministered to children andadolescents with viralillnesses (because of the riskof Reye syndrome),

Note

Diflunisal has essentially noantipyretic effect since it doesnot enter the CNS.

d. Aspirin is indicated for the reduction of fever (antipyresis).

e. Aspirin is given to patients after myocardial infarctions and transient ischemic attacks(TIAs) to reduce the risk of reinfarction and stroke. It is also used in some patients forprophylaxis of thrombosis.

3. Side effects and toxicity

a. Gastrointestinal effects include gastritis with epigastric distress, nausea, vomiting,abdominal pain, and acute and chronic blood loss secondary to gastric mucosalerosion. Gastrointestinal effects are secondary to a decrease in prostaglandins, whichprotect the gastrointestinal mucosa and decrease gastric acid production.

b. Hypersensitivity syndrome may result in urticaria, rhinitis, or asthma (seen in patientswith nasal polyposis).

c. Reversible hepatotoxicity is associated with large doses in juvenile rheumatic diseasesand SLE.

d. Hemorrhage occurs secondary to altered platelet aggregation.

e. Salicylism (i.e., mild chronic intoxication) includes headache, dizziness, tinnitus,hearing loss, drowsiness, nausea, vomiting, and diarrhea.

f. Acute salirylate poisoning causes hlperthermia, dehydration, acid-base disturbances,ketosis, hypokalemia, and acute noncardiogenic pulmonary edema.

g. Aspirin may precipitate renal insufficienry, although this effect is rare.

4. Drug interactions. Aspirin increases the bleeding tendency with warfarin and heparin;increases the salicylate effect seen with acetazolamide and cimetidine; increases hypo-glycemia with insulin and sulfonylureas; increases valproic acid's effect; and blocks theuricosuric effect of probenecid.

B. Diflunisal

l. Pharmacologic properties. Diflunisal is a fluorinated derivative of salirylate, although itis not hydrolyzed to salicylate in vivo. Like aspirin, it inhibits cycloorygenase and haseffects similar to salirylic acid, but it is much more potent. Its half-life is 8-12 hours.

2. Indications for use. This analgesic is used for mild-to-moderate pain, including muscu-loskeletal pain and osteoarthritis, especially when antipyrexia is not desired.


a. Gastrointestinal effects include nausea, dyspepsia, gastrointestinal bleeding, and diar-rhea. These effects are less intense than with aspirin.

b. Other effects may include dizziness, vertigo, neryousness, insomnia, headache, and fatigue.

4. Drug interactions include an increased bleeding tendency with alcohol, warfarin, and hep-arin. Decreased diuretic and antihypertensive effects occur with thiazides and frrosemide,and an increased effect occurs with lithium toxicity.

C. Nonacetylated salicylate derivatives, like aspirin, are indicated for the treatment of pain,inflammation, headaches, and fever.

1. Sodium salicylate is probably less effective than aspirin.

2. Choline magnesium trisalicylate is a combination of choline salirylate and magnesiumsalirylate. It may have fewer gastrointestinal side effects than other salirylates. It is usefulin patients intolerant of aspirin or other nonsteroidal anti-inflammatory agents(NSAIDS).

r08

Pharmacology

3. Salsalate is converted to salirylic acid, an active metabolite. Salsalate may have an advantageover aspirin in that it causes less gastrointestinal blood loss.

D. Selective COX-2 inhibitors: cele- and rofecoxib. The primary difFerence with NSAIDs arethat they cause less gastrointestinal irritation and have less platelet anti-aggregant properties.But they increase PT when used with warfarin.

ACETIC ACID DERIVATIVES

A. Indomethacin


a. Pharmacokinetics.Indomethacin is rapidly absorbed by the gastrointestinal tract fol-lowing oral administration and reaches a peak plasma concentration in 2-3 hours. Itis 90olo plasma protein-bound.

b. Metabolism. Indomethacin is converted to inactive metabolites in the liver.

c. Action. This drug has potent anti-inflammatory, analgesic, and antipyretic action. Itinhibits prostaglandin-forming rycloorygenase and inhibits the motility of polymor-phonuclear leukocytes. It inhibits leukocyte phagocytosis of the sodium urate crystalsby blocking migration of these cells to the site of inflammation.


a. Indomethacin is used as an analgesic and antipyretic, but the high incidence andseverity of side effects limits its routine use for mild symptoms.

b. Its main use is for moderate-to-severe rheumatoid arthritis, osteoarthritis, ankylosingspondylitis, and Bartter syndrome. It is also indicated for tendonitis, bursitis, acutegout, dysmenorrhea, and is the drug of choice for Reiter syndrome.


a. Gastrointestinal effects are the same as for aspirin.

b. Central nervous system effects include headache, dizziness, vertigo, depression,psychosis, hallucinations, and seizures.

c. Hematologic effects include neutropenia, thrombocytopenia, aplastic anemia, andimpaired platelet function.

d. Other effects include hypersensitivity (e.g., rash, urticaria, asthma), pancreatitis, hepato-toxicity, exacerbation of renal insufficienry, and salt retention.

e. Indomethacin is contraindicated during pregnancy and in patients with epilepsy, renaldisease, or peptic ulcer disease.

4. Drug interactions. It reduces the antihypertensive effect of furosemide, thiazides, p-blockers, captopril, and prazosin. It increases lithium levels and prolongs the half-life ofdigoxin in neonates and possibly adults.

B. Sulindac


a. Pharmacokinetics. Ninery percent is absorbed after oral administration. It has a longhalf-life, which allows twice-daily dosing.

Clinical Correlate

Indomethacin is thedrug of choice forclosing a patent ductusarteriosus in a neonate.

t09


b, Met&bolism. Sulindac undergoes oxidation-reduction reactions to form an activesulfide metabolite. Its metabolites are excreted in urine and feces,

c. Action. Sulindac is structurally similar to indomethacin but less than half as potent.There is no anti-inflammatory activity until it is absorbed and metabolized to itssuifide form.

l. Indications for use include rheumatoid arthritis, osteoarthritis, antylosing spondylitis,and acute gouty arthritis.

3. Sid€ eff€cts and toxicitv

a. Gastrointestinal effects include abdominal pain, nausea, and constipation. It hasfewer side effects tlan aspirin. There is an increased risk of gastrointestinal bleedingwhen used witl warfarin and other anti-inflarnmatory drugs.

b. Central n€rvous system effects include drowsiness, dizziness, headache, andnervousness.

c. Odrcr effects include hlpersensitivity reactions (e.g., skin rash, pruritus) and blooddyscrasias. Exacerbations of renal insuffrciency and treated hlpertension are botl lessIikely than with other agents. The main advantage of sulindac over indomethacin is itslack of nephrotoxicity.

C. Tolrnetin

t. Pharrnacologic properties

a. Pharmacokinetics. Tolmetin is completely absorbed after oral administration with aplasma ha.lf-Iife of I hour and requires frequent dosing to maintain therapeutic levels.It is 99% bound to plasma proteins.

b. Maebolism. Tolmetin is excreted in conjugated and unchanged forms in the urine.

c. Action. Tolmetin is more potent than aspirin but l€ss potent than indomethacin.

l' llJ#frftlse include adult and juvenile rheumatoid artluitis'

a. Gastrointestinal side effects are most common, alttrough less than withindomethacin.

b. OtJrer less common effects include hepatotoxicity, renal toxicity, and hypertension.

D. Nabumetone may cause less gastric irritation than indomethacin or naproxen. It exhibitssignificantly lower gastrointestinal blood loss than aspirin.

PROPIONIC ACID DERIVATIVESA. Ibuprofen

l. Pharrnacologic properties

l!* ;]tr--,*Tffitriiii"'*il:,Tli:,'$x1L"f;.Tiitlil.T:'L1*::#f";lbuprofen has greater

dosing four times daily to maintain steady-state plasma levels'

analgesic potency than both b. Metabolism.It is excreted in urine as hydrorylated and carboxylated compounds.

aspirin and acetaminophen. c. Action.Ibuprofen has analgesic, antipyretic, and anti-inflammatory actions.

l. Indications for use include dysmenorrhea, musculoskeletal disorders, rheumatoid arthritis,and osteoarthritis.

il0

Pharmacology

3. Side eff€cts and toxicity

a'Ibuprofenhasfewergastrointestinalsideeffectsthanaspirinorindomethacin

b. Other effects indude thrombocytopenia, skin rashes, dizzines, headache, blurred :vision, tinnitus, and exacerbation of renal insufficiency.

B. Napro)(€n

1. Pharmacologic properties l!9!!

a. Pharmacokinetics. Naproxen is fully absorbed after oral administration. It has aplasma halfJife of I2-I5 hours and ii ee% bound to plasma proteins. itljfrfiffi: f:::ff"

b. Metabolisrn, It is excreted in urine unchanged and as glucuronide conjugates. their long half-lives, whic}

c. Action. Naproxen has potent analgesic activity in both rhzumatic and nonrheumatic allow for les frequent dosing.conditions.

2. Indications for use include moderat€-to-severe postoperative pain (e.g. orthopedicsurgery dental surgery), postpartum uterine cramps, acute musculoskeletal disorders,rheumatoid arthritis, osteoarthritis, anJsylosing spondylitis, dpmenorrhea, and acute goul

3. Side effects and toxicitf

a. Gastrointestinal effects include heartbum, dyspepsia, nausea, vorniting, and gastricbleeding.

b. Central nervous s)'stem side effects include headache, dizziness, ototoxicit)r, dq>ression,and blurred vision.

c. Exacerbation of renal insuffciency may also orcur.

PYRAZOTONE DERIVATIVESA. Pheny'butazone


a. Pharmacokinetics. Phenylbutazone is completely absorbed from the gastrointestinal :tract after oral administration.

b. Action. It inhibits prostaglandin biorynthesis, causing prominent anti-inflammatoryeffects, although it is not as good an analgesic or antipyretic as the salicylates.Usefulness as an analgesic and antipyretic agent is limited by the high incidenc.e oftoxicity.

2. Indications for use. Phenylbutazone has a limited role in treatment. It is not a drug ofchoice because of its toxicity and should not be administered long-term. Nonetheless, itis usefirl as a secondary agent in acute gout and rheumatic disease.

3. Side €ffects and toxicit)'

a. Gastrointestinal effects include nausea, vomiting, gastritis, diarrhea, and pqrtic ulcer-atron,

b. Other effects include electrolyte and water retention with edema formation, rashes,aplastic anemi4 agranulocposis, and rarely, thrombocytopenia.

c. Contraindications include cardiac, renal, or hepatic dysfunction; peptic r.rlcer disease;hypertension; and blood dyscrasias.

4. Druginteractions, Phenylbutazone displaces other anti-inflamrnatory drugs, oral antico-agulants, sulfonamides, and oral hypoglycemics from plasma proteins. It may inhibit or

i l t


accelerate hepatic metabolism of other drugs. An increased anticoagulant effect is seenwith warfarin.

B. Oxyphenylbutazone is an analog (an active metabolite) of phenylbutazone. Significantaccumulation of oxyphenylbutazone during chronic administration of phenylbutazone con-tributes to the toxic effects of the parent drug.

1. Pharmacologic properties. There is slow urinary excretion of the glucuronide conjugate.Pharmacologic effects are similar to those of phenylbutazone.

2. Indications for use are the same as for phenylbutazone.

3. Side effects and toxicity are also the same as phenylbutazone.

OTHER NSAIDSA. Mefenamic acid


a. Pharmacokinetics. Mefenamic acid is rapidly absorbed after oral administration.Peak plasma concentrations occur in 2 hours with a plasma half-life of 3-4 hours.

b. Metabolism. Fifty percent is excreted in the urine as conjugated metabolites, and20o/ois excreted in feces as unconjugated metabolites.

c. Action.Its anti-inflammatory potency is half that of phenylbutazone. Analgesia is pro-

duced by central and peripheral actions.

2. Indications for use include rheumatic conditions, soft tissue iniuries, musculoskeletaldisorders, and dysmenorrhea.


a. Gastrointestinal side effects are seen in 25o/o of patients and include dyspepsia, diar-rhea, colitis, and gastrointestinal ulceration.

b. Other effects include autoimmune hemolytic anemia with long-term use, and exacer-bation of renal insufficiency.

4. Drug interactions include an increased prothrombin time (PT) with warfarin and adecreased hypoglycemic effect with insulin.

B. Piroxicam


a. Pharmacokinetics. There is rapid oral absorption with peak concentrations inplasma in 3-5 hours. There is enterohepatic circulation; therefore, the half-life isapproximately 45 hours, allowing once-a-day dosing.

b. Metabolism. Ten percent is excreted unchanged in the urine, while some metabolitesare excreted in the urine as well.

c. Action. Piroxicam has a similar anti-inflammatory efficacy as aspirin andindomethacin.

2. Indications for use include rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

3. Side effects and toxicity include gastrointestinal effects similar to other NSAIDs.

i l2

Pharmacology

NONOPIOID ANATGESICS AND ANTIPYRETICSA. Acetaminoph€n

r- pharmacologicproperties !!!1|91!9q!1?.Qa. Pharmacokinetics. Acetaminophen is rapidly absorbed ftom tle gastrointestinal tract Acetaminophen, rather than

following oral administration. Peak plasma values are reached in I hour with a half- asoirin. is the antiovretic oflife of l-4 hours. chotce in children with viral

b. Metabolism. It is metabolized by hepatic microsomal enzymes with extensive first- illneses (no risk of Reyepass degradation. Most (90-1009o) is recovered in the urine within 24 hours after hep- syndrome), for patien$ onatic conjugation with glucuronic acid, su.lirric acid, and cysteine. anticoagulanb, and for Sout

c. Action, Acetaminophen is an effective alternative to aspirin as an analgesic and pa(en6 0n uncosunc agens'

antipyretic, but it has very weak anti-inflammatory activity. It is a weak inhibitor ofperipheral prostaglandin biosynthesis and therdore does not affect platelet function.

2. Indicatioas for use include analgesia and antipyrexia, especially when aspirin is con-traindicated. Note that acetaminophen does not have an anti-inflammatory action.

3. Side effects and toxicitf

a. Acetaminophen can cause a dose-dependent hepatic necrosis, r€nal tubular necrosis, ltl*and hypoglycemic coma'

AcetaminoDhen overdose isb. Acute poisoning results in nausea, vomiting, anorexia, and abdominal pain. Severe treated with /V-acetylcysteine,

hepatic damage may develop after 2448 hours from a toxic metabolite. lvtrich helos to reolenishHepatotoicity is decreased if N-acetylqnteine is given within 24 hows ofpoisoning. depleted glutathione stores

B. phenacetin in the liver.


a. Pharmacokinetics. Most of this drug is rapidly metabolized to acetaminophen fol-lowing oral administration.

b. Action, Analgesic, antipyretic, and anti-inflammatory activity is similar toacetaminophen.

2. Indications for use, Phenacetin is not in clinical use because of its toxicity.

3. Side effects and toxicit"

a. Phenacetin causes renal tubular necrosis and chronic renal insufficiency.Methemoglobinemia and hemolytic anemia are also seen in individuals who have alimited ability to convert phenacetin to acetaminophen.

b, Overdose may caus€ cyanosis, respiratory depression, and cardiac arrest.

OTHER ANTIRHEUMATIC AGENTSA. Disease nodifying anti-rheumatic drugs (DMARDs) slow disease progression and may be

used with NSAIDS initially. Hydrorycbloroquine and methotrexate are used for mild andsevere rheumatoid arthritis, respectively. However, new agents targeting tumor necrosis fac-tor (TNF) are curative for refractory cases and can be used in combination. These include:

1. Etinerc€pt which binds TNF (recombinant TNF receptor)

2. Infliximab, a monoclonal antibody to TNF

3. Ieflunomide, a dihydroorotic acid dehydrogenase inhibitor which inhibits lymphocytes' rdivision and maturation

i l5


Bridge toGenegl Principles

Penicillamine is used in thetreatment of Wilson diseaseand primary biliary cirrhosis. ltis discussed in the LeadToxicity and Chelating Agentschapter of Ceneral PrinciplesBook z (Volume ll).

Bridge toGeneral Principles

The antineoplastic uses ofmethotrexate are discussed inthe Antineopla$ic Agentschapter of Ceneral PrinciplesBook z (Volume ll).

B. Gold


a. Pharmacokinetics. Gold can be administered intramuscularly (e.g., aurothioglucose,gold sodium thiomalate) or orally (e.g., auranofin).

b. Action. Gold inhibits macrophage functioning, including migration and phagocyto-

sis. There is no antipyretic or analgesic effect.

2. Indications for use. Gold is indicated in rheumatoid arthritis unresponsive to NSAIDs. It

is most effective taken early in rapidly progressive diseases.

3. Side effects and toxicity. Most of the following effects, except gastrointestinal effects, areless likely to occur with oral auranofin than with intramuscular preparations.

a. Gastrointestinal disturbances are more common with auranofin, especially diarrhea.

b. Skin effects include erythema, dermatitis, and chrysiasis (grayish-blue skin pigmenta-

tion).

c. Mucocutaneous effects include oral ulcers, stomatitis, gastritis, and colitis.

d. Renal effects include proteinuria and a reversible nephrosis.

e. Hematologic effects include thrombocytopenia,leukopenia, aplastic anemia, agranu-locftosis, and eosinophilia.

C. Penicillamine is classed as a chelating agent. Penicillamine decreases bone destruction in

rheumatoid arthritis. Its mechanism of action is unknown but may be related to inhibition ofcollagen formation. Severe side effects limit its use.

D. Chloroquine and hydroxychloroquine are antimalarial agents. Although these drugs haveanti-inflammatory actions, serious side effects limit their use. The mechanism of action is

unknown.

E. Methotrexate is used primarily as an antineoplastic agent, although it is now approved fortreatment of refractory rheumatoid arthritis. Because of the much lower doses used inarthritis, side effects are less severe than in cancer therapy. Side effects include hepaticchanges and pneumonitis.

TREATMENT OF ACUTE GOUTNSAIDs are often preferred in the treatment of acute gout. Although they are as efficacious ascolchicine, symptomatic improvement takes longer. Indomethacin is most commonly used, butnaproxen and sulindac may also be employed. Salirylates, such as aspirin, are not used if goutis being treated with probenecid or sulfinpyrazone because salicylates inhibit the uricosuriceffect of these drugs.

A. Indomethacin (discussed earlier in this chapter)

B. Colchicine


a. Mechanism of action. Colchicine interferes with microtubules, thus preventing themigration of granulocytes to the inflammatory site. It has no uricosuric effects.

b. Routes of administration. Colchicine may be given orally, which causes greater gas-

trointestinal toxicity and a slower onset of action, or intravenously, which has a smallchance of anaphylaxis.

i l4

Pharmacology

2. Indications for use. Colchicine is used to treat acute attacks of gout, especially whenNSAIDs are not tolerated. It is also given prophylactically to prevent recurrent episodes ofacute gout.


a. Gastrointestinal effects include nausea, vomiting, abdominal pain, and diarrhea,which may necessitate discontinuation of the drug.

b. Effects of long-term use and high doses include blood dyscrasias (i.e., aplastic anemia,thrombocytopenia, agranulocytosis), alopecia, neuropathy, myopathy, and hemor-rhagic gastroenteritis.

TREATMENT OF HYPERURICEMIAA. Allopurinol


a. Mechanism of action. Allopurinol is an analog of hypoxanthine that inhibits the con-version of hpoxanthine to uric acid by xanthine oxidase. It lowers both serum andurinary concentrations of uric acid.

b. Pharmacokinetics. Allopurinol is well absorbed orally and metabolized to oxypuri-nol, a xanthine oxidase inhibitor with a half-life of 30 hours.


a. Allopurinol is the drug of choice for most patients with severe hnreruricemia,whether due to gout or other conditions.

b. Acute attacks of gout

(1) If a patient is on allopurinol, it should be continued.

(2) If therapy is to be initiated, it should be delayed until several days after the acuteepisode has resolved and the patient is on maintenance doses of colchicine.


a. Side effects include nausea, diarrhea, and hypersensitivity (e.g., rash, fever, exfoliativedermatitis).

b. Less common side effects include blood dyscrasias, hepatotoxiciry and peripheralneuropathy.

4. Drug interactions. The dose must be reduced in the presence of renal insufficienry.Allopurinol may inhibit the metabolism of oral anticoagulants and have increased toxicitywhen used with thiazide diuretics. The dosage of mercaptopurine, an antineoplastic that ismetabolized by xanthine oxidase, must be lowered when administered concomitantly withallopurinol.

B. Probenecid

l. Pharmacologic properties

a. Mechanism of action. Uricosuric agents are organic acids that compete with otheracids (including uric acid) at anionic transport sites in the renal tubule. Low doses ofuricosuric drugs may selectively inhibit tubular secretion of uric acid and cause someretention of urate. However, at therapeutic doses their predominant effect is to blockuric acid reabsorption in the proximal tubule, thereby increasing the urinary excretionof urate.


Allopurinol, meaning "anotherpurine," is also a prodrug thatis taken by HGPRTase andmade an allopurinalnucleotide. This in turn inhibisPRPP amidotransferase, therat*limiting $ep of de novopurine synthesis, resulting inless purines made. Therefore,less is degraded to uric acid.

Note

Allopurinol can raise serumlevels of some antimetabolites(e.g., azathioprine) byinhibiting their breakdown.

Note

Allopurinol decreases bothserum and urineconcentrations of uric acid,while probenecid decreasesserum levels but increasesurine levels.

i l5


Note

The secretion of other weakacids, e.g., penicill ins,caphalosporins, is reduced byprobenecid, thus increasingtheir half-lives.

In a Nutshell

Drugs Used to Treat Gout

. Colchicine -+ inhibitsgranuloryte migration byinterfering withmicrotubules

. Allopurinol --> inhibitsconversion of hypoxanthineto uric acid by xanthineoxidase

. Probenecid -+ blocks uricacid reabsorption in theproximal tubule(uricosuric)

. Sulfinpyrazone + increasesurinary excretion of uricacid

. NSAIDs + relievesymptoms of pain andinflammation

b. Pharmacokinetics. Probenecid is completely reabsorbed in the nephron, metabolizedslowly, and excreted in urine. The metabolic byproducts are also uricosuric.


a. Probenecid is used when allopurinol is not well tolerated.

b. During acute attacks, probenecid should be continued if the patient is on maintenancetherapy but should not be initiated until the acute attack has subsided.

c. It may also be used to prevent penicillin elimination and raise its serum level.


a. Gastrointestinal effects include nausea and abdomin"l puitt.

b. Hypersensitiviry including rash and fever, may occur.

c. Renal calculi may occur. It should not be used in patients who excrete large amountsof urate. Patients should be instructed to maintain a high fluid intake to help preventstone formation.

d. Nephrotic syndrome and peptic ulceration may occur in rare instances.

e. Hemolytic anemia may occur in patients with glucose-6-phosphate dehydrogenase(G6PD) deficiency.

f. Severe overdoses can cause seizures or fatal respiratory depression.

C. Sulfinpyraznne

1. Pharmacologic properties. Sulfinpyrazone is a derivative of phenylbutazone. Ninetypercent is excreted unchanged in the urine.

2. Indications for use. Use for gout is similar to that of probenecid. It may also be used toinhibit platelet aggregation because of its inhibitory action on prostaglandin synthesis.


a. Gastrointestinal symptoms are more common with sulfinpyrazone than withprobenecid, although gastrointestinal ulceration is uncommon.

b. Other side effects include rash and renal calculi formation.

c. Although the parent compound, phenylbutazone, may, in rare instances, cause blooddyscrasias and volume overload, these side effects have not been reported withsulfinpyrazone.

4. Drug interactions. Sulfinpyrazone potentiates the effects of insulin, sulfonylureas, sul-fonamides, and warfarin.

I t6

SECTION II

Gastrol ntestl na I System

Gastrointestinal Embryology

The primitive gut is formed as a result of cephalocaudal and lateral foldings of the embryo. lt isanatomically divided into the foreguf midgut, and hindgut. The cranial foregut, from thebuccopharyngeal membrane to the laryngotracheal groove, is covered in the chapter on thepharyngeal arches and their derivatives in the Ceneral Principles review book. The remainder of the ;primitive gut and its derivatives are reviewed here. Epithelium and glands of the ga$rointe$inal tract iand biliary systems, and the parenchyma of the liver and pancreas, are derived from primitive gut ,endoderm. The muscles, connective tissue, and blood vessels of the gut wall are derived from isplanchnic mesoderm. Epithelial linings of the mouth and lower onethird of the anal canal arise from Ithe ectoderm of the $omodeum and proctodeum, respectively.

FOREGUT DERIVATIVESA. Esophagus

1. The esophagus extends from the respiratory diverticulum to the stomach. It becomeselongated with the ascent of the pharynx and descent of the heart and lungs.

2. The upper two-thirds of the esophagus contain striated muscle derived from pharyngealarches and innervated by the vagus nerve. The lower one-third contains smooth musclederived from splanchnic mesoderm and innervated by the splanchnic plexus.

B. Stomach

1. The stomach appears in the fourth week as a dilatation of the foregut. During develop-ment, the stomach rotates 90" clockn'ise, making its left side anterior and its right sideposterior.

a. The left side is innervated by the left vagus nerve.

b. The right side is innervated by the right vagus nerve.

2. The caudal, or pyloric, part of the stomach moves upward to the right while the cephaliccardiac region moves downward to the left.

3. The greater and lesser curvatures of the stomach arise by unequal growth of its two sides.

a. The posterior part grows faster than the anterior part and forms the greatercurvature.

b. The anterior part forms the lesser curvature.

il9

Gasfrointestinal System

C. Duodenum

1. The duodenurn is formed by the terminal portion of the foregut and cephalic portion ofthe midgut. This junction is located just distal to the origin of the liver bud.

2. With the rotation of the stomach, the duodenum becomes U-shape4 is pulled to the right,and comes to li€ rctroperiton€ally.

3. The duodenum is supplied by both the celiac and superior mesenteric arteries.

D. Liver and gallbladder

1. The hepatic diverticulum (liver bud) appears as rapidly proliferating endodermal epithe-lial cords at the distal foregut in the middle of the third week.

2, As the liver cords penetrate the septum tranwersum, the connection between the hepaticdiverticulum and foregut (duodenum) narrows to form the bile duct. A ventral growth ofthe bile duct gives rise to the gallbladder and cystic duct.

3. Later in development, liver cords intermingle with vitelline and umbilical veins to formhepatic stnusoids.

4. Hematopoietic cells, Kupffer cells (macrophages) of the mononuclear phagocyte system'and connective tissue stroma (including the fibrous capsule of the liver) are mesodermalderivatives.

5. Bv the 10th week, nests of cells, which produce red and white blood cells, are foundbetween the hepatic cells and the vessel tnat. n formation of blood cells in the liverdeclines during the last 2 months of intrauterine life,

6. Liver cells begin to secrete bile during the l2th week

E. Pancreas begins as two endodermal duodenal buds. The dorsal and ventral pancreas andducts anastomose. The ventral duct remains as the connection to the duodenum. Thedorsal duct either degenerates or remains as the small accessory pancreatic duct.

MIDGUT DERIVATIVESA Primary intestinal loop. Rapid growth of the primary intestinal loop, combined with

reduced space within the abdominal cavity due to expansion of the liver, necessitates its her-. niation into the extraembryonic coelom of the umbilical cord during the sixth week of. dwelopment. Elongation of the small intestines results in the formation of the coiled loops

of the jejunum and ileum. The large intestine from the distal part of the ileum to the proxi-mal two-thirds of the transverse colon remains uncoiled.

B. Intestinal rot tion- Within the umbilical cord and during intestinal re-entry into theabdominal cavity in the 10th week, the intestin€s rotate a total of 270' counterdockwisearound the axis of the superior mesentedc artery.

1. Upon re-entry, tle proximal part of the jejunum comes to lie high on the left side, withthe later-retuming loops taking up positions more to the right.

2. Last to enter is the cecal swelling, which, because of the 270o rotation, lies in the rightupper region in close contact with the right lobe of the liver.

a. The cecal swelling gives ris€ to the cecum and the appendir

b. When the cecum and appendix descend t}te descending colon and hepatic flexure areformed.

C. 'Fixation'' of the midgut occurs as tlle mesenteries of the intestines firse with the parietalperitoneum of the posterior abdominal wall.

t20

Embryology

HINDGUT DERIVATIVESA. The cloaca is an expanded terminal portion of the hindgut, which is in direct contact with

ectoderm at the cloacal membrane. The ectodermal depression at the cloacal membrane isthe proctodeum.

B. A urorectal septum grows caudally in the angle between the allantois and the hindgut. Itspoint of fusion with the cloacal membrane is the perineum. The urorectal septum dividesthe cloaca into an anterior urogenital sinus and a posterior anorectal canal, and thusdivides the cloacal membrane into the urogenital membrane and the anal membrane.

C. The anal membrane ruptures at about the ninth week, resulting in a direct continuitybetween the endodermally derived anorectal canal and the ectodermally derived proc-todeum (anal pit).Thepectinateline marks the location of this transition.

Amniotic cavity (AM)

Yolk sac (YS) Pharyngealpouches

1Stomach

Hepaticdiverticulum

Gall bladderYolkstalk

Vitellineduct

Allantois

Cloaca

Esophagus

bud

Foregut

f,illdgut

Goelom Ventralpancreaticbud

Celiacartery

Gut tube Inferior Superiormesenteric mesentericartery artery

Dorsalpancreaticbud

Figure Il-1-1. Foregut, midgut, and hindgut with ventral and dorsal mesenteries.

r2l

Gastrointestinal System

Thble II-1-1. Primitive gut derivatives.

Borders Organs Included Blood Supply

Foregut Buccopharyngeal membraneto anterior intestinal portal

Midgut Anterior intestinal portalto posterior intestinal portal

Hindgut Posterior intestinalportalto cloacal membrane

Pharynx, esophagus,stomach, part of duodenum,liver, gallbladder, pancreas

Distal duodenum, jejunum,

ileum, cecum and appendix,ascending colon, proximaltwo-thirds of transverse colon

Distal one-third of tranversecolon, descending colon,sigmoid colon, rectum,upper two-thirds ofanal canal

Celiac artery

Superiormesentericartery

Inferiormesentericartery

CONGEN ITTIT MATFORMATION SA. Atresias, stenoses, and duplications may occur anywhere along the alimentary tract and

often are due to incomplete recanalization following epithelial proliferation and lumen

obliteration.

1. In cases of atresia, a thin diaphragm remains across the lumen.

2. Stenosis is marked by a distal narrowing and proximal distention.

3. Duplications may contain mucosa that is very different from that in the segment of origin.

B. Pyloric stenosis is a narrowing of the pyloric lumen, which is due to hlpertrophy of circu-

lar smooth muscle in the pyloric region of the stomach. Patients present 1-3 weeks after

birth with projectile vomiting, constipation, and weight loss. Treatments include diet man-agement, administration of antispasmodics, and surgical longitudinal incision through thehypertrophied muscle. It is more common in males.

C. Atresia of the gallbladder and bile ducts causes persistent occlusion of the gallbladder orbile ducts. Patients present soon after birth with steadily increasing jaundice, clay-coloredstools, and very dark-colored urine.

D. Annular pancreas is an encirclement of the duodenum by pancreatic tissue, which is due to

abnormal movement of part of the ventral pancreas to the right of the duodenum rather

than to the left.

E. Remnants of the vitelline duct

1. Meckel diverticulum is an ileal outpocketing, which may contain gastric and pancreatic

tissue. It may become inflamed and cause symptoms like those of appendicitis.

2. Umbilical or vitelline fistula is a patent vitelline duct, which allows communicationbetween the umbilicus and the intestinal tract.

F. Omphalocele is due to failure of all or part of the intestines to return from the umbilical

cord into the abdominal cavity. The viscera outside the abdominal cavity are then coveredonly by the amnion.

122

Embryology

G. Congenitd umbilical hernia is a herniation of the viscera through a weakened part of theabdominal wall where it is not closed completely. Occurring during the fetal period, the sacformed has no muscle or skin and may tear during delivery.

H. Malrotation may result in the colon and cecum re-entering the abdominal cavity first andsettling on the left. In cases of reversed rotation, the transverse colon passes behind the duo-denum rather than in front of it.

I. Congenital megacolon (Hirschsprung disease) is a constriction of a portion of the colonthrough which the intestinal contents are not moved. It is attributable to the absence ormarked reduction of parasympathetic ganglion cells in that area to which neural crest cellshave failed to migrate. As a result, the segment of the gut proximal to the constricted areabecomes distended. Symptoms include failure to pass meconium and distention of theabdomen. Tieatment is surgical excision of the distal bowel. It is more common in males.

L Imperforate anus may be due to failure of the anal membrane to rupture.

l2t

Gastrointestinal Histology

The gastrointe$inal (alimentary) sy$em consi$s of the dige$ive tract and its associated glands.Beginning in the oral cavity, the tract continues as the pharynx, esophagus, stomach, small intestine,large intestine, rectum, and anal canal. The large glands, consi$ing of the salivary glands, pancreas,liver, and gallbladder, lie outside the dige$ive tract but are connected to it via their ducts. The entiretube is lined by mucosa, or mucous membrane, which consists of a lubricated epithelium with anunderlying thin layer of cellular and vascular connective tissue called the lamina propria that isgenerally surrounded by muscular mucosae.

NoteORAT CAVIIYA. Mucosa of the oral cavity and of the pharynx are similar. il:-Hi#g

|}ffil}-^

l. The qrithelium of the oral cavity is mosdy nonl<eratinized stratified squamous that squamous epithelium, exceptbecomes keratinized at the lips. It provides a tight and flexible barrier. for the ma$icatory mucosa

2. The lamina propria consists main.ly of dense connective tissue with many elastic fibers. It lelneiva;hard palate), which

interdigitates witi tJre epithelium, forming prominent connective tissue papillae that con- ls Keraflnlzed'

tain blood vessels and lymphatics.

3. Scattered glandular acini release lubricating mucous secretions onto the epithelial surfacevia short ducts. These secretions contain immunoglobulin A (IgA) antibodies.

4. The submucosa is rich in adipose cells and mucous glands. In hard surfaces like the palate,there is no submucosa, and the tough lamina propria rests direcdy on the periost€um.

B. T&th are composed of a core of pulp surrounded by a mineralized dentin, which is coveredby a mineralized enamel on the crown and a mineralized cementurn on the root. Each toothis anchored in a socket of alveolar bone by the periodontal membrane (ligament).

1. Pulp cayitl is the central cavity of the tooth.

a. It is composed of a pulp chamber in the crown and upper root and a root canal in tltelower root. which contains nerves and blood vessels.

b. Tooth pulp is loose connective tissue that has a mesenchymal appearance and anabundant ground substance.

t25


ln a Nubhell

Enamel

. The hardest component ofthe human body and therichest in calcium

. Secreted by ameloblasts

. Cannot be repaired orreplaced without clinicalintervention

Clinical Correlate

In scurvy, vitamin C deficiencycauses defects in collagensynthesis. Because periodontalmembrane depends on a highrate of collagen renewal,atrophy of the membraneensues. The teeth thenbecome loose in theirsockets and fall out.

2. Enamel is the hardest substance of the body, being approximately 97o/o calcium salts bydry weight.

a. The enamel matrix is secreted by cells of ectodermal origin called ameloblasts; othertooth components are derived from ectomesenchyme.

(1) The organic matrix secreted by ameloblasts becomes minerahzed early in toothformation prior to eruption.

(2) Ameloblasts die and are lost after the enamel is fully formed, and the tooth eruptsinto the oral cavity. For this reason, enamel cannot be repaired or replaced by thebody.

b. Enamel is organized into prisms (i.e., hexagonal rods) held together by a calcifiedcementing substance.

3. Dentin is approximately 70o/o mineralized.

a. Dentin is also composed of collagen and proteoglycans.

b. The organic matrix is synthesizedby odontoblasts that line the internal surface of thedentin and separate it from the pulp cavity.

c. Odontoblast processes extend to the dentin-enamel junction (DEI) through microscopiccanals called dentinal tubules, which run approximately perpendicular to the DEI.

4. Cementum is a calcified tissue similar to bone that covers the dentin of the root. Two vari-eties are present: cellular and acellular.

a. In cellular cementum, cementocytes are encased in a mineralized matrix within lacu-nae, which intercommunicate via canaliculi.

b. In acellular cementum, cementocytes are lacking.

c. Like bone, cementum is labile, and local stresses cause reabsorption, which requiressubsequent cementum production.

5. Periodontal membrane (ligament) is a specialized dense connective tissue that binds thetooth to the bony walls of the alveolar socket. It continues at the socket with the perios-teum of bone.

a. On the tooth side, the fibers are anchored in the cementum.

b. On the socket side, the fibers are embedded in the bone tissue.

6. Alveolar bone, extensions of the maxilla and mandible, form the sockets of the teeth. Thisbone has an immature appearance,lacking the typical lamellar pattern of adult bone.

7. Gingiva (gum) is a mucous membrane firmly bound to the bone by a dense fibrous con-nective tissue.

a. It is covered by a stratified squamous epithelium that is usually keratinized.

b. At the interface with the teeth, this epithelium also attaches to tooth enamel by meansof its basement membrane.

C. Tongue

1. The bulk of the tongue consists of striated skeletal muscle covered by the oral mucosa.

a. The muscle fibers are arranged in all three planes, resulting in maximum movement.

b. The fibers are grouped in bundles separated by connective tissue.

2. Thste buds are found on the tongue, as well as in the epiglottis, pharynx, and palate.

t26

Histology

3. Dorsal surface. The anterior two-thirds of the tongue on its superior surface is markedby three different types of mucosal elevations, or papillae.

a. Filiform papillae, the most numerous, are elongated cones that give the tongue its roughsurface. Th.y do not contain taste buds and are keratinized at the superior surface.

b. Fungiformpapillae are mushroom-shaped structures that are scattered among the fil-iform papillae and frequently contain taste buds.

c. Vallate (circumvallate) papillae are large circular and flattened papillae that are sur-rounded by moat-like invaginations.

(1) There are 7-12 cirumvallate papillae arranged in a V-shaped configuration onthe posterior part of the tongue.

(2) The lateral surfaces contain numerous taste buds. Serous glands empty into themoat-like furrows that surround each papilla to maintain a continuous flow offluid over the taste buds.

4. Lateral surface. On the posterolateral borders of the tongue, rudimentary foliate papillaealso contain taste buds.

5. Ventral (inferior) surface of the tongue is characterized by a well vascularized mucosawith a thin, smooth nonkeratinized epithelium. For this reason, sublingual administra-tion of certain drugs is used.

PHARYNXA. Posterior to the oral caviry the pharynx is situated between the oral cavity and the digestive

and respiratory systems. It provides the communication between the nasal region and thelarynx. The pharynx contains the palatine (oropharynx) and pharyngeal (nasopharynx)tonsils.

B. A transition in its mucosa can be observed from stratified, squamous, nonkeratinized to cil-iated, pseudostratified, columnar epithelium. Tiansitional zones of stratified columnarepithelium are also seen.

C. The lamina propria is rich in elastic fibers and tightly binds the mucosa to the muscularis.

ESOPHAGUSThe esophagus is a nearly straight muscular tube that functions as a rapid conduit from themouth to the stomach.

A. Mucosa of the esophagus consists of thick, stratified, squamous, nonkeratinized epithelium.

1. The lamina propria is made of dense, elastic, connective tissue. Mucous glands are occa-sionally found near the stomach (esophageal cardiac glands).

2. The muscularis mucosae consists mainly of longitudinal smooth muscle fibers and isthicker closer to the stomach.

B. Submucosa of the esophagus forms longitudinal ridges when the tube is contracted. It con-tains sero-mucous glands (esophageal glands proper).

C. Muscularis externa of the esophageal wall is composed of two thick layers.

1. In the upper third of the esophagus, both layers are striated muscle.

2. Throughout the middle third, striated and smooth muscle fibers are mixed.

Note

The pharynx extends from thebase of the skull to the originof the esophagus and isapproximately 6 inches inlength. lt serves as atransitional area between theoral cavity and the respiratoryand digestive systems.

127


ln a Nutshell

Esophagus. Proximal end: striated

muscle. Mid portions: mixture of

smooth and striated muscle. Distal end: smooth muscle

Note

Rugae (stomach ridges) aretransient folds of the mucosaand submucosa that arepresent in the empty stomachbut disappear in thedistended stomach.

3. In the lower third, only smooth muscle is present.

4. Circular bundles of smooth muscle serve a sphincter-like function at the lower end of theesophagus (lower esophageal sphincter, LES).

5. Recent studies show that the esophageal musculature has a dual innervation with bothvoluntary and involuntary components.

STOMACHThe stomach is a muscular expansion of the digestive tube in which food is stored and mixedwith hydrochloric acid (HCl), mucus, water, and proteolytic enzymes to form chyme.

A. Mucosa consists of surface epithelium, lamina propria, tubular glands, and muscularismucosae.

1. Surface epithelium is composed of simple, columnar, mucus-secreting cells that are peri-odic acid- Schiff ( PAS)-positive.

2. The epithelium is invaginated into the lamina propria, forming l-5-mm gastric pits.

3. A large number of tubular glands enter into the bottom of these pits and exhibit varia-tions according to the region.

4. Gastric mucosa cells turn over rapidly, and the whole surface is replaced every 3 days.

5. Muscularis mucosae consists of inner circular and outer longitudinal layers.

B. Submucosa participates in producing the ridges called rugae, which are smoothed out whenthe stomach is distended. No glands are found in this layer.

l s thmus

Neck

Gland

Lamina.propr ia

Lymph nodule

BodY and lundic Port ion

Figure l l -2-1. Regions of the stomach.

Submucosa

Pyloric Port ion

Junct ion of g landand base of Pi t

Lamina'propria

€cGr n

t28

Cardiac port ion

Histology

C. Muscularis externa consists of partially overlapping layers of smooth muscle that are ori-

ented circularly, longitudinally, and obliquely.

1. The circular layer thickens to participate in the formation of the cardiac sphincter and

the pyloric sphincter.

2. Strong peristaltic waves send chyme through the pyloric sphincter into the duodenum,

and the cardiac sphincter prevents regurgitation into the esophagus above.

D. Serosa is covered by mesothelium that is continuous with the gastric mesenteries (omenta).

E. Regions of the stomach. Anatomically, there are three regions of the stomach: the cardiac

stomach, the body and fundus, and the pyloric stomach (Figure II-2-I).

1. Cardiac stomach is a narrow, circular band at the transition between the esophagus and

stomach, consisting of shallow gastric pits and mucous glands.

2. Bodyand fundus are packed with branched tubular glands that open into the bases of the

gastric pits. Several types of cells occupy the epithelium of these glands.

a. Parietal (oxFntic) cells are found in the neck and body of the gastric glands.

(l) They are large, pyramidal, and acidophilic with a centrai nucleus.

(2) The electron microscope reveals intracellular canaliculi lined with abundant

microvilli.

(3) Parietal cells make and secrete 0.16 M HCI so that the environment is highly

acidic, with a pH of less than 2.

(4) Parietal cells also produce intrinsic factor, a glycoprotein that binds vitamin B12

in the lumen of the stomach for absorption in the intestines.

(5) Acid secretion by parietal cells is stimulated by cholinergic nerve endings, histamine,

and gastrin.

b. Chief cells are the most abundant cells at the base of the gastric glands. They are also

found in the neck region and,less frequently, in the pyloric glands.

(1) These cuboidal-to-low columnar cells have apical membrane-bound secretion

granules containing pepsinogen in an inactive zymogen form.

(2) These zymogens are activated after secretion by the low pH within the lumen.

c. Mucous neck cells are mucus-secreting cells located in the necks of the glands.

d. Enteroendocrine (diffuse endocrine) cells are single cells that synthesize amines,low-

molecular weight polypeptides, or proteins with an endocrine or paracrine function.

( 1) These cells are scattered and are usually located at the base of the glands through-

out the cardiac, gastric, and pyloric glands.

(2) Some cells have an affinity for silver (e.g., argentaffin cells, argyrophils), others

for chromium salts (e.g., enterochromaffin cells), and others are identified by

immunohistochemical procedures.

3. Pyloric stomach has deep gastric pits into which tubular glands open (Figure II-2-1).

a. Pyloric glands are similar to the gastric glands of the cardiac region.

b. The predominant secretion is mucus.

Note

In the stomach, glands arefound only in the mucosa.

Note

The cardiac portion is foundat the transition between theesophagus and the stomach.

Clinical Correlate

Parietal cells secrete HCI andintrinsic factor, which isneeded for the absorption ofvitamin 8,,. A deficiency ofintrinsic factor can lead tovitamin B,, deficiency, and,furthermore, to a defect inRBC synthesis known aspernicious anemia. Recall thatB' deficiency causes amegaloblastic anemia withcha racteristic hypersegmentedneutrophils.

Bridge to Physiology

Acid secretion involves activetransport across cellmembranes. Hydrogen ion(H*), which is pumped intothe lumen, comes from theaction of carbonic anhydraseacting on carbon dioxide andwater to produce carbonicacid. Chloride (Cl-) combineswith H* in the lumen to formhydrochloric acid (HCl).

129


Note

Plica circulares are absent orsmall in initial duodenum,larger and more numerousproximally, and absent in distalileum.

Note

. Disaccharidases anddipeptidases carry out theiractivity at the striated(brush) border.

. Disaccharidases hydrolyzedisaccharides intomonosaccharides

. Dipeptidases hydrolpedipeptides into amino acids.

Clinical Correlate

Lactose intolerance is causedby the deficiency of thedisaccharidase lactase. Lactasehydrolyzes lactose intoglucose and galactose.Without lactase, any foodproduct with a significantamount of lactose (dairyproducts) is not well tolerated:lactose remains undigesteduntil it reaches the largeintestine, where bacteria candigest and ferment it.Symptoms include bloating,gas, and diarrhea.

SMAtt INTESTINEThe small intestine is a tube approximately 4m long that is divided into three anatomic regions:the duodentun, jejunum, and ileum. The final digestion of chyme and the absorption of smallmolecules occurs in the small intestine.

A. Mucosa

1. Grossly, the mucosa of the small intestine has a series of permanent folds, plica circulares,which consist of mucosa and submucosa.

2. The hallmark of the small intestine is the presence of intestinal villi, which are out-growths of the mucous membrane into the lumen (Figure II-2-Z).

3. Epithelium of the villi contains two major cell types: columnar absorptive cells and gob-let cells.

a. Columnar absorptive cells have regular closely packed microvilli on their apical sur-faces and tight junctional complexes around their apical borders.

(1) Lateral membranes form complex interdigitations with neighboring columnar cells.

(2) Each columnar cell secretes its own apical surface coat of glycoprotein enzymes,which, along with pancreatic enzFmes, complete the chemical breakdown of food.

(3) Amino acids, monosaccharides, and fatty acids, as well as water, minerals, andelectrolytes, enter the cell through the apical membrane.

(4) Monoglycerides and fatty acids are esterified to triglycerides in the smoothendoplasmic reticulum (SER) and are coated with protein to be released as chy-lomicrons into the intercellular space.

(5) The cells also synthesize a glycoprotein "transport piece," which attaches to asecretory IgA from plasma cells and is released into the lumen.

b. Goblet cells become more numerous proceeding distally in the small intestine.They produce acid glycoproteins that protect and lubricate the lining of the intestine.

r50

Histology

Striatedborder

Capillary(shown withred blood cell)

Lymphaticlacteal

Goblet cells

Myofibroblast

Argentaffincells

Panethcells

Smoothmuscle

Muscularismucosae

Figure ll-2-2. Structure of small intestine villus and crypts.

4. Several short tubular glands called intestinal glands (crypts of Lieberktihn) open around

the base of each villus.

a. The simple columnar epithelium of the villus is continuous with that lining the crlpts.

b. The epithelium of the crypts is the site of the production of new epithelial cells.

"' :Tt;lj1T#,iiTL':lT#fr .ff Hi:'.fi :" d m av dirrere nti ate into co ru m -

(2) Paneth cells are found only at the base of the crypts and produce acidophilic

cytoplasmic granules that contain enzymes with bacteriocidal activity.

5. Lamina propria of the small intestine penetrates the core of the villi and is composed of

blood vessels,lymphatics, defensive cells, fibroblasts, and smooth muscle cells.

a. The blood vessels consist of a dense net of fenestrated capillaries.

b. A central lacteal in the villus absorbs chylomicrons into the lymphatic circulation

through its junctional gaps.

c. Smooth muscle fibers from the muscularis mucosae course up into each villus and

&\

t 5 l


In a Nutshell

Brunner glands. Duodenum, submucosal

. Secrete alkaline product toprotect duodenal mucosaand to achieveoptimal pH for pancreaticenl/mes.

Peyer Patches. Lymphoid tissue in

submucosa

. l leum

Note

The large intestine normallyreabsorbs large amounts ofwater and small amounts ofsugars and vitamins (e.9.,vitamin l0.The large intestinedoes not contain any villi.

Note

Teniae coli (three thick,longitudinal bands) areuniquely characteristic of thelarge intestine.

Clinical Correlate

Because the appendix is ablind extension, it isfrequently a site ofinflammation (appendicitis).

In a Nutshell

Anal valves --+ Anal opening

simple .$raffied . $mtified .keraunzedcolumnai cuboidal- squam0us-squu*ors

lt2

insert on subepithelial connective tissue. Villi contract several times per minute as aresult of the presence of smooth muscle in their cores.

B. Submucosa of the small intestine exhibits regional differences.

1. In the duodenum, submucosal (Brunner) glands are found.

a. These glands are connected to the lumen by ducts that open into certain crlpts.

b. Their alkaline glycoprotein mucus secretion neutralizes the acidic chyme entering theduodenum.

c. Submucosal glands are lacking in all other portions of the intestines.

2. Submucosal lymph nodules are common, especially in the ileum, where large aggregates ofnodules form Peyer patches.

TARGE INTESTINEThe large intestine extends from the ileum to the anus and consists of the cecum, ascendingcolon, transverse colon, descending colon, rectum, and anal canal. Histologically similar fromthe ileocecal valve to the rectum, the large intestine is approximately 1.5 m long and twice thewidth of the small intestine.

A. Mucosa of the large intestine lacks villi and contains many small holes. These holes are themouths of the straight long tubular intestinal glands (crypts of Lieberktihn).

1. The epithelium is simple columnar enterocytes, with numerous goblet cells and scatteredenteroendocrine cells.

2. The epithelium is continuously renewed by mitosis of the undifferentiated cells in thelower half of the glands.

3. The lamina propria is rich in lymphoid cells and lymph nodules that frequently extendinto the submucosa.

B. Submucosa contains many lymph nodules, which are especially abundant in the appendix.No glands occur in this layer of the large intestine.

C. Muscularis externa is composed of longitudinal and circular muscle layers.

1. The inner circular layer is similar to the rest of the tract.

2. The outer longitudinal layer is different from that in the small intestine because it is gath-ered into three thick longitudinal bands called teniae coli.

D. Serosa of the large intestine contains small pendulous protuberances of adipose tissue calledthe appendices epiploicae.

E. Vermiform appendix is a blind finger-like extension of the cecum, which often has its lumenobliterated by abundant lymphoid follicles. Its general structure is similar to that of the largeintestine, but it contains fewer, shorter, intestinal glands and has no teniae coli.

F. Anal canal is the terminal portion of the large intestine.

1. The proximal half of the anal canal contains a number of vertical folds, which are pro-duced by an infolding of the mucous membrane around the submucosa. They are knownas the rectal columns of Morgagni.

2. The columns are separated from each other by furrow-like rectal sinuses, which end dis-tally in small valve-like folds called the anal valves.

Histology

3. Above the anal valves the epithelium changes ftom simple columnar to stratified cuboidal. l

a. At the level of the valves, it becomes stratified squamous.

b. At the anal orifice, the epithelium becomes keratinized, and apocrine (circumanal)glands and hairs are pres€nt.

4. The submucosa contains a large plexus of veins, which form hemorrhoids when excts-sively dilated.

5. A circular layer of smooth muscle constitutes tle internal enal sPhinct€r, and moresuperficially, skeletal muscle forms the external anal sphincter.

DIGESTIVE TRACT GTANDS

A. salivary glands I !!!!..!!ttbl!.!f

1. Parotid glands are compound, branched, acinar glands. FunCion ol Salivary Glands

a. Their secretory portions are composed almost exclusive$ of serous cells. ' Moistening and lubricating

b. Their secretory granules are high in amy'ase activity. ' DiSestion 0f crbohydrates

(e.9., salivary amylase)2. Submandibular glands are compound, branched, tubuloacinar glands composed of

mucous and serous cells.

3. Sublingual glands are compound, branched, tubuloacinar glands composed predomi-nantly of mucous cells. ll.l ltrbhelt

B. Pancreas. The exocrine portion of the pancreas consists of parenchymal cells ananged in the The oancreas is both anform ofacini, and a system ofbranching ducts that drain into the lumen ofthe small intestine. endocrine and an exocrine1. The pancreas is covered by a thin capsule of connective tissue that sends septa into th€ 8land.

parenchyma to divide it into lobules. . Exocrine + aonar glands2. Acini ar€ composed of pyramidal serous-type cells, each of which produces membrane- . Endocrine _+ lslets ol

bound granules of mixed enzymes for secretion. Lanserhans

a. The acini are surrounded by a basal larnina supported by a delicate sheath of reticularfibers.

b. The enzyme precursors (zymogens) are continually synthesized in the basal roughendoplasmic reticulum (RER), glycosylated, concentrated in Golgi membranes, andreleased by exocytosis.

c. Pancreatic en4rmes cleave proteins (e.g., trypsin, chymotrypsin, carboxyPeptidase,elastase), carbohydrates (e.g., amylase), fats (e.g., lipase, lecithinase), and nucleic acids(e.g., ribonuclease, deoxyribonuclease).

3. The duct system of the pancreas begins with small cuboidal cells that extend into the aci-nar lumen as c€ntroacinar cells,

a- Low cuboidal to columnar intralobular ducts €mpty into large, sirnple, columnarinterlobular ducts.

b. The main secretory ducts contain goblet cells.

c. Enteroendocrine cells occur in both large and small ducts but not in acini.

d. Duct cells secrete water, electrolytes, and bicarbonate (HCO3J, which dilute enzymesecretions and neutralize acidic chvme.

t55


Central vein

Nole

Portal area = vefiul€,arteriole, bile duct, and,often, lymphatic vessels.

Bile canaliculi

Sinusoidethmoidal cell

Sinusoid

Hepatocyte

Inlet venule

Bile duct

Portalvein

Hepatic artery

Figure ll-2-3. Organization of a liver lobule.

C. The liver is the largest gland of the body. It has multiple and complex functions, includingexocrine secretion (via bile ducts into the duodenal lumen), maintenance of optimal con-centrations of various components of blood, and filtering of the blood, which it receives viathe portal vein from the digestive tract and spleen.

l. Parenchyma of the liver is divided into many small lobules shaped like polygonal cylin-ders (FigureIl-2-3).

a. Each cylinder is composed of plates of cells arranged radially around a central vein.Between the plates are radial blood sinusoids.

b. At the periphery of the lobules, branches of the portal vein, hepatic artery bile ducts,and lymphatics course together.

2. Hepatocytes' or liver cells, are 20-30 pm polyhedral eosinophilic cells.

a. Their six or more surfaces may either contact another cell to form gap junctions andbile canaliculi or form a free surface with microvilli exposed to the perisinusoidalspace of Disse.

b. Abundant glycogen in these cells takes the form of electron-dense granules that areclustered near the SER.

c. There are several hundred mitochondria per liver cell.

lr4

Histology

d. The liver cell produces proteins for export (e.g., albumin, prothrombin, fibrinogen),produces and secretes bile, stores lipids and carbohydrates, converts lipids and amino

acids into glucose via the enzymatic process of gluconeogenesis, and detoxifies andinactivates drugs by oxidation, methylation, and conjugation.

3. Bile canaliculi are tubular spaces limited by the plasma membranes of adjacent hepato-

cftes (Figure Il-2-3).

a. They have a small number of internal microvilli and are delimited by tight junctions

formed by adjacent hepatocytes.

b. The bile canaliculi form a network that progresses along the plates of the liver lobulein the direction of the portal canals.

c. At the periphery of the lobule, these ducts empty into Hering canals, which are smallducts composed of cuboidal cells.

d. These ductules terminate in the cuboidal or columnar-lined bile ducts, which gradu-

ally form the right and left hepatic ducts.

e. The hepatic ducts join to form the common hepatic duct.

(1) The walls of the common hepatic ducts and common bile duct have layers compara-ble to those of the intestine.

(2) The circular muscle coat forms sphincters at the terminal part of the duct that

regulate bile flow into the duodenum.

4. Sinusoids of the liver are lined with fenestrated endothelial cells and scattered phagocytic

Kupffer cells, which are part of the mononuclear phagocyte system (Figure ll-2-3).

a. Kupffer cells phagoqtize red blood cells and particles and contain cytoplasmic resid-

ual bodies of iron and pigments.

b. Fat-storing cells also lie in the perisinusoidal space.

5. Liver regeneration can occur rapidly under some circumstances. As much as 90olo can be

replaced in about 2 weeks.

D. The gallbladder stores and concentrates bile.It is a distensible pear-shaped sac with a 50-ml

capaciry located on the underside of the right lobe of the liver. The wall of the gallbladder is

composed of three layers, with no muscularis mucosae.

1. Mucosa

a. Surface epithelium is composed of simple, tall, columnar cells with apical surfaces that

bulge into the lumen. They bear irregular microvilli with a glycoprotein surface coat.

(1) The process of bile concentration depends on active Na+ and Cl- transporting

mechanisms in its epithelium.

(2) Lateral membranes of these cells are extensively interdigitated but separate dur-

ing the transport of water and ions (especially Na*) from the cytoplasm to the

intercellular space. From there, the water moves into blood vessels, and the bile

is concentrated.

(3) Some mucous cells and enteroendocrine cells are present in the neck of this

organ.

b. The lamina propria/submucosa is a continuous layer of connective tissue because

there is no muscularis mucosa.


Cluconeogenesis is the denovo synthesis of glucosefrom noncarbohydrateprecursors (lactate, glycerol,amino acids). lt is reviewed indetail in the Carbohydrateschapter in the Biochemistrysection of Ceneral PrinciplesBook I (Volume l).

ln a Nutshell

Bile Flow

Bile canaliculi -+ bile ductules(Hering's canals) -+ right andleft hepatic ducts + commonhepatic duct

t35


2. Muscularis externa of the gallbladder consists of a thin layer of irregularly arrangedsmooth muscle fibers.

a. Contraction of the muscle layer of the gallbladder is induced by the hormone chole-cystokinin, which is produced in the mucosa of the small intestine.

b. When the gallbladder is empry, the contraction of the muscularis throws the mucosainto folds or rugae.

3. Serosa of the gallbladder covers its surface except where the organ is in contact with the liver.

4. The gallbladder communicates with the common hepatic duct through the cystic duct,which is composed of mucosa (tall columnar epithelium and lamina propria), muscularis,and serosa.

r56

Gastrointestinal Anatomy

The organs residing within the abdominal cavity may be classified as either extraperitoneal orretroperitoneal (i.e., lacking a mesentery) or as having a mesentery. Mesenteries are double-layeredfolds of peritoneum, the serous membrane that lines the abdominal cavity. They suspend the viscerafrom the body wall and provide a conduit whereby nerves and blood vessels originatingretroperitoneally can reach the viscera.

PERITONEUMA. Ligaments and folds. The following is not a complete listing because the mesenteries of

specific viscera are named in conjunction with the descriptions of the respective organs.

l. Folds of the inner surface ofanterior wdl Cliniol Correlate

a. Median umbilical fold is produced by a single, midline ligament running ftom the Serous exudate from thesuperior surface of the urinary bladder to the umbilicus, Also known as the urachus, tinind .att( ̂t iha nanr^nF,rmit was the allantoic duct in fetal life.

rrrnrr6 rsrJ v' u'! P!"!v"Lu"'may produce an excess of

b. Medial umbilical folds are bilateral structures folmed by ligaments running ftom the ffuid known as ascites thatvesicular branches of tle internal iliac arteries to the umbilicus. They were the oblit- accumulates in the peritonealerated umbilical arteries of the fetus. cavity. lt is seen wth cancers

c. Lateral umbilical folds are bilateral structures formed by the inferior epigastric ol the abdominal organsvessels, which function in adult life. or it may be the result of

2. L€ss€r omertum runs between the liver and the lesser curvature of the stomach ( sastro- advanced liver disease- lt can

hepatic ligament) and between tre liver and the first part or trt ar.l."r. ii.piiJrr also occur as a result of riSht

denal ligament). The hqratoduodenal ligament contains the common bile duct, the neaft lallure'

proper hqratic artery and the portal vein, i.e., the portal triad (Figure II-3-1).

3. Falciform ligament attaches the liver to the anterior abdominal wall and divides the liverinto anatomic right and left lobes. The ligamenturn teres within the fulciform ligamentwas the feta.l umbilical vein.

t t7

Gastointestinal System

Anterior Lesser omentum Stomach Gastrosplenicligament

PortaltriadHepatic arteryBile ductPortal vein

Omental(epiploicforamen

Parietalperitoneum

Splenorenall igament

Right kidney Left kidney

Posterior lnferior vena cava

Figure ll-3-l.Transverse section through the abdomenat the level of the omental bursa.

4. Greater omentum is a four-layered fold of peritoneum that hangs from the greater cur-vature of the stomach and attaches to the transverse colon.

B. Peritoneal compartments. The peritoneal cavity is subdivided into regions by the peritonealligaments and mesenteries.

1. Greater sac is the major part of the peritoneal cavity.

2. ksser sac is the area posterior to the stomach and the lesser omentum. It is enteredthrough the epiploic (Winslow) foramen, which is posterior to the hepatoduodenal por-tion of the lesser omentum.

3. Hepatorenal recess is located posterior to the right lobe of the liver and anterior to theright kidney.

4. Right and left paracolic gutters are located alongside the ascending and descendingcolons, respectively.

ORGANIZATION OF ABDOMINAL VISCERAAs discussed in the Embryology section, the organs of the gastrointestinal tract may be classi-fied as derivatives of three embryonic regions: foregut, midgut, and hindgut. Organs belongingto each of the three regions share a common blood supply and preganglionic, parasympatheticinnervation. Arterial supply is derived from the three unpaired visceral branches of the abdom-inal aorta. Venous drainage of the gastrointestinal system and spleen leads to the portal vein,which is formed behind the neck of the pancreas from the joining of the splenic, superiormesenteric, and inferior mesenteric veins.

Visceralperitoneum(coveringspleen)

Bridge tg FgbwofggyAduh sfucture Fetal Sbucture

Median umbilical Allantoic ductfold (urachus)

Medialumbilical Umbilicalfolds arteries

Ligamentum Umbilicalveinteres

clinical --C.ttqL?tSThe greater omentum is amobile $ructure that mayprevent the spread of infectionwithin the peritoneal cavityby sealing off inflamed areas,e.9., an inflamed appendixthat is about to rupture.

t58

Anatomy

A. The foregut includes the esophagus distal to the respiratory diverticulum, stomach, liver,gallbladder, pancreas, and duodenum to the point of entry of the common bile duct (ante-rior intestinal portal). The spleen, although not a part of the gastrointestinal system, sharesthe blood supply of the foregut.

1. Arterial supply. The artery of the foregut is the celiac trunk.

a. Left gastric artery supplies the lesser curvature of the stomach and the lower third ofthe esophagus.

b. The right gastric branch of the common hepatic artery supplies the lesser curvature.The gastroduodenal branch supplies the greater curvature of the stomach via the rightgastroepiploic (gastroomental) branch; it supplies the pancreas and the duodenum bythe superior pancreaticoduodenal branch. The proper hepatic branch divides into rightand left hepatic arteries. The rystic artery is usually a branch of the right hepatic artery.

c. Splenic artery, the largest branch of the celiac trunk, passes posterior to the stomachto supply the spleen. It gives off short gastric arteries to the fundus of the stomach,pancreatic branches, and the left gastroepiploic (gastroomental) artery,which suppliesthe left half of the greater curvature and anastomoses with the right gastroepiploicartery.

2. Venous drainage. Blood from all parts of the gastrointestinal system drains to the hepaticportal system; thus, products of digestion are first brought to the liver by the portal veinbefore being returned by the hepatic veins to the inferior vena cava. Foregut tributaries tothe portal system include the splenic vein and the left gastric vein, which has an importantesophageal branch (Figure II-3-2).

3. tymphatic drainage. Most foregut lymphatic channels ultimately drain to the celiacnodes, which surround the celiac trunk. From the celiac nodes, lymph passes to the tho-racic duct.

4. Innervation. Preganglionic, parasympathetic fibers to foregut structures are all derivedfrom the vagi. Preganglionic sympathetic fibers to foregut structures travel in thoracicsplanchnic nerves, synapsing mostly in the celiac plexus.

B. The midgut commences at the point of entry of the common bile duct into the second(descending) part of the duodenum (anterior intestinal portal). It ends at the junction of theproximal two-thirds and distal one-third of the transverse colon (posterior intestinal portal).The midgut includes half of the duodenum, jejunoileum, cecum, appendix, and ascendingcolon as well as two-thirds of the transverse colon.

1. Arterial supply. The artery of the midgut is the superior mesenteric artery.

a. Inferior pancreaticoduodenal artery supplies the pancreas and the duodenum.

b. fejunoileal arteries supply the jejunum and the ileum.

c. The anterior and posterior branches of the ileocolic (ileocecal) artery supply the cecum,and the appendicular artery supplies the vermiform appendix.

d. Right colic artery supplies the ascending colon and may arise from the ileocolic artery.

e. Middle colic artery supplies the transverse colon.

2. Venous drainage. The major midgut tributary to the portal system is the superior mesen-teric vein.

3. Lymphatic drainage. Most midgut lymphatics drain to the superior mesenteric nodes,which lead to the intestinal trunk of the thoracic duct.

Clinical Correlate

Portacaval anastamosis occu rswhen a blockage is present inthe liver as a result of cirrhosisor the presence of a tumor.Blood within the portal systemmust then seek an alternateroute to return to the heart. Asignificant alternate pathwayinvolves the esophagealbranch of the left gastric vein,which ultimately drains intothe superior vena cava. Sincethe esophageal veins are smalland are not meant for such"heavy traffic," they maybecome varicose and rupture.This causes the patient toVOmit cODiOuS amOUnts Ofblood. Ruptured esophagealvarices are a common causeof death in patients withadvanced liver disease.

t59


Azygos veinEsophagealvein

lnferior vena cava Lelt gastric vein

Stomach

Paraumbilical vei

Umbilicus

Epigastricveins

Rectum

Superior reclal vein

Middle rectalveins

lnlerior rectaf vein

Figure ll-3-2. Portacaval anastomoses.

4. Innervation

a. Preganglionic parasympathetic fibers to midgut structures are all derived from thevagi.

b. Preganglionic sympathetic fibers to midgut structures travel in thoracic splanchnicnerves, synapsing mostly in the superior mesenteric plexus.

C. Hindgut begins at the junction of the proximal two-thirds and distal one-third of the trans-verse colon (posterior intestinal portal). It terminates at the junction of the upper one-thirdand middle one-third of the rectum. The hindgut includes the distal one-third of the trans-verse colon, the descending colon, and the sigmoid colon, as well as the upper one-third ofthe rectum.

t40

Anatomy

1. Arterial supply. The artery of the hindgut is the inferior mesenteric artery.

a. Left colic artery supplies the descending colon.

b. Sigmoid arteries (usually three) supply the sigmoid colon.

c. Superior rectal artery, the terminal branch of the inferior mesenteric artery, suppliesthe upper one-third of the rectum.

2. Venous drainage. The major hindgut tributary to the portal system is the inferior mesen-teric vein.

3. Lymphatic drainage. The hindgut lymphatics drain to both the superior and inferiormesenteric nodes.

4. Innervation

a. Preganglionic parasympathetic fibers to hindgut structures arise from sacral spinalsegments 2,3, and 4 and run in the pelvic splanchnic nerves.

b. Preganglionic sympathetic fibers arise from the lumbar portion of the sympathetictrunk. Postganglionic sympathetic fibers arise from the hypogastric and inferiormesenteric plexuses.

STRUCTURES OF THE FOREGUTA. Esophagus (abdominal portion)

1. The abdominal portion of the esophagus passes through the esophageal hiatus of thediaphragm at the level of the 1Oth thoracic vertebra (T10).

2. It enters the cardiac region (cardia) of the stomach.

B. Stomach

1. The stomach has a lesser curvature, which is connected to the porta hepatis of the liver bythe lesser omentum, and a greater curvature from which the greater omentum is suspend-ed.

2. The cardiac region receives the esophagus.

3. The dome-shaped upper portion of the stomach, which is normally filled with air, is thefundus.

4. The main center portion of the stomach is the body.

5. The pyloric portion of the stomach has a thick muscular wall and narrow lumen thatleads to the duodenum.

C. Duodenum

1. The duodenum is C-shaped, has four parts, and is located retroperitoneally except at thebeginning and end.

Note

Branches of the superior andinferior mesenteric arteriesmay anastomose to form acontinuous arterial channelalong the perimeter of thelarge intestine (marginal arteryof Drummond). The presenceof this vessel increases thechances that the arterialsupply to the colon is notcompletely interrupted if asmall area is cut off from itsblood supply.

Clinical €orrelate

Pyloric stenosis, which occursmost frequently in first-bornmale infants, results in thenarrowing of the pyloriclumen. lt is manifested byprojectile vomiting andrequires surgical dilatation ofthe pylorus.

t 4 l

Gasfointestinal System

Bridge to Embryology

The ligamentum venosum wasthe ductus venosus in fetal life.This $ructure connects theumbilical vein to the inferiorvena cava; oxygenated bloodtherefore bypassed the liverand went straight to the rightatrium.

2. It receives the common bile duct and pancreatic duct in its second (descending) part.The common opening for these structures is the hepatopancreatic ampulla (of Vater).Smooth muscle in the wall of the ampulla is known as the sphincter of Oddi. Note thatthe foregut terminates at the point of entry of the common bile duct or the anteriorintestinal portal; the remainder of the duodenum is part of the midgut.

3. The duodenum is suspended by the ligament of Treitz at the duodenojejunal junction.

D. Liver

1. The liver is invested by peritoneum (i.e., the coronary ligament and the right and left tri-angular ligaments) except over the bare area that lies in direct contact with thediaphragm. It lies mostly in the right hypochondrium and is protected by the rib cage.

2. The liver has two surfaces: a superior, diaphragmatic surface and an inferior, visceral sur-face (Figure II-3-3).

Hepaticartery

Commonbile duct

Portalvein

Ligamentum Quadrateteres lobe

Gallbladder

Figure ll-3-3. Visceral surface of the liver.

The liver is divided into two lobes of unequal size by the falciform ligament. The rightlobe may be further subdivided by fissures for the ligamentum teres and the ligamentumvenosum, the porta hepatis, and the fossa for the gallbladder into the right lobe proper,the quadrate lobe, and the caudate lobe. The quadrate and caudate lobes are anatomi-cally part of the right lobe but functionally part of the left. They receive their blood sup-ply from the left branches of the portal vein and hepatic artery and secrete bile to the lefthepatic duct.

The liver has a central hilus, or porta hepatis, which receives venous blood from the gas-trointestinal system via the portal vein and arterial blood from the hepatic artery. Thecentral hilus also transmits the common bile duct, which collects bile produced by theliver. These structures, known collectively as the portal triad, are located in the hepato-duodenal ligament, which is the right free border of the lesser omentum.

3 .

4.

142

Anatomy

5. The hepatic veins drain the liver by collecting blood ftom the liver sinusoids and retum-ing it to the inferior vena cava.

E. Gallbladder

i. The gallbladder lies in a fossa on the visceral surface of tle liver to the right of tle 9jUg.'|!g*!*qua&ate lobe'

The ,trian$e of Calof is2. It stores and concentrates bile, which enters and leaves through the cystic duct. The cys- bound by the cystic du(

tic duct joins the common hepatic duct to form ttle common bile duct. hepatic duq and the lower. border of the liver. De{ining

srRucruREs oF THE MIDGUT this area when performing acholecystectomy (emoval

The structures of tle midgut begin at the anterior intestinal portal in the duodenum. of the gallbladder) protecS

AJe juno i l eun the |oa | i zedduc t sandcwtc anery.

1. The jejunum begins at the duodenojejunal junction and comprises two-fifths of theremaining small intestine. The beginning of the ileum is not clearly demarcated; it con-sists of the distal three_fifths of the small bowel. Cliniol Conelate

2. The jejunoileum is suspended ftorn the posterior body wall by tle mesentery proper. , Vitamin 8,, and bile salts areAlthough the root of the mesentery is only 9 inches long, the mobile part of the small absorbed in the terminalintestine is approximately 22 feet in length. ileum. pernicious anemia and

B. Cecum . fat malabsorption can

1. The cecum is the first part ofthe colon, or large intestine, and begins at the ileocecal junc- [::tffi::[H]:*'tron.

2. It is a blind pouch, which has a mesentery and giv€s rise to the vermiform appendix. Theappendix has its own mesentery the mesoappendil

C. Ascending colon lies retroperitoneally and lacl$ a mesentery. It is continuous with the trans-verse colon at the right colic (hepatic) flexure.

D. Tlansverse colon

1. The transverse colon has its owrt mesentery called the transverse mesocolon,

2. It becomes continuous with tle descending colon at the left colic (splenic) flexure. Notethat the midgut terminates at the junction of the proximal two-thirds and dista.l one-thirdof the tranwerse colon (posterior intestinal portal).

STRUCTURES OF THE HINDGUTA. The descending cnlon lacks a mesentery. It ioins the sigmoid colon where the large bowel

crosses the pelvic brim.

B. The sigrnoid colon is suspended by the sigmoid mesocolon. It is the terminal portion oftlrelarge int€stine and enters the pelvis to continue as th€ rectum.

C. The superior one-third of the rectum is covered by peritoneum anteriorly and laterally. It isthe fu<ed, terminal, straight portion of tle hindgut.

t45

Gastrointestinal Physiology

The ga$rointestinal system is composed of a set of specialized organs involved in the digestion andabsorption of nutrients. Proteins, fats, and carbohydrates are broken down into absorbablemolecules, which, along with water, enter the blood and lymph for distribution throughout the body.This complex set of actions is mediated by a variety of hormonal and neural inputs integrated withthe internal feedback controls of the gastrointestinal system.

APPETITE AND THIRSTA. Appetite is primarily regulated by two regions of the hypothalmus: a feeding center and a

satiety center. Normally, the feeding center is active but is transiently inhibited by the sati-ety center. It is not known whether food intake itsell a body weight set point, or both, areregulated by the hypothalamus. Genetic factors probably account for approximately 70o/o ofadult body weight, while the balance is attributable to environmental factors. Appetiteaccommodates growth in children as well as maintenance of adult weight. In humans, manypoorly understood psychological factors regulate the appetite.

1. Hypothalamus

a. Feeding center. The feeding center is situated in the lateral hypothalamus. Stimulationof this area induces eating, while destruction of this center causes anorexia.

b. Satiety center. The satiety center is located in the ventromedial nucleus. Stimulationof this center causes the cessation of eating, and lesions in this area lead to hypothala-mic obesity syndrome.

2. Hormones. The introduction of food into the gastrointestinal tract causes the release ofhormones that inhibit further eating.

a. Cholecystokinin (CCK) is released from cells in the mucosa of the small intestine.CCK-A receptors in the periphery and vastly more sensitive CCK-B receptors in thebrain reduce appetite when stimulated.

b. Calcitonin, released mainly from the thyroid gland, has also been reported todecrease appetite by an unknown mechanism.

3. Mechanical distention. Distention of the alimentary tract inhibits appetite, whereas thecontractions of an empty stomach stimulate it. Some satiety is derived from masticationand swallowing alone.

4. Glucostatichlpothesis. The ventromedial nucleus is one region of the brain where glucoseutilization varies according to levels of blood insulin. Cells in the satiety center, calledglucostats, are sensitive to arteriovenous (AV) dififerences of glucose concentration.

In a Nubhell

Hypothalamus./ :.

/ \Feeding Satietycenter center

(lateralhypothalamus)(+) + eating

Destruction ->anorexia

(ventromedialnucleus)(*) -rcessation ofeating

Destruction ->hypothalamicobesitysyndrome

r45


Bridge to RenaflUrinary

Angiotensin ll acts as part of thereni n-an giotensin-aldosteroneqptem. lt is discussed in detailin the Rena/Urinary Physiologychapter of Organ Sy$emsBook t (Volume lll).

Nole

lncreased plasma osmolarityalso increases ADH secretionfrom the posterior pituitary.ADH increases waterreabsorption in the nephron'scollecting duct.

a.High AV glucose difference activates the glucostats, which, in turn, activate thecenter, resulting in inhibition of the feeding center and cessation of eating.

b. LowAV glucose difference inactivates glucostats, relieving the satiety center's inhibi-tion of the feeding center; eating ensues.

5. Lipostatic hypothesis. The size of body fat deposits may regulate appetite by neurohu-moral communication with the brain.

6. Ambient temperature. A warm environment inhibits appetite, whereas a cold one stim-ulates it.

B. Thirst. Like appetite, thirst is also regulated primarily by the hypothalamus. It may be regu-lated in concert with appetite or independently of it.

1. Extracellular fluid (ECF) volume. A decline in ECF volume regulates thirst through therenin-angiotensin system and through cardiac and vascular baroreceptors.

a. Angiotensin II acts on the subfornical organ in the diencephalon, stimulating neuralthirst control areas. It may also act on the organum vasculosum of the lamina termi-nalis (OVII). These regions are located circumventricularly, outside the blood-brainbarrier.

b. Baroreceptors and sensory volume detectors in the vascular system also regulatethirst. Consequently, blocking the action of angiotensin does not totally ablate thecontrol of thirst.

2. Plasma osmolality. Increased plasma osmotic pressure leads to stimulation of osmo-receptors in the anterior hypothalamus. This action promotes drinking.

3. Other factors

a. Dryness of the pharyngeal mucosa stimulates thirst.

b. Mechanical stimulation of the pharynx and stomach by volume stretching mayinhibit drinking.

GHEWTNG AND MOTSTENTNG (MASTTCATTON)A. Teeth. The incisors and canine teeth cut and tear food into sizes suitable for the buccal

cavity. The molars pulverize the chunks into a mash, which is mixed by the tongue withsaliva and other secretions from the salivary glands. Mastication is not necessary fordigestion, but its absence makes swallowing very difficult or painful.

B. Salivary glands. Approximately 1.5 llday of saliva with a pH of slightly less than 7.0 is pro-duced. The pH rises to approximately 8.0 during the active secretion associated with eatingor the anticipation of eating.

1. Salivaryglands consist of three main pairs of glands and some subsidiarybuccal and lingualglands.

a. Submandibular glands produce approximately 70o/o of the saliva (moderately viscoussecretion).

b. Parotid glands produce approximately 20o/o of the saliva (mostly water).

c. Sublingual glands produce approximately 5o/o of the saliva (very viscous secretion).

d. tingual and other minor buccal cavity gluttdt produce the remaining 5o/o of the saliva.

t46

Physiology

3 .

4.

2. Salivary composition. Saliva is generally isotonic with plasma when initially secreted bythe glands.

a. At low salivary flow rates, as saliva travels down the ducts toward the oral caviry Na+and Cl- are reabsorbed, and K+ and HCO3- nre secreted. The resultant saliva is hypo-tonic because of the low water permeability of the ducts and the fact that more ions arereabsorbed than secreted.

b. At high flow rates (e.g., with parasympathetic stimulation), saliva osmolality approach-es that of plasma.

Salivary function. Saliva eases swallowing, maintains mouth moisture, dissolvesmolecules that stimulate taste, and initiates starch digestion. Additionally, it helps keepthe teeth clean and provides an alkaline rinse for the esophagus, neutralizing any refluxedgastric acid.

Salivaryenzymes

a. Salivary a-amylase (ptyalin). Secretory acinar cells of the salivary glands secretezymogen granules, which release salivary u-amylase into the saliva, where it initiatesthe breakdown of polysaccharides (starch) in the mouth.

b. Lingual lipase. Glands on the tongue secrete lipase, which initiates the breakdown offats into monoglycerides and fatty acids.

Other salivary gland secretions

a. Mucins are glycoproteins that lubricate the food and protect the buccal andesophageal mucosa from scratching.

b. Lysozyme breaks down the cell wall of bacteria, an apparently protective measureagainst infection.

c. Lactoferrin binds iron and is bacteriostatic.

d. High-proline proteins protect the tooth enamel and bind toxic tannins.

e. Immunoglobulin A (IgA) helps defend against bacteria on mucosal surfaces.

f. Kallikrein is a proteolytic enzyme that cleaves kininogens to form bradykinin.

Regulation of salivation

a. Parasympathetic innervatiorr-+timulation causes :

( 1) An increase in the synthesis and secretion of watery saliva via acetylcholine act-ing at muscarinic receptors

(2) Secretion of kallikrein, a vasodilator that causes an increase in blood flow to thesalivary glands, resulting in an increase in saliva secretion

b. Sympathetic innervatiorr--stimulation cau ses :

(1) Production of viscous saliva rich in amylase, K+, and HCO3-, mainly via nor-epinephrine's action on B-adrenergic receptors.

(2) Contraction of myoepithelial cells and constriction of blood vessels, causing adecrease in blood flow to the salivary glands, leading to the production of athicker, more viscous secretion.

c. Reflex innervation causes salivation as a result of the presence of food in the mouth;the taste, smell, sight, or thought of food; and the stimulation of vagal afferents at thedistal end of the esophagus.

5 .

ln a Nubhell

Digestion begins in themouth:

. Salivary cr-amylase initiatesthe breakdown ofpolysaccharides (starch).

. Lingual lipase initiates thebreakdown of fats.

Bridge to lmmunology

lgA deficiency, the mostcommon immune deficiency,leads to increasedsusceptibil ity to i nfections,particularly upper respiratoryinfections.

Bridge toNeruous System

Remember that cholinergicblockers (e.g., atropine) oftencause dryness of the mouth.

In a Nubhell

Salivation is increased by bothsympathetic andparasympathetic i nnervation.

6.

147


ln a Nutshell

Swallowing is triggeredby CN lX and CN X.

swArrowr NG (DEcrurriloN)A. Swallowing is a reflex action with its afferent impulses carried primarily by the glossopha-

ryngeal (CN IX) and vagus (CN X) nerves. The nucleus of the solitary tract integrates theafferent information and coordinates the swallowing mechanism via the nucleus ambiguusand hnroglossal nucleus. Food is moved to the esophagus by the movement of tongue(hypoglossal nerve, CN XII) and the palatal and pharyngeal muscles (CNs IX and X).Swallowing occurs frequently, up to 600 times per day. Approximately one-third of swallow-ing occurs during eating, one-twelfth during sleep, and the balance at various times duringthe waking day.

1. Initiation of swallowing occurs voluntarily when the mouth is closed on a bolus of foodand the tongue propels it from the oral cavity into the pharynx.

2. Involuntary contraction of the pharynx advances the bolus into the esophagus.

3. Automatic closure of the glottis during swallowing inhibits breathing and preventsaspiration.

Perrslalticwave

4>

Esopnagus

<n

Stomach

Figure ll-4-1. Peristalsis in the esophagus.

Peristaltic contraction of the esophagus (Figure II-4-1) propels food along the esophagustoward the stomach, starting at the pharyngoesophageal junction. Located here is theupper esophageal sphincter (UES), a band of esophagus approximately 3 cm in lengthwith high resting wall tension. The UES automatically relaxes at the initiation of swallow-ing, closing rapidly behind the bolus of food; it then contracts, preventing reflux.

Lower esophageal sphincter (LES) is the muscle at the gastroesophageal junction. (It issometimes called a physiologic sphincter because it is not a true anatomic sphincter.)

a. Contraction of the LES occurs tonically, but the LES relaxes on swallowing.

4.

5 .

t48

Physiology

b. Regulation of the LES is controlled by the vagus nerve. The most important neuro-transmitter is VIP.

c. High muscle tone normally keeps gastric contents from entering the esophagus. Thetone is supported by:

(1) Pressure difference between intra-abdominal and intrathoracic cavities, whichhelps keep the LES closed

(2) Musculature of the diaphragm

(3) Phrenicoesophageal ligament

(a) Folds in the esophageal mucosa

d. Hormones may modulate the tone of the LES: Gastrin may increase tone, whereassecretin and CCK may decrease tone.

B. Achalasia is a pathologic inability of the LES to relax during swallowing. It results in foodaccumulating in the esophagus and grossly dilating the structure. Characteristics of achala-sia include increased LES tone, incomplete relaxation of the LES on swallowing, weakesophageal peristalsis, and a reduction in VlP-containing neurons in the lower esophagus. Itcan be treated by pneumatic dilatation of the LES or by esophageal muscular incision(myotomy).

C. Esophageal reflux results from an incompetent LES, allowing gastric acid to enter theesophagus. The condition can be treated with H2-receptor blockers, proton pump inhibitors,prokinetic agents, or fundoplication (a surgical procedure that raises a fold of gastric fundusup over the base of the esophagus).

Clinig4l Correlat-e

The most commonsymptomatic complaintof reflux is a burning sensationin the chest (substernal area).This sensation is oftenconfused with a myocardialinfarction.

t49


Esophagus

Adventitia

Longitudinal muscle

Lesser curvature

Duodenum

curyature

Gastric rugae

Submucosa

Pyloric sphincter Mucosa

Figure ll-4-2. Major regions and structures of the stomach.

GASTROI NTESTI NAt MOTI IITYA. Stomach. The bolus of swallowed food is received by the stomach, where it is further mac-

erated and mixed with HCl, mucus, and pepsin. The food is then discharged at a controlledrate into the duodenum. Only a small amount of chemical digestion actually occurs in thestomach (Figure lI-4-2). The major functions of the stomach are storage, mixing, and con-trolled emptying.

1. Motiliw

a. Muscular structure consists of outer longitudinal and circular muscles with a unique,third, inner oblique layer.

Clinical Correlate

With strong adrenergic stimuli,as in major trauma or severepain, gastric atony may occurand aspiration of retainedcontents is a danger.

b. The pacemaker is locatedrhythm (BER) is about 3this region.

(1) The rate of peristaltic contraction is governed by neuronal and other inputs, butcannot exceed the BER of the pacemaker.

(2) The magnitude of contraction is modulated by sympathetic (decreases) andparasympathetic (increases) influences via the myenteric and submucosal plexiand by hormonal stimuli.

c. The pylorus is continuous with the circular muscle layer and its contraction is modu-lated by enkephalins.

2. Receptive relaxation is critical for the storage function of the stomach. As the stomach fills,there is a reflex relaxation of muscle tone, principally of the fundus, that allows the reten-tion of gastric contents without increasing stomach wall tension.

in the midcorpus of the greater curvature. Its basal electriccpm. Peristaltic slow waves sweep toward the pylorus from

t50

Physiology

a. Afferent stimuli originate in stretch receptors.

b. Afferent and efferent impulses run through the vagus nerve. The relaxation is mediat-ed byVIP and nitric oxide.

3. Chyme. Contraction of the stomach, principally in the antrum, snd the conical shape ofthe stomach permit the mixing of food with the stomach acids and the formation ofchyme. This activity is hormonally and neuronally mediated.

4. Gastric emptying. The contractions of the stomach propel chyme through the pylorus ata regulated rate.

a. Peristalsis is the coordinated propulsive contraction that advances food down thedigestive tract.

(1) Initiation of the contraction occurs through action potentials in longitudinaland circular muscle.

(2) Intensity increases steadily as the contractions sweep toward the pylorus.

(3) Pyloric sphincter contraction at the time of antral contraction limits the move-ment of chyme into the duodenum. This encourages emptying to occur in shortspurts, and promotes mixing by forceful regurgitation of antral contents backinto the fundus.

b. Volume of chyme and liquids entering the duodenum depends on the pressure gra-dient between the antrum and the duodenum and on the degree of pyloric relaxation.

c. Hormone modulators of emptying include CCK, which inhibits gastric emptying.During fasting, a peptide named motilin is thought to be responsible for the migrat-ing myoelectric complex (MMC). This is a cycle of gastrointestinal motor activity,usually initiated in the stomach and propagated through the small intestine, that pre-vents the stasis of material in the gut.

d. Physicochemical modulators of emptying include the liquid-solid nature of food, theparticle size, antral distention, caloric densiry osmolariry and the pH of the contents.Favoring emptying are low caloric densiry iso-osmolality, and neutral pH.In contrast,hlperosmolariry low pH, and high lipid content in the duodenum each slow gastricemptying. Receptors in the small intestine for pH, products of digestion, distention,and osmolality are the major regulators of gastric emptying. This is logical since amajor stomach function is to meter out food slowly enough for the small intestine todigest.

B. Small intestine. The duodenum is the proximal pyloric end of the small intestine. Distal tothe duodenum is the jejunum, and then the ileum. In the small intestine, the chyme fromthe stomach is mixed with mucosal cell secretions, exocrine pancreatic juice, and bile.

1. Mucus secretion. Mucus is secreted as mucins (complex glycoproteins), which hydrateand gel, forming the mucus covering the intestinal epithelium.

a. Mucus production occurs in surface epithelial cells throughout the gastrointestinaltract, Brunner glands in the duodenum, and goblet cells in the mucosa throughoutthe intestine.

b. Mucus functions include lubrication of the gastrointestinal tract, binding bacteria,and trapping immunoglobulins where they have access to pathogens.

c. Rate of mucus secretion is increased by cholinergic stimulation, chemical irritation,and physical irritation.

d. Differently constituted mucins are produced by different varieties of goblet cells.

Clinical Conelate

A compromise of the mucusprotection can lead tosignificant damage andirritation of the ga$rointe$inaltract, leading to ga$ritis,duodenitis, or even pepticulcer disease.

t5 l


Clinical Correlate

Peristalsis is activated by theparasympathetic system. Forthose suffering fromdecreased intestinal motilitymanifesting as constipation(paralytic ileus, diabeticgastroparesis), dopa mi nergicand cholinergic agents areoften used (e.9., cisapride,metoclopramide).

2. Intestinal motility. Segmentation contractions and peristalsis require an intact myenter-ic nerve plexus but not extrinsic innervation.

a. Small bowel slow waves. The smooth muscle depolarizes caudally in a slow wave inthe circular smooth muscle. The rate slows from approximately l2lmin in the jejunum

to approximately 9/min in the ileum.

b. Segmentation contractions are ring-like contractions that occur at random "nodes"

along the intestine. They relax, and then new nodes are formed at the former intern-odes. This motile action moves the chyme back and forth, increasing the mucosal expo-sure to the chyme. These contractions do not result in any net caudad movement.

c. Peristalsis is a reflex response initiated by stretching of the lumen of the gut, usuallyby the bolus of food or chyme. The stimulus causes a contraction of the muscle at theoral end of the stimulus and a relaxation of the muscle at the caudal end, thus pro-pelling the contents caudally.

(1) The rate of content propulsion varies from 20 mm/s to 250 mm/s. Although peri-stalsis is modulated by autonomic input, it can occur even in isolated loops ofsmall bowel with no extrinsic innervation.

(2) The intrinsic control senses stretch with calcitonin gene-related polypeptideneurons (CGRP).

(3) The contractile wave is initiated by acerylcholine (ACh) and substance P.

(a) The relaxation caudal to the stimulus is initiated by nitric oxide (NO) and VIP.

3. Intestinal secretions are generally alkaline, serving to neutralize the acidic nature of thechyme entering from the pylorus.

C. Large intestine (colon). The colon is larger in diameter and shorter in length than the smallintestine. Three longitudinal bands of muscle, the teniae coli, constitute the outer layer.Since the colon is longer than these bands, pouching occurs, creating haustra between theteniae, giving the colon its characteristic "caterpillar" appearance. The mucosa has no villi,and mucus is secreted by short, inward-projecting colonic glands. Abundant ly-ph folliclesare found in the cecum and appendix, and more sparsely elsewhere. The major functions ofthe colon are reabsorption of fluid and electrolytes and temporary storage of feces.

1. Motility. The caudal end of the ileum projects into the larger colon in such a way thatincreased colonic pressure squeezes it closed (Figure II-4-3). When ileum pressure isgreater than colonic pressure, there is free movement of chyme into the colon.

Cecum

Figure ll-4-3. Diagrammatic view of the projectionof the ileum into the cecum.

t52

Physiology

a. Peristaltic waves briefly open the normally closed ileocecal valve, passing a littlechyme into the cecum. Peristalsis also advances the chyme in the colon. Slow waves,approximately 2lmin, are initiated at the ileocecal valve and increase to approxi-mately 6/min at the sigmoid colon.

b. Gastroileal reflex. When the bolus passes through the pylorus, the cecum relaxes,transiently increasing the flow of chyme out of the small intestine.

(1) Relaxation of the ileocecal valve may occur through vagal activity.

(2) Constriction of the ileocecal valve occurs through sympathetic stimulation.

c. Segmentation contraction. The contents of the colon are mixed back and forth bysegmental contractions.

d. Mass action contraction is found only in the colon. Constriction of long lengths ofcolon propel large amounts of chyme from one region to the next. This contractionalso moves feces into the rectum, distending the rectum and initiating the reflex ofdefecation.

(1) Approximately 4 hours elapse before ingested food first reaches the cecum.

(2) By 12 hours, almost all ingested food has reached the colon.

(3) As long as 72 hours may be needed for progression to the anus.

2. Absorption. The mucosa of the colon has great absorptive capability. Na+ is activelytransported with water following, and K+ and HCO3* er€ secreted into the colon.

3. Feces contain undigested plant fibers, bacteria, inorganic matter, and water. Nondietarymaterial (e.g., sloughed-off mucosa) constitutes a large portion of the feces. Defecationcontinues even during prolonged fasting or starvation.

4. Bacteria (flora). In normal feces, 30o/o of the solids may be bacteria.

a. Bacteria synthesize vitamin K, B complex vitamins, and folic acid; split urea to NH.;and produce small organic acids from unabsorbed fat and carbohydrate.

b. The brown color of feces is mainly due to the action of bacteria on bile pigments.

c. The odor of feces is due to sulfides and indolic compounds.

5. Defecation. Rectal distention with feces activates intrinsic and sacral reflexes that causerelaxation of the internal anal sphincter (smooth muscle) and produces the urge to defe-cate. If the external anal sphincter (skeletal muscle innervated by the pudendal nerve) isthen voluntarily relaxed, defecation occurs.If the external sphincter is held contracted, theurge to defecate temporarily diminishes.

6. Gastrocolic reflex. Distention of the stomach by food produces the urge to defecate, areflex mediated by parasympathetic innervation as well as by gastrin and CCK.

a. In the transverse and descending colon, a programmed motor action fitting the pat-tern of coordinated peristalsis occurs.

b. This propulsion causes "mass movement" of feces over considerable distance.

c. Laxatives (castor oil), parasites, and enterotoxins acting on mucosal receptors may alsoinitiate "power propulsion" or mass movement.

t55


GASTROINIESTINAT PEPTIDE HORMONESA. Metabolism of hormones

1. Clearance ftom circulation is rapid.

2. Degrad.tion is accomplished by gut peptidases, hepatic metabolism, and renalmetabolism.

3. Function is through receptors with high affinity and specificiry The hormonal respons-es are mediated by cAMP-dependent and Ca2+-dependent pathways.

ln a Nu8hellB. Gastrin

Gastrin 1. Synthesis and storage of gastrin occurs predorninantly in the G cells of the duodenum. Produced by G cells of and in the pyloric antrum.

antrum and duodenum 2. Stirnulus for gastrin secretion includes increased vagal discharge (mediated by gastrin. Secretion is stimulated by releasing peptide, or GRP), digestive products (i.e., amino acids, polypeptides), calcium

vagal discharge and salts, and gastric distention.

product of digestion 3. Inhibition ofgasrin release occurs through acidfication ofpyloric glandular mucosa to

. Main role is fre $imulation of pH <1'5'

HCI secetion by parienl cells 4. Physiologic roles of gastrin include:

a. Stimulation of HCI secretion by parietal cellsC!!!91 Conglatg b. stimulation of histamine release from enterochromaffin-like cells

Zollinger-Ellison Syndrome c. Stimulation of pepsinogen secretion by chief cellsNon-p islet cell pancreatictumor that produces Sastrin.

(1' lncrease or gastrlc Dlooo tlow

ThiS t prOduction of gastrin e. Prornotion of contraction of circular musde of the stomach

leads to t ga$ric acid f. Trophic effect on gastric and small-intestinal mucosa and pancreassecretion and develooment olDeDtic ulcer disease. C. Cholecystokinin (CCK)

. Symptoms: pain, dianhea 1. Synthesis and storage is in I cells of duodenal and jejunal mucosa and the cNS.

. Diagnosis: t gastrin levels 2' stimulus for secretion

. Treatment: omeprazore, H, a' Fat dig€stion products (monoglycerides and fatty acids)

blockers b. Amino acids, especially tr'?tophan, and peptides in the duodenum

3. Physiologic roles

a. Stimulation ofgallbladder contraction and relaxation of the sphincter of Oddi

b. Stimulation of pancreatic enzl'rne secretion predominantly via an atropine-sensitive(cholinergic) pathway.

c. Inhibition of gastric emptying

d. Trophic effect on the exocrine pancreas and gallbladder mucosa

D. Secretin

1 . Synthesis and storage takes place in S cells in the mucosa of the duodenum.

t54

Physiology

2. Stimulus for secretion

a. Acidification of duodenal rnucosa (amount released is inversely proportional to pH ofdryme entering duodenum)

b. Fatty acids


a. Stirnulation of the secretion ofbicarbonate-containing fluid ftom the pancreas andbiliary ducts

b. Increases bile production (noncompetitive)

c. Inhibits H+ secretion by the pari€tal celt. In 1m{t9lt

E. Gastric inhibitorl peptide (GIP) is produced in the duodenal and jejunal mucosa by K cells Main Role of CCK

and is released when stimulated by intraluminal glucose, amino acids, and fatty acids. GIP is ' Stimulates pancreaticsometimes called 'glucose-dependent insulinotropic" peptide (which aids in remembering enzyme secretionits tunction)' . stimulates gallbladder1. It stimulates pancreatic insulin release in the presence ofhyperglycemia (Figure II-4-4). contracton

2. It inhibits gastric acid secretion. . Decreases gastric emptyingF. Vasoactive intestind polypeptide (VIP) is located in the parasympathetic ganglia in

sphincters, gallbladder, andsmall intestine, and has neurotransmitter funaion (nonidrJnergic Main Role of Secretin

and noncholinergic). . Stimulates HCO,- secretion

l. stimulus for release is vagal stimulation and intestinal distention. from the pancreas and liver

2. Inhibition occurs by adrenergic input Main Role of GtP

3. Physiologic roles ' Stim-ulates pancrmtic

a- Stimulation of water and electrolyte secretion by the jejunum, ileum, and colon (via Insulln secreton

.AMP) oinial Gonelareb. Relaxation of intestinal smooth muscle, including sphincters. With nitric oxide, medi-

ates swallow-induced relaxation of LES and recqrtive relaxation of stomach. ' VlPoma -q tumor of non-

c. stirnuration of pancr€atic Hco3- secretion d" non-F islet cells of the

d. Intestinar vasodilatation Dancreas that secretes vlP

. Symptoms: watery diarrheaG' somatostrtin

. Treatment resection ofl. Synthesis and storage occur in D cells of the pancreatic islets, gastric antrum, and tumor

throughout the intestine. It is also present in tlle hypothalamus.

t55


Increased pancreaticsecretion

lncreased bile secretion

Figure ll-4-4. Combinedcholecystokinin (CGK), and

+ Promotion

action of gastrin, secretin,gastric-inhibitory peptide (GlP).

1 r ' ; * 6 t , '

' , , 1 , r t

a t , i f ' r i ( ' '

v V 1 1 " \ ( ' 2. Physiologic roles. Somatostatin inhibits the release of gastrin, CCK, and most othergastrointestinal hormones.

a. Inhibits gallbladder contraction and pancreatic secretion

b. Inhibits gastric acid and pepsinogen secretion

c. Inhibits small intestinal fluid secretion

d. Inhibits ACh release from the myenteric plexus and decreases motility

e. Inhibits cr-cell release of glucagon, and B-cell release of insulin in pancreatic islet cells

H. Pancreatic polypeptide

1. Synthesis and storage takes place in F cells of the pancreas and also in the CNS. It isreleased in response to vagal cholinergic stimulation and protein-containing meals.

2. Physiologic roles include the inhibition of pancreatic secretion of HCO3- and enzymesand the relaxation of the gallbladder. It plays no role in the regulation of acid secretion. Itinhibits vagal activity antrally and acetylcholine release locally.

I. Motilin

l. Production occurs in M and enterochromaffin (EC) cells in the duodenum and jejunum.

2. Secretion occurs during fasting.

3. Physiologic role is to regulate the migrating myoelectric complex (MMC).

' , { ) i 1 i

! I.""' ' '"t \

+I

5 t t t ' '

C C KL

' r ' l '

[ - i l ' t i ' ! z

t56

Physiology

a. Erythromycin binds to the motilin receptor and seryes as an agonist, promoting gastric Clinkal COrrelateemptfing.

L Entemgucagon it.:,t..., ' ': '- ' '.. In addhion to ib use asan antibiotic, erythromycin

1 Synthesis occurs in the L cells of the intestine. is therapeutic for patienb

2. physiologic roles with Sastroparesis. A common

a. Inhibition of gastric and pancreatic secretion and smooth muscle contraction sidetffect of erythromycin

b. Stimulation of insulin s€cretion

K. Substance P ', . -,. :

1. Synthesis occurs in the enteroduomaffin cells ofthe upper small intestine and colon and : . : '

also in the CNS. r... 1., - . .

2. Stirnrdus for release ftom tle myenteric plexus occurs tlrough vagal efferent pathways. .' ;......

3 . P h y s i o l o g i c r o l e s . ) : " . , . , , " A

a. Stimulation of salivary flow and gastroint€stinal motility

b. Tiansmission of pain impulses in the nervous system

GASTROINTESTINAT SECRETIONSA. Gastric secretions

I . Glandular cells of tlle mucosa

a. Cardiac glandular region surrounds the esophageal opening and contains cells thats€crete primarily mucus,

b. Oxyntic glandular region is found in the proximal 80% of the stomach and sparselyin the antrum; it contains:

( 1 ) Parietal cells, which secrete HCI and intrinsic factor

(2) Chief cells, which secrete pq>sinogen

(3) Mucous neck cells, which secrete mucus

c. Py'oric glandular region contains:

( 1) Mucus-secreting cells

(2) G cells, which secrete gastrin

(3) D cells, which secrete somatostatin

d. Other cells:

(1) Enterochromaffin cells, which secrete serotonin and histamine

(2) Paracrine cells, which s€crete somatostatin, VIB and glucagon

(3) Mast cells, which secrete histamine

(4) Plasma cells, which secrete IgA

2. Hydrodrloric acid (HCl)

a. HCI is secreted by parietal (oxyntic) cells. It denatures proteins, kills ingested bacte-ria, and activates digestive enzymes (e.g., pepsinogen to pepsin).

157


Bridge to Pharmacology

H, blockers (cimetidine,ranitidine) decrease acidproduction by bindingto the histamine receptorson parietal cells.

Omeprazole inhibits acidsecretion by blocking the H./K.ATPase of the parietal cell.

In a Nutshell

Pepsin is a protease, involvedin the digestion of proteins(peptide bonds). lt is stored asthe nTmogen pepsinogen.

b. H- is generated by the combination of CO2 and H2O in the parietal cell. It is secretedinto the gastric lumen in exchange for K*; H* secretion is coupled with secretion ofCl- (Figure II-4-5).

c. The HCO3- generated in the parietal cell is absorbed into the bloodstream in exchangefor Cl-.

d. Major stimuli for acid secretion are substances that bind to specific receptors on theserosal membrane of parietal cells.

(1) Histamine, released from the mast cells in gastric mucosa

(2) ACh, released from the vagus nerve, activates parietal cell muscarinic receptors

(3) Gastrin, released from G cells into the bloodstream

e. Major inhibitors of acid secretion (many act by stimulating gastric D cells to releasesomatostatin).

(1) Low pH inhibits HCI secretion by decreasing gastrin production

(2) Prostaglandins

Interstitialf luid

Gastriclumen

' K fNa+

K+

K+

cl-

HCOt

6+

;1+

Figure ll-4-5. Hydrochloric acid secretion by parietal cellsin the stomach.

3. Pepsin

a. Pepsin is synthesized and stored in granules in chief cells as pepsinogen, a zymogenor proenzfme (inactive precursor) of pepsin. The obvious advantage of producingand storing digestive enzfmes in zymogen form is to protect the cell against the effectsof its own products.

b. Pepsinogen is secreted into the gastric lumen and is activated to pepsin both by H+and by pepsin itself (autocatalytic). pH optimum is 1-3; it is irreversibly inactivatedat pH >5.

)) Co2 + H2o4

| Carbonic

J anhydrase

HzCOs

r58

Physiology

c. Pepsin digests up to 20o/o of. proteins by cleaving them at peptide bonds involving theamino acids tyrosine and phenylalanine. It is especially effective at digesting collagenin connective tissue.

d. Secretion is stimulated by ACh (vagal stimulation), gastrin, and HCl.

4. Mucus

a. Produced by mucous neck cells, mucus is 80o/o carbohydrate, 20o/o protein, andhighly viscous.

b. It forms a gel on the gastric mucosa that protects the mucosa from the proteolyticeffects of HCI and pepsin. It also traps HCO3- secreted by the mucosal cells toneutralize acid near the cell surface.

5. Intrinsic factor

a. Production occurs in the parietal cells.

b. Intrinsic factor is necessary for vitamin B, absorption by the ileum. Vitamin B, istaken up as a complex with intrinsic factor.

B. Phases of gastric secretion

1. Cephalic phase. The smell, sight, or thought of food can increase gastric secretion viaparasympathetic (vagal) pathways acting directly on parietal and chief cells.

2. Gastric phase. Depending on the chemical composition and volume, food in the stom-ach increases secretion. The greatest effects occur with proteins and peptides (alcohol andcaffeine also exert a strong effect). These changes are mediated by the vagus nerve, bystretch reflexes in the stomach wall, and by gastrin. Gastrin is secreted by endocrine cellsin the mucosa of the antrum and travels via the bloodstream to parietal and chief cells.

3. Intestinalphase. Protein digestion products in the duodenum stimulate duodenal gastrinsecretion. In addition, absorbed amino acids act to stimulate H+ secretion by parietalcells. However, the intestinal phase accounts for less than 10o/o of the gastric secretoryresponse to a meal.

C. Pancreatic secretions. The exocrine secretions of the pancreas are produced by the acinarcells, which contain numerous enzyme-containing granules in their cytoplasm, and by theductal cells, which secrete HCO3-. The secretions reach the duodenum via the pancreaticduct. The major components of the pancreatic secretions are H2O, HCO3-, and digestiveenzymes.

1. HCO3-

a. HCO3- is produced by the action of carbonic anhydrase on CO2 and H2O in the pan-creatic ductal cells. HCO3- is secreted into the lumen of the duct in exchange for Cl-.

b. The function of HCO3- in the duodenum is to neutralize the HCI in chyme enteringfrom the stomach. This also deactivates pepsin.

c. The rate of HCO3- secretion is dependent on the degree of acidity of the chyme andis controlled by the duodenal hormone secretin (nature's antacid).

2. Pancreatic enzymes. Approximately 15 digestive enzymes are produced by the pancreas.They are responsible for the breakdown of proteins, carbohydrates, lipids, and nucleicacids. The primary enzymes are listed in Thble II-4-1.


In the treatment of ulcers,agents are sometimes used toprotect the mucosa.

. Sucralfate + acts as aprotective coating on thestomach

. Misoprostil + a syntheticprostaglandin that alsoprotects the gastric mucosa

These drugs are discussedin the Ca$rointestinalPharmacology chapterof this book.

ln a Nutshell

Pancreatic Secretions' Hro

. HC03-

. Digestive enrymes

r59


Thble II-4-f . The primary pancreatic enzymes.

En4rme Reaction Catalvzed

Proteases

Tiypsin Proteins + peptides

Chymotrypsin Proteins -+ peptides

Carboxypeptidase Peptides -+ amino acids

Polysaccharidases

Amylase Starch and glycogen + maltose,maltotriose, and a-limit dextrins

Lipases

Phospholipases A and B Phospholipids + phosphate, fattyacids, and glycerol

Esterases Cholesterol esters -+ free cholesteroland fatty acids

Triarylglycerol Triglycerides + fatty acids and

Lipases monoglycerides

Nucleases

Ribonuclease RNA + ribonucleotides

Deoxyribonuclease DNA + deoxyribonucleotides

a. Protection of pancreatic acinar cells against self-digestion occurs through two mainmechanisms:

( 1) Synthesis as inactive precursors. Some enzymes are secreted as inactive precur-sors and are activated by partial proteolysis. For example, the proteolytic enzymetrypsin is secreted in an inactive form, trypsinogen. A duodenal enzyme,enterokinase, splits six amino acids from the N-terminus of trypsinogen togenerate the active enzyme. Tiypsin then catalyzes the formation of more trypsinand activates chymotrypsinogen, procarboxypeptidase, and prophospholipasesA and B. Ribonucleases, amylase, and lipase do not exist as proenzymes.

(2)Enarme'*:il"x'il:;:,"J:[li]fiffi ',".;T;lT:inhibitorsinactivatetrace

b. Stimulation of pancreatic enrqe secretion occurs via CCK, which is released inresponse to amino acids and fatty acids in the duodenum. Acerylcholine also stimulatesenzyme secretion via vagovagal reflexes.

D. Hepatic secretion


a. Excretion of bfirubin, cholesterol, drugs, and toxins

b. Promotion of intestinal lipid absorption

c. Delivery of IgA to small intestine

2. Components of bile flow

a. Bile salt-dependent canalicular flow

t60

Physiology

(1) Bile flow is directly proportional to bile salt output. Uptake of bile salt is sodium-

dependent and energized by the Na+ gradient maintained by the sinusoidal

Na--K--ATPase.

(2) Water flow is a passive ultrafiltrate of plasma with its electrolyte composition

modified in the bile ducts. Water flows in response to the osmotic pressure gener-

ated by bile salt secretion.

(3) Flow is determined by the rate at which bile salts are available to hepatocytes(enterohepatic circulation) and the rate of hepatocyte bile salt synthesis.

b. Bile salt-independent canalicular flow (composition is similar to plasma)

c. Ductal flow

(1) Added to the canicular flow in the biliary ducts

(2) High HCO3- concentration, similar to pancreatic ductal secretion

3. Control of bile secretion

a. Secretin stimulates the secretion of bile high in HCO3- content from the biliary

ductules. Secretin does not alter bile salt output.

b. Bile flow is also enhanced by the migrating myoelectric complex, which speeds the

enterohepatic circulation of bile acids.

4. Bilirubin is a product of heme metabolism. It is taken up by hepatocytes and is

conjugated with glucuronic acid prior to secretion into the bile. In the large intestine,

bilirubin is deconjugated and metabolized by bacteria to form urobilinogens (colorless).

Some of the urobilinogens are reabsorbed; most of the reabsorbed urobilinogens are

secreted into bile, with the remainder being excreted in urine. However, most urobilinogen

remains in the gut and is further reduced to pigmented compounds (stercobilins and

urobilins) and excreted in feces.

5. Bile acids are synthesized from cholesterol by hepatocytes as bile acids.

a. The primary bile acids are cholic and chenodeoxycholic acid. Secondary bile acids(deoxycholic and lithocholic) are products of bacterial metabolism of primary bile

acids in the gut. All bile acids must be conjugatedwith taurine or glycine before being

secreted into bile.

b. The rate of bile acid synthesis is dependent upon the rate at which bile acids return to

the liver via enterohepatic circulation. Some bile acids are reabsorbed by passive dif-

fusion in the small intestine. Most are reabsorbed by active transport in the distal

ileum.

c. Bile salts (the ionized form of bile acids) enhance the efficienry of absorption of fats

and fat-soluble vitamins. They emulsifyfat droplets into micelles, preparing them for

digestion by pancreatic lipases and subsequent absorption.

( 1) Bile salts carry the products of fat digestion (fatty acids, monoglycerides) and fat-

soluble vitamins in micelles and transport them to the brush border of the

intestinal epithelium.

(2) One therapy for hypercholesterolemia involves binding bile salts (e.9.,

cholestyramine). These bound bile salts are excreted and not returned to the liver

via the enterohepatic circulation. So, the liver must synthesize more bile salts

from cholesterol.

6. Gallbladder. The function of the gallbladder is bile concentration and storage for release

during meals.

Note

Bile flow is dependent uponbile salt concentration, andthus on enterohepaticcirculation from the ileum.

Clinical Correlation

Jaundice (yellowing of the skinand whites of the eyes) is aresult of elevated bilirubin.lncreased bilirubin can resultfrom numerous etiologies(hepatic failure, hemolysis,biliary obstruction, etc.).

t 6 l


In a Nutshell

Bile = H,O, bile acids,cholesterol, bilirubin, andphospholipids.

Clinical Correlate

Gallstones

Cholesterol stones are themost prevalent gallstones inWestern society. Rememberthe four F s (for riskfactors):

. Female

' Fat E.

. Fertile

' FoO

Clinical Correlate

Any time there is an 1 in thesecretory state (e.9., choleratoxin) a secretory diarrhea willensue.

a. Interdigestive pattern. While the gallbladder is relaxed and the sphincter of Oddi isconstricted at a low resistance, approximately 50% of bile is stored and the remainderenters the duodenum.

b. Digestive pattern. Gallbladder contraction begins approximately 30 minutes after ameal, stimulated by ACh (vagal-cephalic phase of digestion) and the hormone CCK.

c. The gallbladder wall absorbs water (90o/o) and electrolytes.

d. The gallbladder concentrates cholesterol, reabsorbs Na+ by an electrogenic pump, andmoves Cl- passively.

7. Bile is composed of water, electrolytes, phospholipids, bile acids, cholesterol, and bilirubin.

a. When their concentration is high, lecithin (phospholipids), cholesterol, and bile acidsform micelles spontaneously in the gallbladder and bfiary tree. The micelles have ahydrophobic center and solubilizefatty acids,lipids, monoglycerides, and cholesterol.Inthe intestine, the phospholipid and some of the cholesterol is replaced by faffy acids,monoglycerides, and fat-soluble vitamins. The lipid-carrying micelles diffirse to thebrush border cells of the mucosa, delivering fatty acids, monoglycerides, and fat-solublevitamins to the enterocFtes.

b. Cholesterol dissolution is proportional to lecithin and bile acid concentrations.

(1) When cholesterol concentration exceeds the capacity of the micelles, bilebecomes supersaturated.

(2) The presence of a nucleus (i.e., bile pigment) permits microscopic crystals toform.

(3) Increasing the size of microcrystals eventually results in cholesterol gallstoneformation.

Small intestinal secretion

1. Water and electrolytes are transferred from the serosal to the mucosal surface.

2. Active secretion occurs in the crypts of Lieberkuhn.

a. Cl- and HCO3- are actively secreted. Na+ and HrO movement is passive, maintainingisotonicity.

b. Secretion is stimulated by local ACh release from plexus.

3. Cholera toxin stimulates intestinal secretion by increased cAMP production via the stim-ulatory G protein action. Cl- and HCO3- secretion is enhanced.

Vomiting

1. Vomiting occurs in three phases

a. Nausea is a psychic and physical phenomenon.

(1) It is marked by hypersalivation, decreased gastric tone, and decreased or absentperistalsis.

(2) Increased duodenal and proximal jejunal tone results in reflux of contents intostomach.

b. Retching

( 1) Spasmodic respiratory movement against a closed glottis decreases intrathoracicpressure.

162

Physiology

(2) The pyloric end of the stomach contracts, and the upper part relaxes in associa-

tion with contraction of abdominal muscles.

(3) Herniation of the abdominal esophagus and proximal stomach into thorax fol-

lows contraction of abdominal muscles.

(4) Secretion of mucus by the stomach increases, but acid secretion falls.

c. Vomiting

(1) Gastric contents are forcefully extruded from the mouth with sustained contrac-

tion of abdominal muscles and pylorus.

(2) If the hypopharyngeal sphincter is contracted, no expulsion occurs and the vomitus

refurns to the stomach.

2. Neural pathways

a. Chemoreceptortrigger r,olneis located in the areapostrema in the floor of the fourth

ventricle.

( 1) It stimulates the vomiting center.

(2) The neurotransmitter is dopamine, which is increased by apomorphine and

bromocriptine, and is decreased by haloperidol, metoclopramide, and marijuana.

b. Vomiting center is located in the reticular formation of the medulla adjacent to the

salivary and respiratory centers.It coordinates activities of the surrounding structures.

DIGESTION AND ABSORPTIONA. Carbohydrate digestion

1. Salivary amylase normally hydrolyzes approximately 10 to 20o/o of ingested starch. It

hydrolpes only cr-(f:a)-glycosidic linkages to maltose, maltotriose, and cr-limit dex-

trins.

2. Pancreatic amylase is found in the highest concentration in the duodenal lumen, where

it rapidly hydrolyzes starch to oligosaccharides, maltose, maltotriose, and cr-limit dex-

trins.

3. Oligosaccharide hydrolases (maltase, lactase, sucrase, and isomaltase) are found in the

brush border, with the highest concentrations in the midjejunum and proximal ileum.

B. Carbohydrate absorption

1. Glucose absorption occurs in the duodenum and proximal jejunum and affects plasma

insulin levels via plasma GIP.

a. Glucose is transported across cell membranes by a carrier-mediated active process.

(Galactose competes with glucose for the carrier.)

b. Glucose transport into the intestinal cell is coupled to Na+ transport by the sodium-

dependent glucose transporter. Na+ moves down its concentration gradient to enter

the cell. This concentration gradient is maintained by the active transport of Na+ out

of the cell.

c. Glucose is transported from the cell into the interstitial layer and through the basolat-

eral membrane bv facilitated diffirsion.

Note

The chemoreceptor triggerzone uses dopamine as itsneurotransmitter, and alsodirectly senses irritantmolecules. Antipsychotia haveantiemetic actions becausethey are dopamineantagonists.

Clinical Correlate

Lactose lntolerance

Due to lactase deficiency.lnability to breakdown lactoseinto glucose and galactose.Consequence: i ncreasedosmotic load, giving rise todiarrhea and flatulence. Verycommon in Blacks, Asians, andMeditenaneans, and to a lesserdegree in Europeans and theirAmerican descendants.

t65

Gaslrointestinal System

ln a Nutshell

Fat digestion occurs in thesmall intestine by pancreaticlipases and is aided by theemulsifying bile salts.

Clinical Correlate

Numerous Etiologies CanGive Rise to Steatorrhea. Pancreatic insufficiency

(chronic pancreatitis, CF,pancreatic cancer)

. Bile salt deconjugationsecondary to bacterialovergrowth

. Deficiency of conjugatedbile salts (due to cholestasisor liver disease)

2. Fructose absorption is by carrier-mediated diffrrsion.

3. Water osmotically follows movement of the carbohydrates.

C. Fat digestion

1. Gastric digestion. Emulsification of fat begins in the stomach through the churning andmixing function. However, little fat digestion occurs in the stomach. Gastric and linguallipase action normally accounts for approximately l0o/o of fat hydrolysis.

2. Intestinal digestion

a. Fats, insoluble in water and chyme, are made soluble in the duodenum bylecithin, bilesalts, and fatty acids. Absorption of most fat has occurred by the time chyme reachesthe midjejunum.

b. Pancreatic lipase

(1) Luminal concentration is highest within the first hour after a meal.

(2) Contact between lipase and triglycerides is enhanced by emulsifring agents.

(3) Colipase bridges the triglyceride-lipase interface, allowing lipase hydrolysis tooccur.

(+) Triglycerides are hydrolyzedto fatty acids and 2-monoglycerides.

c. Bile salts enter the duodenum on gallbtadder contraction, usually within 30 minutesof a meal.

D. Fat absorption

1. Monoglycerides, free fatty acids, and other lipids (e.g., cholesterol, fat-soluble vitamins A,D, E, K) collect in micelles, which are mixed by segmentation. Micelles carry these prod-ucts of fat digestion across the unstirred (aqueous) layer to the brush border, where theycan diffirse into the cell.

2. Enterocytes re-esterifr the fatty acids to form triglycerides, phospholipids, and choles-terol esters.

3. Triglycerides, phospholipids, cholesterol, cholesterol esters, fat-soluble vitamins, andapoproteins are incorporated into chylomicrons in the enterocftes.

4. Chylomicrons are released by exocytosis into the intercellular space and enter the lactealsthrough gaps in their membranes.

5. Glycerol diffrrses into portal blood and is either oxidized for energy or is stored as glyco-gen.

6. Triglycerides with medium- and short-chain fatty acids arehydrolyzed quickly and donot require micelle formation for absorption. They undergo little re-esterification and areabsorbed directly into the portal venous system.

7. Fat-soluble vitamins A, D, E, and K require bile acid micelles in order to be absorbed.

E. Protein digestion and absorption

1. Gastric digestion. Maximally, l0-l5o/o of protein is broken down to amino acids in thestomach. Pepsin functions best at pH 2 and is irreversibly deactivated above pH 5; there-fore, HCI secretion is critical.

2. Intestinal absorption

a. Approximately 50o/o of protein is digested and absorbed by the time it reaches the endof the duodenum.

TIt64

Physiology

(1) Most protein is rapidly hydrolyzed by pancreatic enzymes activated by brush-

border peptidases.

(2) Small polypeptides are absorbed faster than amino acids and are hydrolyzed by

enterocyte peptidases. Absorption is active and carrier-mediated.

b. Amino acid absorption is the rate-limiting step in protein digestion.

(1) Active transport occurs via a Na+-linked carrier.

(2) Amino acids appear rapidly in portal venous blood.

(3) Many different transport systems have been identified, €.8., carriers for neutral,

basic, and acidic amino acids.

F. Water and electrolyte absorption. The absorption of water and electrolytes occurs mainly

in the small intestine.

l. Permeability. The jejunum and duodenum are highly permeable to water and electrolytes

across "leaky" tight junctions. Tight junctions bind epithelial cells together, forming a

barrier to ion and solute movement. The strength of the barrier varies, and some tightjunctions are more permeable to solutes than others. Permeability decreases distally.

2. Na+-K+ exchange. A low intracellular Na+ concentration is maintained by Na+/K+-

ATPase on the basolateral membrane throughout the small intestine.

3. Water flow. As noted, water permeability decreases distally.

a. Approximately 5-10 liters of fluid must be absorbed daily (intake and secretion), with

80-90% being absorbed in the small intestine at a maximal rate of 700 ml/h.

b. Water flow maintains the osmolarity of chyme in the duodenum.

4. Na+ absorption. Ion and molecular transport decreases distally.In the proximal intestine,

there is Na+-H+ exchange, Na+-glucose cotransport, and intercellular flow of Na+

through l.uLy tight junctions.

5. Cl- absorption occurs in association with Na+ absorption through tight junctions and in

exchange with HCO3- in the ileum and colon. Cl- moves inward from the lumen of the

gut, across the enterocftes and down the electrochemical gradient maintained by Cl-

extrusion at the basolateral membrane.

6. K+ absorption occurs down an electrochemical gradient through tight junctions and cells

with apical K+ channels.

7. Calcium absorption. Approximately 50olo is absorbed through enterocytes by active

transport bound to a carrier. Carrier synthesis is mediated byvitamin D. The complex of

Ca2+ and its carrier is extruded across the basolateral membrane.

8. Iron absorption. Approximately 10olo of ingested iron is absorbed, depending on its

chemical form, the amount ingested, and need.

a. Absorption of iron is a saturable, active transport process that competes with other

divalent cations and is enhanced by vitamin C.

b. Ferrous iron is absorbed better than ferric iron.

c. Absorption is increased to two to five times normal in anemia, iron deficiency, or

hypoxia.

d. Iron is transported in the form of transferrin.

Clinical Correlate

Hartnup disease is a disorderof neutral amino acidabsorption.

Bridge to Endocrine

The role of vitamin Din Ca2* absorption is discussedin detail in the EndocrinePhysiology chapter of this book.

Note

Most Ca2*, iron, and folate areabsorbed in the duodenum.

t65

Gastroi ntestina I System

Ll !.!JFFI! e. Vitamia B12 absorption

8,, absorption requires binding a. Vitamin B12 binds to R protein secreted into saliya, gastric juice, and bile.

of intrinsic laclor (produced by b. The R protein-Bl2 complex is hydrotped by pancreatic enzyrnes and Bl2 subs€quentlyparietal cells of stomach). binds to intrinsic factor, which is produced by the parietal cells of the stomach.Actual absorption occurs inthe ileum.

c. Intrinsic factor-B12 complex binds to a receptor on the terminal ileum, where absorp-tron occurs.

G. Absorption in the colon

l. The most important absorptive function is Na+ absorption (in exchange for K+).

a. H2O and Cl- movement ar€ passive,

b. There is paracellular K+ movement,

c. Exchange of Cl- and HCO3- ocrws.

d. There is litde glucose or amino acid absorption.

2. The colon can become secretory if stimulated by bile salts or medtanical or surface-activeirritants. Disease processes can also have this effect.

cti!9al iollelate H' Regulation of absorption and secretion

l. Glucocorticoids regr:late the small intestine, colonic fluid, and electrol)'te transport.uprarcs aso + mouttyof the Cl tract patienb on 2. Opiates stirnulate Na+ absorption and inhibit secretion in the ileum.

opiate pain medications often 3. Somatostatin stimulates Na+ absorption and decreases motility.become con$ipated 4. choli!€rgic agonists increas€ Na+, cl-, and fluid secraion.

5. VIP stimulates fluid secretion yia cAMp.

6. Bacterial toxins (e.g., drolera toxin) stimulate cAMP and thereby activat€ a Cl secr€torypump in the mucosal cell.

MUSCULAR FUNCTIONA. Innervation of the gastrointestinal tract

1. Structure

a. Groups of muscle cells are organized into bundles, which contract as a unit aftersimultaneous depolarization.

b. Bundles are electrically coupled, primarily in the circular layer through gap junc-tions (areas of low membrane resistance).

c. Membrane potential of muscle cells is maintained by the Na+-K* pr'rrnp located on thebasolateral membrane and is responsible for the resting tension of the muscle cell.

2. Intrinsic innervation of the gastrointestinal tract. The enteric nervous system extendsthe primary nervous control of the gastrointestinal tract. It is made up of dense, inter-connecting networks of nerve cells called plexi. It helps to integrate motor and secretionactivity of the gastrointestinal tract.

a. Plexus tnres

(1) Myenteric plexus (Auerbach plexus) lies between the circular and longitudinalmuscle layers from the esophagus to the anus.

r66

Physiology

(2) Submucosal plexus (Meissner plexus) lies in the submucosa of the gut wall.

(3) Subserosal plexus lies beneath the serosa.

(4) Deep muscular plexus is located in the circular layer.

(5) Mucosal plexus is located in the subglandular, intraglandular, and intravillous

areas.

b. Neurons of several kinds are found:

(l) Cholinergic neurons (myenteric)

(2) Serotonergic neurons

(3) Peptidergic neurons (containing VIR substance R and somatostatin).

c. Axons are distributed to effector cells (smooth muscle, secretory, and absorptive cells)

and other plexi.

d. Efferents stimulate muscular, absorptive, and secretory activity, as well as hormone

release.

(1) Stretch and the presence of polypeptides in the stomach stimulate plexus to

release ACh.

(2) This induces HCI secretion into the lumen via direct effect on parietal cells and

through gastrin secretion.

e. Tiansmitters of three ffpes are contained in plexi:

(l) Cholinergic (excitatory)

(2) Adrenergic

(3) Noncholinergic and nonadrenergic (inhibitory)

f. Mucosal chemoreceptors sensitive to H+ and polypeptides and stretch receptors are

also found in plexi.

Extrinsic innervation of the gastrointestinal tract. The sympathetic and parasympa-

thetic nervous systems exert primarily a modulating effect on gut activity.

a. Sympathetic nervous system

(1) Preganglionic fibers originate in cell bodies in lateral horns of the thoracolum-

bar region of the spinal cord.

(2) Postganglionic fibers synapse indirectly via thoracic splanchnic nerves on

smooth muscle cells of blood vessels (constriction) and the lamina muscularis

mucosa (excitatory).

(3) Postganglionic fibers synapse directly on the myenteric plexus (inhibitory), sali-

vary glands (excitatory), smooth muscle cells in the circular layer (inhibitory),

and smooth muscle cells of sphincters (excitatory). They also inhibit pancreatic,

small intestinal, and colonic function.

(4) Effects are accentuated by epinephrine and norepinephrine from the adrenal

medulla, which inhibit smooth muscle (decrease motility) and stimulate vaso-

constriction to decrease blood supply.

b. Parasympathetic nervous system acts in the opposite way, by increasing motility and

promoting vasodilatation, thereby increasing blood flow to the gut.

(l) Preganglionic fibers (cholinergic, purinergic, and peptidergic) originate in the

Bridge to Pathology

Hirschsprung Disease

Congenital defect leading toincomplete development ofneural innervation of thecolon (absence of Auerbachand Meissner plexi). Leads tosevere obstruction,constipation, and evenmegacolon.

3 .

167


In a Nutshell

Sympathetic Nervous System

. .L Motility

. J Blood supply to gut

. J Secretion

ParasympatheticNervous System

. t Motility

. t Blood supply to gut

. t Secretion

In a Nutshell

Segmentation provides formixing of chyme, whileperistaltic movements propelchyme along the gut.

craniosacral division of the neuraxis and consist of vagus (cranial) and pelvicsplanchnic (sacral) outflow to the intrinsic plexi.

(2) Vagal parasympathetic fibers originate in the dorsal motor nucleus of the vagusin the floor of the fourth ventricle and project to three areas: esophageal plexusinnervates the esophagus, heart, and other thoracic structures; the anterior vagaltrunk innervates gastric, celiac, hepatic, and pyloric areas; the posterior vagaltrunk innervates the pylorus, duodenum, pancreas, small intestine, cecum, andascending and right transverse colon.

(3) Sacral parasympathetic fibers flow out from sacral segments 2,3, and 4 andinnervate the anorectal area, descending sigmoid, and left colon.

(4) Most PNS nerves are postganglionic, cholinergic, and excitatory, providinginnervation to longitudinal muscle bundles that increase the motiliry.

(5) PNS nerves bring circular bundles closer to their depolarization threshold,increasing motility. The PNS is inhibitory to the LES and stomach. Theseinhibitory fibers are neither cholinergic nor adrenergic. The predominanttransmitters are NO and VIR but dopamine, purine, and small peptides may alsoserve as neurotransmitters in some cases.

c. Sensory receptors influence secretion and motility.

(1) Chemoreceptors are slow adapting, and respond to changes in pH, osmolariryfat, and carbohydrate concentrations.

(2) Mechanoreceptors are slow adapting and respond to stretch and distention.

(3) Nociceptors transmit painful stimuli over somatic sensory fibers (basis forreferred pain).

4. Smooth muscle physiology

a. Contraction of the smooth muscle cell follows electrical changes in its membranepotential, which depend on electrolyte distribution, permeability of the membrane,and the Na+-K+ pump.

b. Hyperpolarization is associated with decreased wall tension.

c. Depolarization is associated with increased wall tension.

B. Types of muscle contraction

l. Tonic contraction. Constant, low-grade tone is maintained in the gut wall on whichstronger contractions are superimposed. Tonic contractions prevent the distention of gut.Loss of tone (loss of parasympathetic stimulation) results in retention of gut contents andconstipation.

2. Rhythmic contraction. Stretching of any part of the gut (e.g., by filling) directly elicitsbursts of action potentials in the enteric nervous system and causes a reflex contraction.There are two types of rhythmic contraction:

a. Mixing movements, called segmentation, look like beads on a string, with narrowconstricted areas of the gut alternating with bloated areas. The stretch in these bloat-ed areas initiates contractions, which cause these areas to become narrow and to bloatthe adjoining previously narrow regions. This results in mixing of the gut contents.

b. Propulsive movements (peristalsis) consist of rhythmic contraction and relaxation ofcircular and longitudinal muscles, which create a moving ring of constriction thatmoves food along the gut.

r68

Gastrointestinal Pathology

There are many different organs included in the gastrointestinal system. Castrointestinal pathology,therefore, includes a wide variety of disorders, from peptic ulcer disease to colorectal cancer togallstones. Since many of these disorders initially present with similar symptoms (abdominal pain,diarrhea, constipation), it is important to be able to recognize the specific risk factors and signsassociated with each disorder. This chapter will discuss the pathology of each organ in thegastrointestinal system, along with the associated risk factors and clinical presentations.

ORAI CAVITYA. Congenital malformations include cleft lip and cleft palate. Both are generally treated

surgically within the first six months of life.

B. Teeth

1. Enamel hypoplasia is due to a defect in enamel formation, resulting from dysfunction ofameloblasts, which form horizontal bands of discolored, pitted indentations. It may becaused by deficiencies of calcium, phosphorus, vitamins A, C, and D; excess fluoride;infections (e. g., syphilis) ; hypoparathyroidism; and hypothyroidism.

2. Pigmentation of developing teeth may be caused by excess bile pigments in biliary dis-ease, bilirubin in hemolytic anemias, or tetrarycline.

3. Congenital syphilis leads to malformation of teeth as a result of inflammatory changes inameloblasts and odontoblasts.

C. Oral mucosa

1. Common periodontal diseases

a. Gingivitis is a chronic inflammation of the gingivae.

b. Periodontitis, or pyorrhea, is gingivitis that has spread into tooth cementum and alve-olar bone. Complications include suppurative infection, abscess, and bone resorption.

c. Aphthous ulcers are painfi.rl ulcers commonly known as "canker sores." They are notinvasive and may be present as a single lesion or in crops, each of which is usually lessthan 0.5 cm. They often appear during febrile illness or other physical or emotionallystressfrrl situations, and are often found in patients with ulcerative colitis.

2. Oralmanifestations of systemic disease

a. Vitamin deficiencies

( 1) Vitamin B deficienry leads to atrophic glossitis as a result of reduced cell divi-sion in the squamous mucosa.


The pathologic effect oftetracycline on developingbones and teeth has long beena favorite USMLE side effect.Remember: No tetraryclinefor pregnant women!

r69


(2) Vitamin C deficienry causes bleeding gums as a result of weakened connectivetissue.

b. Pregnancy may cause gingivitis and increased vascularity of the gingivae.

c. Hematologic abnormalities

(1) Thrombocytopenia may cause petechiae and excess bleeding.

(2) Leukemia may cause red, boggy gingivae infiltrated by leukemic cells.

(3) Pernicious anemia causes a smooth, beefr, red tongue due to squamous atrophy.

d. Diabetes may produce dryness of the mucosa and a tendency to form abscesses as aresult of impaired microcirculation.

e. Addison disease leads to generalized excessive pigmentation; Peutz-feghers syndromeleads to patchy pigmentation.

f. Systemic infectious diseases

(1) Scarlet fever, toxic shock syndrome, and Kawasaki's disease cause a strawberrytongue.

(2) Measles produces Koplik spots, which are tiny white specks on a red base, foundon the buccal mucosa in the prodromal stage of illness.

3. Infections

a. Necrotizing gingivitis ("trench mouth") produces crater-like depressions at the gin-gival margin. It is painful and causes a fetid odor.

b. Herpetic gingivostomatitis is due to herpes simplex and is usually seen in children.

c. Oral thrush is caused by Candida alhicans, which produces white adherent patches.Thrush is associated with impaired immunity or debilitation, and is commonly seenin patients with AIDS or in patients undergoing chemotherapy.

d. Herpangina is due to coxsackievirus A and causes vesicular lesions, typically in thepharynx.

e. Syphilis may produce a variety of lesions:

(1) Primary syphilis produces chancres on the lips.

(2) Secondary syphilis produces maculopapular eruptions.

(3) Tertiary syphilis produces gummae of the palate and atrophic glossitis.

4. Keratotic abnormalities

a. Lichen planus appears as white reticulate lesions on the buccal mucosa and tongue.

b. Leukoplakia appears as white plaques on oral mucosa, produced by hyperkeratosisof the epithelium. Ten percent of cases of leukoplakia have epithelial dysplasia, aprecancerous lesion. Smoking, smokeless tobacco, alcohol abuse, chronic friction, andirritants are predisposing factors.

c. Erythroplakia (dysplastic leukoplakia) appears flat, smooth, and red. Significantnumbers of atypical epithelial cells are seen microscopically. There is a high risk ofmalignant transformation.

t70

Pathology

d. Hairy leukoplakia is so named because of its wrinkled surface. Patches occur on theside rather than the middle of the tongue. There arefar fewer arypical cells than are seenin erythroplasia. Malignant transformation does not occur, despite its association withHIV and associated infections, including papilloma and Epstein-Barr viruses.

5. Tumors

a. Benign tumors include hemangiomas, hamartomas, fibromas, lipomas, adenomas,papillomas, neurofibromas, and nevi.

b. Malignant tumors. By far, the most common malignant tumor is squamous cell (epi-dermoid) carcinoma. The peak incidence ranges from age 40-70. Squamous carcino-ma is associated with tobacco and alcohol use, particularly when used together.Pathologicully, it may be papillary or ulcerative. The lower lip is the most common site,but cancer of the floor of the mouth, tongue, and buccal mucosa are frequently seen.

D. Salivaryglands

1. Inflammation

a. Sialolithiasis produces a secondary inflammatory reaction to obstruction and theresultant enlargement of ducts by stones. It may be complicated by actual infectionwith mouth flora.

b. Sialadenitis is a primary inflammatory reaction, but it is not always infectious. It maybe part of an autoimmune disease (e.g., Sjogren syndrome), or the result of bacterialor viral (e.g., mumps) infection.

2. Tumors. The parotid gland accounts for more than three-quarters of these tumors, mostof which are benign. Of the remainder, more occur in the submandibular gland than inthe sublingual, and most of these are malignant. Many are surgically cured, but localrecurrence is common.

a. Pleomorphic adenoma is generally benign and accounts for approximately three-quarters of all salivary gland tumors. It is composed of multiple epithelial andmesenchymal cell types. Complications may arise due to involvement of cranialnerve VII.

b. Warthin tumor (adenolymphoma) is also benign, occurring almost exclusively in theparotid gland. It is grossly cystic. Microscopic examination reveals cell types sugges-tive of branchial cleft origin embedded in a lymphoid matrix.

c. Mucoepidermoid tumors also occur primarily in the parotid and have a high rate ofmalignant transformation. The malignant component is usually squamous cell.

d. Cylindroma (adenoid rystic carcinoma) is more common in the minor salivaryglands found in the oral mucosa, and metastases are more common than in othertumors of the salivary glands. Facial nerve complications are frequent.

(1) Grossly, the tumor forms multiple lobules surrounded by a capsule.

(2) Microscopically, small cells form glands containing mucoid material.

l7l


Clinical Correlate

e"opn"gu"---+ (H i lrrachea-r

I I tt | lI\U)Nl(/\) \\ |

Tracheoesophagealfistula

ESOPHAGUSA. Congenital malformations

l. A tracheoesophageal fistula (the most prevalent esophageal anomaly) occurs most com-monly as an upper esophageal blind pouch with a fistula between the lower segment of theesophagus and the trachea. It is associated with hydramnios, congenital heart disease, andother gastrointestinal malformations.

2. Esophageal atresia is associated withVATER syndrome (vertebral defects, anal atresia,tra-cheoesophageal fistula, and renal dysplasia). It does not usually occur as an isolatedanomaly.

3. Stenosis refers to a narrowed esophagus with a small lumen. It may be congenital oracquired, e.g., through trauma or inflammation.

B. Inflammatory disorders

1. Esophagitis most often involves the lower half of the esophagus.

a. Clinical features. Patients experience substernal burning associated with regurgita-tion, mild anemia, dysphagia, hematemesis, and melena. Esophagitis may predisposeto esophageal cancer.

b. Etiology

(l) Refluxesophagitis is due to an incompetent lower esophageal sphincter thatpermits reflux of gastric juice into the lower esophagus.

(2) Irritants such as citric acid, hot liquids, alcohol, smoking, corrosive chemicals,and certain drugs, such as tetrarycline, may provoke inflammation.

(3) Infectious etiologies include herpes, CMV and C. albicans. The immunocom-promised host is particularly susceptible to infectious esophagitis.

c. Pathology

(1) Grossly, there is hyperemia, edema, inflammation, and superficial necrosis.

(2) Microscopically, the inflammatory exudate is usually nonspecific.

d. Complications include ulceration, bleeding, stenosis, and squamous carcinoma.

2. In Barrett esophagus, gastric or intestinal columnar epithelium replaces normal squa-mous epithelium in response to chronic reflux. Ulceration, if present, is usually at thesquamocolumnar junction, increasing the risk of adenocarcinoma by 30-a0 times whensmall bowel-type epithelium is present.

C. Motor disorders. Normal motor function requires effective peristalsis and relaxation of thelower esophageal sphincter.

1. Achalasia is a lack of relaxation of the lower esophageal sphincter (LES), which may beassociated with aperistalsis of the esophagus and increased basal tone of the LES.

a. Clinical features. Achalasia occurs most commonly between the ages of 30 and 50.Typical symptoms are dysphagia, regurgitation, aspiration, and chest pain. The lack ofmotility promotes stagnation and predisposes to carcinoma.

b. Pathology. The loss of ganglion cells in Auerbach plexus may be secondary toChagas disease (Trypanosoma cruzi), or an infiltrating malignancy, or it may have anidiopathic cause.

Figure l l-5-1.The most

common type oftracheoesophageal

fistula

Note

Reflux occurs when LESpressure decreases enough toallow seepage of stomachcontents back into theesophagus.

In a Nutshell

Achalasia is a lack ofappropriate LES relaxation andesophageal peristalsis from aloss of myenteric plexus cells.Dysphagia is the hallmarksymptom.

172

Pathology

2. Hiatal hernia is the herniation of the abdominal esophagus, the stomach, or both,through the esophageal hiatus in the diaphragm.

a. Sliding hernia, making up approximately 90o/o of cases, occurs when the esopha-gogastric junction slides into the thorax. The condition is often associated with reflux.

b. Paraesophageal hernia occurs when an area of gastric cardia rolls along the esopha-gus through an incompetent hiatus into the thorax. The esophagogastric junctionremains in the abdomen. Paraesophageal hernia may cause postprandial bloating andbelching. The herniated organ is at risk for strangulation and infarction.

3. Scleroderma is an autoimmune disease, seen primarily in women, that causes subcuta-neous fibrosis and widespread degenerative changes. (A mild variant is known as CRESTsyndrome, which stands for calcinosis, Raynaud phenomenon, esophageal dysfunction,sclerodactyly, and telangiectasia.) The esophagus is the most frequently involved region ofthe gastrointestinal tract.

a. Clinical features are mainly dysphagia and heartburn due to reflux esophagitis causedby aperistalsis and incompetent LES.

b. Pathology is predominantly atrophy of smooth muscle with fibrous replacement.Chronic reflux results in stenosis and ulceration. Anti-ScL 7O and anticentromereantibodies are typically associated with this disease.

D. Rings and webs

1. Webs are mucosal folds in the upper esophagus above the aortic arch.

2. Schatzki rings are mucosal rings at the squamocolumnar junction below the aortic arch.

3. Plummer-Vinson syndrome consists of a triad of dysphagia, atrophic glossitis, and ane-mia. Webs are found in the upper esophagus. The syndrome is associated specifically withiron deficiency anemia and sometimes hypochlorhydria. Patients are at increased risk forcarcinoma of the pharynx or esophagus.

E. Mallory-Weiss tears refers to small mucosal tears at the gastroesophageal junction sec-ondary to recurrent forcefrrl vomiting, usually seen in alcoholics. The tears occur along thelong axis and result in hematemesis (sometimes massive). The course is usually benign, andthe tears cease without intervention if the patient stops drinking.

F. Esophageal varices are dilated tortuous vessels of the esophageal venous plexus resultingfrom portal hlryertension. When portal blood pressure increases, collateral circulationthrough the coronary veins to the esophageal veins and then to the arygous system develops,yielding vessel engorgement. Portal hypertension is most often caused by hepatic cirrhosis.Another common cause is obstructive thrombosis of the portal or splenic vein. Esophagealvarices are prone to bleeding and ulceration, which may be life-threatening, especially incirrhotics.

G. Diverticula are sac-like protrusions of one or more layers of the pharyngeal or esophageal wall.

1. Zenker diverticula occur at the junction of the pharynx and esophagus. They are falsediverticula formed by herniation of the mucosa only. The frequency is greater in men thanwomen, and they occur most often in the elderly. Symptoms include dysphagia and regur-gitation of undigested food soon after ingestion.

2. Tiaction diverticula occur in the midpart of the esophagus. They are true diverticula (alllayers of the esophagus outpouch). These diverticula are caused by the adherence of theesophagus to a scarred mediastinal structure such as a calcified lymph node. They are usu-ally asymptomatic.

ln a Nutshell

Plummer-Vinson Syndrome

. Dysphagia

. Clossitis

. lron deficiency anemia

. Esophageal webs

In a Nutshell

Esophageal varices are oftendue to portal hypertension.They may bleed or ulcerate,which can be lifethreatening.

In a Nutshell

Mallory-Weiss Tears VersusEsophageal Varices

While both are associatedwith alcohol abuse and canpresent with hematemesis,Mallory-Weiss tears typicallyoccur acutely as a result ofretching/vomiti ng. Esophagealvarices result from portalhypertension and will usuallypresent with a moresignificant bleeding episode.

l7 t

Gastointestinal System

Clinical Correlgte

Pyloric stenosis is congenitalhypertrophy of pyloric muscle,presenting with projectilevomiting and requiringsurgical treatment.

H. Tumors

1. Benign tumors are rare.

2. Carcinoma of the esophagus most commonly occurs after age 50 and has a male:femaleratio of 4:1.

a. Incidence. Carcinoma of the esophagus is prevalent in northern Iran, Central Asia,and Southeastern Africa. In the United States, the incidence is much higher in AfricanAmericans than in Caucasians.

b. Etiology. It is associated with smoking, alcohol ingestion, nitrosamines in food, acha-lasia, webs, rings, diverticula, Barrett's esophagus, and deficiencies of vitamins A andC, riboflavin, and some trace minerals.

c. Clinical features include dysphagia (first to solids), retrosternal pain, anorexia, weightloss, melena, and symptoms secondary to metastases.

d. Pathology

(1) Fifty percent occur in the middle third of the esophagus,30o/o in the lower third,and2}o/o in the upper third. Most esophageal cancers are now adenocarcinomas inCaucasians and squamous carcinomas in African Americans. Adenocarcinomasarise mostly out of Barrett's esophagus.

(2) There are three types of carcinomas. Polnroid carcinomas are large fungatingmasses protruding into the lumen; ulcerating carcinomas form a centralnecrotic crater, eroding deeply into surrounding structures; and infiltrative car-cinomas spread within the esophageal wall.

e. Prognosis is poor. Fewer than l0olo of patients survive 5 years, usually because diag-nosis is made at a late stage. The most common sites of metastasis are the liver andlung. The combination of cigarette smoking and alcohol is particularly causative foresophageal cancer (over 100x risk compared to nondrinkers/nonsmokers).

STOMACHA. Congenital malformations

1. Pyloric stenosis

a. Incidence. Pyloric stenosis occurs in roughly 1/600 live births, often in a first*bornmale child. The syndrome is four times more common in males than in females.

b. Clinical features. Projectile vomiting 3-4 weeks after birth associated with a palpa-ble "olive" mass in the epigastric region is observed.

c. Pathology shows hlpertrophy of the muscularis of the pylorus and failure to relax.

2. Diaphragmatic hernias are due to weakness in or absence of parts of the diaphragm,allowing herniation of the abdominal contents into the thorax.

B. Inflammation

1. Acute gastritis (erosive)

a. Etiology. Alcohol, aspirin and other NSAIDs, smoking, shock, steroids, and uremiamay all cause disruption of the mucosal barrier, leading to inflammation.

b. Clinical features. Patients experience heartburn, epigastric pain, nausea, vomiting,hematemesis, and even melena.

174

Pathology

c. Pathology

(1) Endoscopicallp patches of congested, edematous, erythematous mucosa areseen; petechiae and ulceration may also be noted.

(2) Microscopically, there is superficial acute inflammation and focal necrosis of themucosa.

2. Chronic gastritis (nonerosive) may lead to atrophic mucosa with lymphocytic infiltration.

a. Types

(1) Fundal (Type A) gastritis is often autoimmune in origin. It is the type associat-ed with pernicious anemia and, therefore, achlorhydria and intrinsic factor defi-cienry. It is associated with hyperplasia of G cells, hypergastrinemia, and occa-sionally with Hashimoto's thyroiditis and Addison's disease.

(2) Antral (Type B) gastritis is most commonly caused by Helicobacter pylori and isthe most common form of chronic gastritis in the U.S. H. pylori is also responsi-ble for proximal duodenitis in regions of gastric metaplasia. H. pylori is a spiral-shaped organism found in the mucosal layer of the stomach but is not invasive.It damages this protective layer by producing urease.

(3) Lymphocytic gastritis describes a dense lymphocytic infiltration of surfaceepithelium. It is not associated with H. pylori and may represent a gastric mani-festation of celiac sprue.

(4) Hypertrophic gastritis causes extreme enlargement of mucosal folds and thick-ened mucosa, which may mimic lymphoma on x-ray and may cause a protein-losing enteropathy (Menetrier disease).

b. Clinical features. The patient may be asymptomatic or suffer epigastric pain, nausea,vomiting, and bleeding. Gastritis may predispose to peptic ulcer disease, probably relat-ed to H. pylori infection.

c. Pathology

(1) Grossly, a thin, smooth, mucosa with flattened rugae is seen in atrophic gastritis.

(2) Microscopically, there is atrophy of gastric glands with infiltration by lympho-cftes and plasma cells; there is also mild atypia in superficial epithelial cells. InH. pylori-associated gastritis, atrophy is usually not present, but the mucosa isinfiltrated by polymorphonuclear leukocFtes. The infecting organism may alsobe seen in the mucous membrane.

3. Peptic ulcers are usually chronic, isolated ulcers observed in areas bathed by pepsin andHCl; they are the result of mucosal breakdown (Figure II-5-2).

a. Common locations are the proximal duodenum, the stomach, and the esophagus,often in areas of Barrett esophagus.

b. Etiology. There are several important etiologic factors. Duodenal ulcers occur pre-dominantly in patients with excess acid secretion, while gastric ulcers usually occur inpatients with lower than average acid secretion. Other predisposing conditions includesmoking, cirrhosis, pancreatitis, hyperparathyroidism, and H. pylori infection.Aspirin, steroids, and NSAIDs are known to be assoicated with peptic ulcer disease.Next to H. pylori colonization, aspirin or NSAID ingestion is the most common causeof peptic ulcer.

Clinical Correlate

Castritis may be acute(NSAIDs, alcohol, stress, etc.)or chronic (autoimmune orH pylorl.

Clinical Correlate

H. pylorihas now beenshown to be associated withgastritis, peptic ulcer disease,gastric adenocarcinoma, andsome gastric lymphomas (e.9.,MALTomas or mucosalassociated lymphoid tumors).Some MALTomas have beenshown to regress ontreatment with antibiotia thateradicate H. pylori.

Clinical Conelate

Recent evidence raises theimportance of H. pyloriin thepathogenesis of peptic ulcerdisease. Modification of acidsecretion alone does noteffect a lasting remission, butcoupling this with antibiotictherapy that eradicates H.pyloriis apparently curative inmost patients.

175

Gashointestinal System

ln a Nutshell

Castric ulcers may developinto, or develop from, amalignancy. Duodenal ulcersare never malignant.

c. Clinical features. Patients experience episodic epigastric pain. Duodenal and mostgastric ulcers are relieved by food or antacids. Approximately one-fifth of gastric ulcerpatients get no relief from eating or experience pain again within 30 minutes.

d. Pathology. Benign peptic ulcers are well-circumscribed lesions with a loss of themucosa, underlying scarring, and sharp walls.

e. Complications include hemorrhage, perforation, obstruction, and pain. Duodenalulcers do not become malignant. Gastric ulcers do so only rarely; those found to bemalignant likely originated as a cancer that ulcerated.

f. Diagnosis is made by upper gastrointestinal series, endoscopy, and biopsy to rule outmalignancy or to demonstrate the presence of H. pylori.

4. Stress ulcers are superficial mucosal ulcers of the stomach or duodenum or both. Stressmay be induced by burns, sepsis, shock, trauma, or increased intracranial pressure. Ulcersoccurring in burn victims (Curling ulcers) are particularly susceptible to bleeding. Thosedeveloping in CNS trauma patients (Cushing ulcers) pose a high risk for perforation.

Figure ll-5-2. Peptic ulcer disease of the stomach (gross).

C. Tirmors

1. Benign

a. Leiomyoma, often multiple, is the most common benign neoplasm of the stomach.Clinical features include bleeding, pain, and iron deficienry anemia.

b. Gastric polyps are due to proliferation of the mucosal epithelium.

(1) Hyperplastic polyps account for 80o/o of gastric polyps.They are small (<1 cm),oval, and are composed of hyperplastic glands. They do not undergo malignanttransformation, but because they are associated with gastritis, some patientsdevelop carcinoma elsewhere in the stomach.

(2) Adenomatous polyps are often larger than 2 cm, forming papillary projectionson a wide base. They have a high malignant potential (75o/o of lesions larger than2 cm demonstrate malignant changes).

176

Pathology

2. Matignant tumors

a. Carcinoma

Clinical Correlate

The Virchow node is a leftsupraclavicular lymph node.Its presence suggestsmeta$atic stomachcarcinoma.

Note

An infiltrating gastriccarcinoma with a diffusefibrous response is called alinitis pla$ica (leather-bottlestomach).

Note

Signet ring cells arecharacteristic of ga$riccarcinoma, but are not theonly type of cell found.

(1) Etiology. Primary factors include genetic predisposition and diet; other factorsinclude hypochlorhydria, pernicious anemia, atrophic gastritis, adenomatouspolyps, and exposure to nitrosamines. H. pylori are also implicated.

(2) Clinical features. Stomach cancer is usually asymptomatic until late, then pre-sents with anorexia, weight loss, anemia, epigastric pain, and melena. TheVirchow node is a common site of metastasis.

(3) Pathology.Approximately one-half of cancers arise in the antrum and pylorus andone-quarter in the gastric cardia. Early asymptomatic gastric carcinoma has notyet microscopically invaded the muscularis propria. Symptomatic late gastric car-cinoma may be expanding or infiltrative. In both cases the prognosis is poor(approximately 10olo 5-year survival), and metastases are frequently present at thetime of diagnosis. Adenocarcinomas are most common (Figures II-5-3 andII-5-4). Neuroendocrine (undifferentiated) tumors may present with symptomsof hormone excess, which are produced by tumors derived from normally secret-ing cells in the stomach. These tumors may secrete several amine or peptide hor-mones such as histamine, 5-hydroxytryptamine, and adrenocorticotropic hor-mone (ACTH).

Figure ll-5-3. Adenocarcinoma of the stomach (gross).

177


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1;H#' L

1 : . J

lW',ru:S;@,.,;:s

Figure ll-5-4. Carcinoma of the stomach (microscopic).

b. Gastrointestinal lymphomas may be primary in the gastrointestinal tract as solitarymasses.

(1) Grossly, there are three types: polypoid masses, large plaques with necrotic ulcers,and infiltrative.

(2) Microscopically, the most common are the diffirse histiocytic $rpe, followed bylymphocytic lymphomas.

c. Sarcoma is a rare,large, ulcerating mass that extends into the lumen.

d. Metastatic carcinoma. Krukenberg tumor is an ovarian metastasis from a gastriccarcinoma.

e. Kaposi sarcoma. The stomach is the most commonly involved gastrointestinal organin Kaposi sarcoma.It occurs primarily in homosexual men, appearing as hemorrhagicpolypoid, or umbilicated nodular lesions, typically in a submucosal location. It rarelycauses symptoms.

SMAtt INTESTINEA. Congenital anomalies

1. Meckel diverticulum (a true diverticulum) is due to persistence of the omphalomesen-teric vitelline duct. It is located within 12 inches of the ileocecal valve. Approximately50olo cause ulceration, inflammation, and gastrointestinal bleeding due to the presence ofectopic acid-secreting gastric epithelium.

2. Atresia is a congenital absence of a region of bowel, leaving a blind pouch or solid fibrouscord. It leads to obstruction and vomiting in the neonatal period.

3. Stenosis refers to a narrowing of any region of the gastrointestinal tract, which may causeobstruction.

4. Duodenal diverticula are areas of congenital weakness permitting saccular enlargement.The duodenum is the most common region of the small bowel to contain diverticula.

t78

Pathology

5. Diverticula of jejunum and ileum are herniations of mucosa and submucosa at pointswhere the mesenteric vessels and nerves enter.

B. Infections

1. Bacterial enterocolitis may be caused by the ingestion of preformed bacterid toxins,producing symptoms ranging from severe but transient nausea, vomiting, and diarrhea(Staphylococcus aureus toxin) to lethal paralysis (Clostridium botulinun toxin). Ingestionof toxigenic bacteria with colonization of the gut (e.g., Vibrio cholera, toxigenic E. coli,various species of Campylobacter jejuni, Shigella, Salmonella,Yersinia, and many others) isanother potential cause.

2. Nonbacterial gastroenterocolitis

a. Viral

(1) Rotavirus (children)

(2) Norwalk virus (adults)

b. Fungal-Candida

c. Parasitic

(l) Entamoeba histolytica

(2) Giardialamblia

3. In HIV patients. Causes of infectious diarrhea in HIV patients include Crlrytosporidium,Microsporidia, lsospora belli, CMV and M. avium-intracellulare. HW infection itself canbe associated with abnormal small bowel mucosa, including partial villous atrophy andcrlpt hyperplasia (also known as "idiopathic AIDS enteropathy").

C. Malabsorption is defined as impaired intestinal absorption of dietary constituents. Clinicalfeatures include diarrhea, steatorrhea, weakness, lassitude, and weight loss. Steatorrhearesults in deficiency of fat-soluble vitamins (A, D, E, and K) and calcium.

1. Celiac sprue

a. Etiology. Celiac sprue (nontropical sprue or gluten enteropathy) is caused by an aller-gic, immunologic, or toxic reaction to the gliadin component of gluten. There is agenetic predisposition.

b. Clinical features reflect malabsorption. There is a reversal of symptoms with a gluten-free diet, and morphologic changes usually revert to normal. The disease predisposesto neoplasm, especially lymphoma.

c. Pathology shows atrophy of villi in the jejunum, crypt hyperplasia and lengthening,flattening of the mucosal surface, and a chronic inflammatory reaction in the laminapropria. It affects only the proximal small bowel.

2. Tropical sprue

a. Etiology. Tiopical sprue is of unknown etiology, but maybe caused by enterotoxigenicE. coli.

b. Incidence. There is a high incidence in the tropics, especially in Vietnam and PuertoRico. Occasionally, the disease occurs in epidemics.

c. Pathology. Pathologic changes are variable but are similar to the changes in celiac dis-ease. Unlike celiac sprue, however, tropical sprue affects the entire length of the smallbowel. It often responds to long-term treatment with tetrarycline and folic acid.

t79


Clinical Correlate

Lactase deficiency leads tomilk intolerance, withsymptoms of bloating,diarrhea, and crampingfollowing ingestion of dairyproducts.

Clinical Correlate

Small bowel infarcts are oftendue to thromboembolicevents, and present as anacute abdomen.

3. Whipple disease is a rare systemic disorder characterized by clumps of periodicacid-Schitr (PAs)-positive macrophages in the lamina propria of intestines fi,rll of andsurrounded by small bacilli (Tropheryma whippelii).

a. Incidence. The ratio of men to women is 10:1.

b. Clinical features includephadenopathy, and rarely,tetracvcline.

diarrhea, steatorrhea, weight loss, fever, arthralgias, lym-neurologic abnormalities. Whipple disease also responds to

c. Pathology shows villi distended with macrophages full of bacilli in the lamina propriaand mesenteric lymph nodes.

4. Disaccharidase deficiency is due to a deficiency of brush border enzymes. Lactase defi-ciency is most common.

D. Vascular abnormalities often lead to ischemic bowel disease.

l. Transmural infarction is more common in the small intestine, which does not have therich collaterals of the colon.

a. Etiology

(1) Thrombosis or embolism of the superior mesenteric artery accounts forapproximately 50olo of cases. The thrombosis is most often secondary toatherosclerosis, but emboli may arise from cardiac sources or atheroscleroticplaques higher in the aorta. The inferior mesenteric artery accounts for approx-imately 25o/o of cases.

(2) Venous thrombosis accounts for 25o/o of. cases. It typically occurs post CHF, inpolycythemia, in hypercoagulable states, or in inflammations of the abdomen.

(3) Internal hernias can strangulate entrapped loops of bowel. They can occurcongenitally in children and young adults, or as a result of abdominal surgery(peritoneal adhesions) in adults.

b. Clinical features. There is a 50-757o mortality rate. Infarction of the bowel usuallyoccurs after age 60 and presents as an acute abdomen with abdominal pain, nausea,and vomiting.

c. Pathology shows a hemorrhagic infarction with fibrinous or fibrinosuppurative exu-date on the mucosa, leading to ulceration, secondary bacterial infection, or perfora-tion.

2. Mucosal and mural infarction (acute hemorrhagic gastroenteropathy) is characterizedby patchy hemorrhagic necrosis of the mucosa and submucosa sparing the deeper layers.This pattern is related to nonocclusive hypoperfusion in CHF or shock.

E. Obstructive lesions

1. Hernias cause l5o/o of small intestinal obstruction. They are due to a protrusion of aserosa-lined sac through a weakness in the wall of the peritoneal cavity. They occur mostcommonly at the inguinal and femoral canals, at the umbilicus, and with scars. They maylead to entrapment, incarceration, and strangulation of the bowel.

2. Adhesions are fibrous bands connecting loops of bowel to each other or to other regionsof the peritoneal cavity. They usually occur after surgery and are caused by the bandingof scar tissue. They may result in internal hernias with subsequent obstruction andinfarction.

r80

Pathology

3. Intussusception is due to invagination and telescoping of one segment of bowel into anadjacent region. It is more common in infants and children. In children, some may bereduced with a diagnostic barium enema. It is usually caused by an intraluminal mass(e.9., polyp, tumor, hematoma, Meckel diverticulum, etc.).

4. Volvulus is the twisting of the bowel about its mesenteric base. It may cause obstructionand infarction. Volvulus frequently occurs in the elderly at the sigmoid colon as a resultof redundant mesentery at that site.

5. Other causes of mechanical obstruction include obstruction by gallstones or the extrin-sic compression by a mass (e.g., a tumor) in adjacent bowel.

F. Tirmors of the small bowel account for only 5o/o of gastrointestinal tumors. The benign tomalignant ratio is 2:3.

1. Benign tumors in descending order of frequency include: leiomyomas, lipomas, adeno-mas (polyps), angiomas, and fibromas. Adenomatous polyps are most common in thestomach and duodenum and may be single or multiple, sessile or pedunculated. The larg-er the polyp, the greater the incidence of malignant transformation.

2. Malignant tumors, in descending order of frequency, include: endocrine cell tumors,lymphomas, adenocarcinomas, and leiomyosarcomas.

a. Endocrine cell tumors (e.g., carcinoid, argentaffin carcinoma) are slow growing butmay invade, metastasize, or cause the carcinoid syndrome when they metastasize tothe liver. They arise from enterochromaffin cells. This family of tumors is known asAPUD (amine precursor uptake and decarboxylation) tumors, which produce, store,and secrete amines and polypeptides.

(1) Clinical features. Carcinoids may present with abdominal pain, weight loss,anorexia, diarrhea, and rectal bleeding. Tumors in the small intestine may causeobstruction and even metastases. Five to ten percent of tumors produce thecarcinoid syndrome characterizedby vasomotor disturbances, such as flushingor cyanosis, intestinal hypermotiliry bronchoconstriction, hypotension, andright-sided cardiac involvement. The carcinoid syndrome occurs if there iswidespread liver metastases or if the venous blood from the tumor does notdrain into the liver. The liver deaminates the vasoactive products secreted by thetumor, including serotonin, histamine, various kinins, and prostaglandins. Whennot metastatic, carcinoid tumors are usually treated successfully by surgery.

(2) Pathology. Typical tumors are l-2 cm in diameter, yellow, nodular, and causemucosal elevation. Microscopically, nests of cells arranged in cords and rosettesare seen. There is a uniform cell type with round nuclei and abundanteosinophilic cytoplasm. Electron microscopy examination reveals secretorygranules. Carcinoids invade the submucosa and muscularis and may penetratethe bowel wall.

b. tymphoma of the small bowel is usually of the non-Hodgkin, large cell, diffr,rse type.In immunosuppressed patients, the incidence of primary lymphomas of the smallintestine is increasing. These have a poor prognosis. Another form of primary lym-phoma of the bowel is called MAtlloma. These are often follicular and follow a morebenign course. Some lymphomas that are associated with H. pylori infection regressafter antibiotic therapy.

c. Adenocarcinoma is rare. It typically forms an encircling mass. Symptoms occur late.

Clinical Correlate

Carcinoid tumors may presentwith abdominal pain, rectalpain, and other symptoms.Systemic symptoms includeflushing, hypotension, andbronchoconstriction.

Note

Histologically, carcinoidtumors appear as otherneu roendocrine tumors, withnests of small. uniform cells.

Bridge to Heme/tymph

Non-Hodgkin lymphoma isdiscussed in detail in theH ematol o gi c/Lym p h o reti cu la rPathology chapter of OrganSystems Book t fl/olume lll).

t 8 l


rARGE TNTESTTNE (COTON)A. C,ongenital anornalies

I . Hirschsprung disease produces a markedly distended colon, usually proximal to the rec-tum.

a. Incidence. The overall incidence is approximately 1 in 5,000 births, with an increasedincidence in Down's syndrome to about 2qo.

In a Nubheil b' clilicarfeaturcsJ::ii:::.H:HliT:"n$i:Hffi::$xfi:"*H:ffd::

Hrrscnsprung orsease rs a tion' vomiting' and abdominal distention'

congenital absence of c. Diagnosis is made by barium enema and rectal biopsy.

ParaslmPathetic Sanslion cells d. Pathogenesis is an absence ofganglion cells ofMeissner andAuerbach plexus in thein the distal colon and distal iolon. Muscle in this region is unable to relax frrlly to permit adequate peristal-presents soon after birth with sis. Passage of contents is blocked, and the proximal colon dilates. The disease alwaysinadequate passaSe of stool. involves the recturn and may extend as far back as the ileum.

e. Pathology

(1) crossly, there is a distended bowel with either hypertrophy or thinning of thewall proximal to the segment that is aperistaltic.

(2) Microscopicalln there is absence of ganglion cells in the submucosa and muscu-laris with proliferation of nonmyelinaGd nerves in undilated regions of the colon.

2. Imperforate anus is due to a failure of perforation of the membrane tlat separates the

Note endodermal hindgut from the ectodermal anal dimple.

B. Benign conditionsBecause onlv two lave6 of thegut wall are involved, the 1. Diverticular disease refers to multiple outpouchings of the colon.

outpouchings are technically a. Incidence. Diverticular disease is present in 30-50o/o of adult autopsies in the Unitedpseudodiverticula. States. There is a higher incidence with increasing age.

b. Pathogenesis. Hemiation of mucosa and submucosa through weak areas of the gutwall where arterial vasa recta perforate the muscularis is a characteristic pathologicfinding of the disease. It appears that increased intralurninal presswe and segmentalhlperactive peristalsis are not responsible for the development of diverticula; how-ever, they may exacerbate symptoms of the disease,

c. Clinical featwes

(l) Diverticulosis is often asymptomatic, but may present with pain and/or rectalbleeding.

(2) In contrast, diyerticulitis presents with pain and fever. It is distinguished fromdiverticulosis by the presence of inflammation, which may or may not causesymptoms. When symptomatic, the patient experiences colicky left lower abdom-inal pain, change in bowel habits, and melena, so-called "left-sided appendicitis."When there are inflammatory chang€s, they may present with fever, leukocytosis,and a left Iower quadrant mass that raises suspicions of cancer.

d. Pathology

( 1 ) Grossly, diverticula are seen most frequently in the sigrnoid colon along mesen-teric and antimesenteric surfaces. Oupouchings are typically 0.5-l cm.

r82

Pathology

(2) Microscopically, attenuation of the muscularis with or without inflammation isseen. In diverticulitis, there may be perforation with inflammation and micro- ormacroabscess formation.

C. Inflammatory diseases

1. Crohn disease, or regional enteritis, causes a segmental, recurrent, granulomatousinflammatory disease of the bowel. It most commonly involves the terminal ileum andcolon but may involve any part of the gastrointestinal tract. There is a familial disposition.

a. Etiology. There is probably a similar etiology for both Crohn disease and ulcerativecolitis, which together are called inflammatorybowel disease. The following possibleetiologies have been considered: infectious; immunologic (both antibody-mediatedand cell-mediated); deficiencies of suppressor cells; and nutritional, hormonal, vascu-lar, and traumatic factors.

b. Clinical features. Crohn disease usually begins in early adulthood and is common inAshkenazic fews. Patients present with colicky pain, diarrhea, weight loss, malaise,malabsorption,low-grade fever, and melena. Crohn disease is a systemic disorder thatmay be associated with arthritis, erythema nodosum, uveitis, immunologic disorders,and ankylosing spondylitis. There is typically a remitting and relapsing course. If theinvolved bowel is resected,lesions frequently develop in previously uninvolved regionsof the bowel. Crohn disease leads to a minimally increased incidence of small boweladenocarcinoma, a very rare tumor.

c. Pathology. Crohn disease has a very characteristic pathology.

(1) Grossly, there are segmental areas (skip lesions) of involvement, most com-monly in the terminal ileum. Edema, inflammation, and fibrosis are seen. Thelumen becomes narrow causing a "string sign" on barium enema. Involved areaslead to adhesions, fistulae, fissures, strictures, possible anal involvement, andserositis.

(2) Microscopically, there is classically a transmural inflammation with lymphoidaggregates and noncaseating granulomas in about half the cases (Figure II-5-5).

: i+ , i ^ . ; : ,

,,t'fu'.' 1 . ; f t t

: ?!1,. :e

Clinical Correlate

Crohn disease presents withpain, diarrhea, weight loss,malabsorption, and malaise.

%,,,

l',i:|.

w?:t

fii

" : : ! : . ; : 1 ^ ; 4 : :e|'i:'qry.

i# ' ' , "

: : ' &'&

a.. *

!&-

%n

Figure ll-5-5. Crohn disease (microscopic).

t8r


ln a Nutshell

Ulcerative colitis is a chronicdisease characterized bycolonic mucosal andsubmucosal ulcerations.Bloody diarrhea is thehallmark clinical presentation.

ln a Nutshell

Crohn Disease. Anywhere along

gastrointestinal tract(usually terminal ileumand cecum)

. Skip lesions (notcontinuous)

. Transmural

. Fissures and fistulas

. Cranulomas

. Cobblestone mucosa

. "String sign" on bariumenema

Ulcerative Colitis. Continuous involvement

from rectum proximally

. Limited to mucosa andsubmucosa (not transmural;no fissures or fi$ulas)

. Pseudopolyps

. Crypt microabscesses

. Creater risk of developingcolon adenocarcinoma thanin Crohn disease

t84

2. Ulcerative colitis is a chronic relapsing disease characterized by ulcerations, predomr-nantly of the rectum and left colon, but which may affect the entire colon and occasion-ally the terminal ileum.

a. Incidence is higher in Caucasians than in Blacks, and is also more frequent in womenthan in men. The typical age of onset ranges from 12-35 years of age. There is adefi nite familial predisposition.

b. Etiology. Etiologic theories are similar to those for Crohn disease. Some inflammatorybowel disease has microscopic features of both ulcerative colitis and Crohn disease.

c. Clinical course is characterized by relapsing bloodymucus diarrhea, which may leadto dehydration and electrolyte imbalances, lower abdominal pain, and cramps. Thepatient may also experience systemic manifestations as with Crohn. The disease istreated initially with steroids and antibiotics, but eventually, most patients come tocolectomy. There is an increasedincidence of carcinoma of the colon, up to 50o/o after25 years with the disease.

d. Pathology

(1) Grossly, the disease almost always involves the rectum. It may extend proximal-ly to involve part of the colon or its entirety. There are superficial mucosal ulcers,shortening of the bowel, narrowing of the lumen, pseudopolypr, and backwashileitis.

(2) Microscopically, there is vascular congestion, an inflammatory infiltrate charac-terized by crypt microabscesses, which increase in size and undermine themucosa, then progress to ulceration. In contrast to Crohn disease, the inflamma-tion is usuallv confined to the mucosa and submucosa.

Thble II-5-1. Crohn disease versus ulcerative colitis.

Pathology Crohn Disease Ulcerative Colitis

Gross pathology Skip lesions, fistulae,strictures, fissures

Tiansmural fibrousthickening

Rectum often sparedOccasionally involves

total colon

Micropathology Tiansmural involvement Superficial involvementGranuloma formation No granulomas

Crypt abscessescharacteristic

Continuous involvement,superficial ulcers

PseudopollpsRectum involvedOften involves total colon

Endoscopicfindings

Cobblestoning, skip Generalized erythemalesions,aphthousulcers Contiguousinvolvement

3. Pseudomembranous colitis is an inflammatory process characterized by a pseudomem-branous exudate coating the colonic mucosa.

a. Pathogenesis. The syndrome is associated with antibiotic use (especially clindamycin),allowing proliferation of Aostridium dfficile, which produces an exotoxin.

b. Pathology. Gross pathology shows plaques of yellow-green mucinous exudate over-lnng an erythematous mucosa.

Pathology

'#+w,fu*. 1*,,

W,Figure ll-5-6. Ulcerative colitis (microscopic).

c. Clinical features include diarrhea that is often bloody, fever, and leukocytosis.

d. Diagnosis is made by identification of C. dfficile and toxin in stool.

e. Treatment includes stopping the original antibiotic and starting oral vancomycin ormetronidaz.ole. This disease is often a terminal complication in immunosuppressedpatients.

D. Vascular lesions

1. Ischemic injury. The large bowel is relatively protected because of a dual vascular supplyfrom both enteric vessels and accessory vessels from the posterior abdominal wall. Whenischemia does occur, pathologic processes are the same as in the small intestine.

2. Angiodysplasia (vascular ectasia) causes dilated tortuous vessels of the right colon,which cause lower gastrointestinal bleeding in the elderly. The highest incidence is inthe cecum.

3. Hemorrhoids are variceal dilatations of the anal and perianal venous plexus. They arecaused by elevated intra-abdominal venous pressure, often from constipation and preg-nancy, and are occasionally due to portal hypertension, where they are associated withesophageal varices. Hemorrhoids may undergo thrombosis, inflammation, and recanal-ization. External hemorrhoids are due to dilatation of the inferior hemorrhoidal plexus,while internal hemorrhoids are due to dilatation of the superior hemorrhoidal plexus.

E. Polyps are mucosal protrusions.

1. Hyperplastic polyps comprise 90o/o of all polyps. They are non-neoplastic and occurmostly in the rectosigmoid colon.

a. Grossly, they form smooth, discrete, round elevations.

b. Microscopically, glands and sawtooth crlpts are composed of a proliferation of gob-let and columnar epithelial cells. There is no atypia.

2. Adenomatous polyps are true neoplasms. There is a higher incidence of cancer in largerpolyps and in those containing a greater proportion of villous growth.

t85


In a Nutshell

Tubular, villous, andtubulovillous adenomata arefound in the colon. lncreasedvillous nature increases thelikelihood of malignancy.

a. Tubular adenomas (pedunculated polyps) make up 75o/o of adenomatous polyps.They may be sporadic or familial. For sporadic polyps, the ratio of men to women is2:1. The average age of onset is 60.

(1) Grossly, most occur in the left colon; 50o/o are single with a thin stalk supportinga tufted head.

(2) Microscopically, there is increasing anaplasia in large polyps. Nuclei lose theirbasal orientation and pile up. The nuclear-to-cytoplasmic ratio decreases andmitoses increase. The stalk is covered by normal colonic epithelium; the head ofthe polyp is covered by adenomatous epithelium, forming atypical glands andtubules. Cancerous transformation (i.e., invasion of the lamina propria or thestalk) occurs in approximately 4o/o of patients.

b. Villous adenomas are the largest,least common polyps, and are usually sessile. Aboutone-third are cancerous. Most are within view of the colonoscope.

(1) Grossly, they form "cauliflower-like" sessile growth 1-10 cm in diameter, whichare broad-based and have no stalks.

(2) Microscopically, multiple papillary projections make up at least half the polyps.In different microscopic fields, well-differentiated areas, carcinoma in situ, andinvasive cancer may be seen.

c. Tubulovillous adenomas have combined tubular and villous elements. Any increasein villous elements increases the likelihood of malignant transformation.

3. Familial polyposis is due to deletion of a gene located on chromosome 5q.

a. Familial multiple polyposis (adenomatous polyposis coli) shows autosomal domi-nant inheritance and the appearance of polyps during adolescence; polyps start in therectosigmoid area and spread to cover the entire colon. The polyps are indistinguish-able from sporadic adenomatous polyps. Virtually all patients develop cancers. Whendiagnosed, total colectomy is recommended.

b. Gardner syndrome refers to colonic polyps associated with other neoplasms (e.g., inskin, subcutaneous tissue, bone) and desmoid tumors. The risk of colon cancer isnearly 100o/o.

c. Peutz-feghers syndrome presents with polyps on the entire gastrointestinal tract(especially the small intestine) associated with melanin pigmentation of the buccalmucosa,lips, palms, and soles. The polyps are hamartomas and are not premalignant.Peutz-|eghers syndrome shows autosomal dominant inheritance.

d. Turcot syndrome is characterized by colonic polyps associated with brain tumors(i.e., gliomas, medulloblastomas ).

F. Malignant tumors

1. Adenocarcinoma is the histologic type of 98o/o of all colonic cancers. Both environmen-tal and genetic factors have been identified.

a. Incidence is very high in urban, Western societies. It is the third most common tumorin both women and men. The peak incidence is in the seventh decade of life.

b. Pathogenesis is associated with villous adenomas, ulcerative colitis, Crohn disease,familial pollposis, and Gardner syndrome. Incidence is possibly related to high meatintake,low-fiber diet, and deficient vitamin intake. A number of chromosomal abnor-malities have been associated with the development of colon cancer.

t86

Pathology

c. Clinical features include rectal bleeding, change in bowel habits, weakness, malaise,and weight loss in high-stage disease. The tumor spreads by direct extension andmetastasis to nodes, liver, lung, and bones. Carcinoembryonic antigen (CEA) is atumor marker that helps to monitor tumor recurrence after surgery or tumor pro-gression in some patients.

d. Pathology

(1) Grossly,T5o/o of tumors occur in the rectum and sigmoid colon (Figure II-5-7).Left-sided lesions often show annular constriction, infiltration of the wall, andobstruction. Most tumors begin as a small raised mass forming a flat plaque thatencircles the colon and begins to infiltrate deeper layers of the colonic wall. Rightcolonic lesions are often bullcy, polypoid, protuberant masses that penetrate thecolonic wall. They rarely obstruct because the fecal stream is liquid on the rightside.

(2) MicroscopicallS these tumors are typical mucin-producing adenocarcinomas.Differentiation, mucin production, mitotic rate, and stromal fibrous reaction vary.

2. Squamous cell carcinoma forms in the anal region. It is often associated with papillomaviruses and its incidence is rising in homosexual males with AIDS.

Figure ll-5-7. Carcinoma of the colon (gross).

APPENDIXA. Inflammation

1. Appendicitis is almost always acute in onset.

a. Pathogenesis. Obstruction leads to mucus retention and distention, compromise ofblood supply, and subsequent bacterial infection.

b. Clinical features typically include initial periumbfical pain that then lqsalizes to theright lower quadrant, accompanied by anorexia, nausea, vomiting, fever, and moderateleukocytosis.

In a NuBhell

Adenocarcinoma is the mo$common type of colon cancer.It can present with rectalbleeding, changed bowelhabits, weight loss, and othersystemic symptoms.

Clinical Correlate

Appendicitis pain beginsperiumbilically and thenlocalizes to the actualanatomic site of the appendix.

t87


Bridge toEndocrine System

Disorders of the endocrinepancreas are discussed in theEndocrine Pathology chapterof this book.

c. Pathology. Earh acute appendicitis shows vascular congestion and edema withlittle cellular infiltrate. Acute suppurative appendicitis shows an extensive transmuralneutrophilic exudate with areas of necrosis. Acute gangrenous appendicitis developsas the blood supply is compromised by inflammation, edema, and thrombosis.

B. Mucocele of the appendix is dilatation of the appendix caused by mucin accumulation.

1. Mucinous cystadenoma is a benign neoplasm, which may perforate. This is the mostcommon type.

2. Mucosal hyperplasia does not perforate.

3. Mucinous cystadenocarcinoma is the penetration of the bowel wall by malignant cells,forming peritoneal implants. Pseudomlaroma peritonei is a condition in which the peri-toneal caviry is filled with mucin-secreting cells of rystadenocarcinomas.

C. Tumors. Carcinoids are most common; carcinomas are rare. Primary lymphoma is occa-sionally seen.

PERITONEUMA. Peritonitis is inflammation of the peritoneum.

1. Sterile peritonitis may be caused by bile, pancreatic enzymes, and foreign materials.

2. Bacterial peritonitis. In this condition, the membrane becomes dull with an accumula-tion of turbid fluid. The exudate becomes frankly purulent and may cause abscesses andadhesions after healing.

B. Mesenteric cysts are cysts within the mesenteries or attached to the peritoneum. They areusually single and of variable size. Most are benign.

C. Sclerosing retroperitonitis is a dense fibrotic proliferation of the retroperitoneum. Theetiology is unknown.

D. Tirmors of the peritoneum are usually malignant.

1. Primary mesotheliomas are rare. Eighty percent are associated with asbestos e4posure.

2. Secondary (metastatic) tumors are common; most are ovarian or pancreatic. Implants frommetastatic teratomas sometimes mature and lose their capacityto invade or metastasize further.

EXOCRINE PANCREASA. Congenital anomalies

1. Ectopic pancreatic tissue most commonly occurs in the stomach, duodenum, jejunum,Meckel diverticulum, and ileum. It may be either asymptomatic or cause obstruction,bleeding, or intussusception.

2. Annular pancreas is a ring of pancreatic tissue that encircles the duodenum and maycause duodenal obstruction.

B. Cystic fibrosis is a systemic disorder of exocrine gland secretion, presenting during infancyor childhood.

1. Incidence is 1:2,500 in Caucasians; it is less common in Blacks, and extremely rare inAsians.

2. Pathogenesis. Cystic fibrosis shows autosomal recessive transmission; heterozygotes areunaffected. The defect is in the CFTG (the cystic fibrosis transporter gene) located on

t88

Pathology

chromosomeT. More than 200 mutant alleles have been demonstrated. It results in adefective chloride channel, which leads to secretion of verythickmucus.

3. Characteristics

a. Tissues other than exocrine glands are normal, and glands are structurally normaluntil damaged by rystic fibrosis.

b. The only characteristic biochemical abnormalities are an elevation of sodium andchloride levels in sweat, and a decrease in water and bicarbonate secretion from pan-creatic cells, resulting in a viscous secretion.


a. Fifteen percent of cases present with meconium ileus.

b. Most cases present during the first year with steatorrhea (with resultant deficienciesof vitamins A, D, E, and K), abdominal distention, and failure to thrive.

c. Complications are also related to pulmonary infections and obstructive pulmonarydisease as a result of viscous bronchial secretions.

5. Pathology

a. There is mucus plugging of the pancreatic ducts with cystic dilatation, fibrous pro-liferation, and atrophy. Similar pathology develops in salivary glands.

b. Lungs. Mucus impaction leads to bronchiolar dilatation and secondary infection. Theclinical course is characterized by bronchitis, bronchiectasis, abscesses, emphysema,and atelectasis. Psezdomonas aeruginosa is the most common etiologic agent.

c. The gastrointestinal tract shows obstruction caused by mucus impaction in theintestines with areas of biliary cirrhosis, resulting from intrahepatic bile duct obstruc-tion.

6. Diagnosis depends on demonstrating a "sweat test" abnormality associated with at leastone clinical feature. In the sweat test, high levels of chloride are demonstrated.

7. Prognosis. Mean survival is age 20; mortality is most often due to pulmonary infections.

C. Degenerative changes

1. Iron pigmentation (e.g., from hemochromatosis) may be deposited within acinar andislet cells and may cause insulin deficiency.

2. Atrophy

a. Ischemic atrophy is due to atherosclerosis of pancreatic arteries and is usually asymp-tomatic.

b. Obstruction of pancreatic ducts affects only the exocrine pancreas, which becomessmall, fibrous, and nodular.

D. Acute hemorrhagic pancreatitis presents as a diffirse necrosis of the pancreas caused by therelease of activated pancreatic enzymes. Associated findings include fat necrosis and hemor-rhage into the pancreas.

1. Incidence. This disorder is most often associated with alcoholism and biliary tract disease.It affects middle-aged individuals and often occurs after a large meal or excessive alcoholingestion; approximately 50olo of patients have gallstones.

2. Pathogenesis. There are four theories.

Note

The gene on chromosome 7encodes a 1480 amino acidpeptide that appears to play arole in chloride and sodiumchannels in cell membranes.The most common form ofcystic fibrosis seems to resultfrom an inability to glycosylatethis protein and insert it in thecell membrane.

Clinical Correlate

CF presents with steatorrheaand frequent respiratoryinfections in young children(often Pseudomonos). Anabnormal sweat chloride testwill confirm the diagnosis.

Note

Hemochromatosis is alsocalled "bronze diabetes";iron deposition causesdamage to pancreaticand hepatic arteries.

r89


a. Obstruction of the pancreatic duct causes an elevated intraductal pressure, whichresults in leakage of enzfmes from small ducts. Obstruction may be caused by a gall-stone at the ampulla of Vater; chronic alcohol ingestion may cause duct obstructionby edema.

b. Hypercalcemia may cause activation of trypsinogen; its mechanism is unclear.Pancreatitis occurs in 20o/o of patients with hlperparathyroidism.

c. Direct damage to acinar cells may occur by trauma, ischemia, viruses, and drugs.

d. Hyperlipidemia may occur as a result of exogenous estrogen intake and alcoholingestion.

3. Mediators

a. Proteases, particularly trypsin, may cause activation of pancreatic proenzymes.

b. Lipases such as phospholipase A convert bile lecithin to toxic lysolecithin and alsodirectly damage cell membranes.

c. Elastase, after it is activated by trypsin, dissolves the elastic fibers of ducts and bloodvessels,leading to enzyme leakage and hemorrhage.

4. Other etiologies include penetrating peptic ulcers, metabolic abnormalities (e.g., hlper-calcemia), and familial relapsing pancreatitis.

5. Clinical features are typically the sudden onset of acute, continuous, and intense abdom-inal pain, often radiating to the back and accompanied by nausea, vomiting, and fever.This syndrome frequently results in shock. Laboratory values reveal elevated amylase(lipase elevated after 34 days) and leukocytosis. Hypocalcemia is a poor prognostic sign.

6. Pathology

a. Grossly, gray areas of enzymatic destruction, white areas of fat necrosis, and red areasof hemorrhage are seen.

b. Microscopic findings

(1) Enzymatic necrosis leads to liquefactive necrosis. An inflammatory infiltratesurrounds regions of necrosis. Necrosis of blood vessels with hemorrhage is alsoseen.

(2) Fatnecrosis is characterized by fat cells filled with amorphous, granular pinkmaterial. It occurs in the pancreatic parenchyma and stroma and in distant fatdeposits within the abdominal cavity.

(3) Bacterial infection may occur late,leading to suppuration and abscess formation.

7. Tieahnent is supportive, including no oral intake, nasogastric suction, and intravenous fluids.

8. Comptcations. Grey Tirrner sign (bluish discoloration of the flanks) and Cullen sign(periumbilical discoloration) indicate extensive damage. Abscess, pseudoryst, duodenalobstruction, shock lung, and acute renal failure may all occur in any combination.

E. Chronic pancreatitis refers to remitting and relapsing episodes of mild pancreatitis, causingpro gressive p ancreatic damage.

1. Incidence is similar to acute pancreatitis. It is also seen in patients with ductal anomalies.Almost half the cases occur without known risk factors.

2. Pathogenesis is unclear; possibly, there is excess protein secretion by the pancreas, caus-ing ductal obstruction.

r90

Pathology

3. Clinical features include flareups precipitated by alcohol, overeating, and drugs. Attacksare characterized by upper abdominal pain, tenderness, fever, and jaundice. Laboratoryvalues reveal elevated amylase and alkaline phosphatase. X-rays reveal calcifications inthe pancreas. Chronic pancreatitis may result in pseudocyst formation, diabetes, and steat-orrhea.

4. Pathology

a. Chronic calcifying pancreatitis is associated with alcoholism.

(1) Grossly, the organ is indurated, with multiple calcifications. Pancreatic calculiand pseudorysts are common.

(2) Microscopically, there is acinar atrophy, fibrous proliferation, and mononuclearinflammatory reaction in a lobular distribution. Occasionally, there is squamousmetaplasia of the ductal epithelium.

b. Chronic obstructive pancreatitis is associated with gallstones. The lesions are moreprominent in the head of the pancreas. The pattern does not have a lobular distribution.

F. Carcinoma of the pancreas

1. Incidence

a. Carcinoma of the pancreas accounts for approximalely 5o/o of all cancer deaths.Increased risk is associated with smoking, high-fat diet, and chemical exposure. Thereis a higher incidence in the elderly, Blacks, males, and diabetics.


a. The disease is usually asymptomatic until late in its course.

b. Manifestations include weight loss, abdominal pain, frequently radiating to the back,weakness, malaise, anorexia, depression, and ascites.

c. There is jaundice in half of the patients who have carcinoma of the head of the pancreas.

d. Courvoisier law holds that painless jaundice with a palpable gallbladder is suggestiveof pancreatic cancer.

3. Pathology. Carcinomas arise in ductal epithelium. Most are adenocarcinomas.

a. Carcinoma of the head of the pancreas accounts f.or 600/o of all pancreatic cancers. Itproduces small, white, fibrous, infiltrating lesions that frequently invade the wall of thecommon bile duct, duodenum, or ampulla of Vater. These lesions frequently cause bil-iary obstruction (50o/o of cases have a dilated gallbladder).

b. Carcinoma of the body (20o/o) and tail (5olo) produce large, indurated masses thatspread widely to the liver and lymph nodes.

c. In 15olo of patients, carcinoma involves the pancreas diffusely.

4. Complications include Trousseau syndrome, a migratory thrombophlebitis that occursin 10olo of patients. This may also occur with other mucin-producing adenocarcinomaswhose secretions activate clotting.

5. Prognosis is very poor. If resectable, the 5-year survival rate is less than 5olo. The usualcourse is rapid decline; on average, death occurs 6 months after the onset of symptoms.

G. Cysts

1. Congenital cysts frequently occur with rystic disease of the liver and kidney. They areusually multiple.

In a Nutshell

Chronic pancreatitispresents with steatorrhea,diabetes, and abdominalmass (pseudocy$),

In a Nubhell

Pancreatic cancer is oftenadenocarcinoma; 600/o arise inthe pancreatic head.0bstructive jaundice, weightloss, and abdominal pain arethe most common symptoms.

l 9 l


2. Pseudocysts occur as sequelae of pancreatitis or trauma. They are caused by loculation offluid (suppurative, hemorrhagic, or necrotic debris).

a. Single pseudocysts are usually 5-10 cm in diameter with a fibrous capsule. There is noepithelial lining and no direct communication with pancreatic ducts.

b. Pseudorysts present as an abdominal mass, often with pain, and they may cause peri-tonitis if ruptured.

3. Cystadenomas and cystadenocarcinomas are neoplastic rysts. They are usually single,5-15 cm in diameter, and multiloculated. These are true rysts, lined by epithelium withpapillary projections.

TIVERA. Congenital malformations

1. Accessory lobes are most often inferior. They are not associated with any specific diseaseprocess.

2. Congenital cystic disease is associated with congenital polyrystic disease of the kidneysand is asymptomatic.

3. Congenital hepatic fibrosis is a disorder demonstrating autosomal recessive inheritance.It is characterized by periportal fibrosis, resulting in hepatosplenomegaly and esophagealvarices.

4. Extrahepatic biliary atresia causes cholestasis,hypertension. It presents within the first weeksstools, and hepatosplenomegaly.

5. Intrahepatic biliary atresia results in a diminished number of bile ducts. It is sometimesassociated with cr,-antitrypsin deficiency. It presents in infancy with cholestasis, pruri-tus, growth retardation, and increased serum lipids.

B. |aundice, or icterus, is caused by excess bilirubin accumulation in the skin and sclerae,producing a yellow discoloration of these tissues. Icterus is visible when the serum bilirubinexceeds 2 mgldl. In unconjugated hyperbilirubinemia, bilirubin is not excreted into theurine because of tight protein binding in serum. In conjugated hyperbilirubinemia, smallamounts of bilirubin are excreted in the urine because it is less tightly protein bound.

1. Unconjugated hyperbilirubinemia may be caused by:

a. Excess production, such as occurs in hemolytic disease.

b. Reduced hepatic uptake, which may produce kernicterus in neonates.

c. Impaired conjugation, such as occurs in Gilbert syndrome and Crigler-Najjar syn-drome

2. Conjugated hyperbilirubinemia

a. Dubin-Johnson syndrome produces benign conjugated hyperbilirubinemia due toimpaired transport of anions. Liver is grossly black.

b. Rotor syndrome is asymptomatic. It is similar to Dubin-|ohnson, but the liver is notpigmented.

which results in cirrhosis and portalof life with jaundice, dark urine, light

In a Nutshell

UnconjugatedHyperbilirubinemia. Hemolysis

. Decreased uptake due todiffuse hepatocellulardamage

. lmpaired conjugation(Crigler-Najjar and Cilbert'ssyndromes)

ConjugatedHyperbilirubinemia. DubinJohnson syndrome

. Rotor's syndrome

. Cholestasis

192

Pathology

c. Cholestasis causes the impaired excretion of conjugated bilirubin.

(1) Intrahepatic causes of cholestasis include hepatocellular cholestasis, which

may be seen in viral hepatitis, cirrhosis, and drug toxicity.

(2) Extrahepatic causes of cholestasis include gallstones, carcinoma of bile ducts,

ampulla of Vater or head of the pancreas' and cholangitis.

(3) Clinical features are typically pale stools, decreased urinary urobilinogen, fat malab-

sorption, pruritus, elevated serum cholesterol, xanthomas, and bilirubin in the urine.

C. Hepatic failure

1. Etiology. Chronic hepatic disease (e.g., chronic active hepatitis or alcoholic cirrhosis) is the

most common cause of hepatic failure, although acute liver disease may also be responsible.

a. Widespread liver necrosis may be seen with carbon tetrachloride and acetaminophen

toxicity. Widespread steatosis is seen in Reye syndrome, a cause of acute liver failure

most often seen in children with a recent history of aspirin ingestion for an unrelated

viral illness.

b. Massive necrosis may also be seen in acute viral hepatitis, after certain anesthetic

agents, and in shock from any cause.

2. Ctinical features. Hepatic failure causes jaundice, musty odor of breath and urine,

encephalopathy,renal failure (either by simultaneous toxicity to the liver and kidneys or

the hepatorenal syndrome), palmar erythema, spider angiomas, gynecomastia, testicular

atrophy (secondary to impaired estrogen degradation), prolonged prothrombin time

(impaired hepatic synthesis of coagulation factors), weight loss, muscle wasting, pruritus,

malabsorption, hypoalbuminemia, hypercholesterolemia, and anemia.

D. Hemodynamic and vascular abnormalities

l. Chronic passive congestion is associated with right heart failure and is a common post-

mortem finding.

a. Pathology shows congestion of central veins and centrilobular hepatic sinusoids

known as "nutmeg liver" (Figures II-5-8 and II-5-9).

b. Ctinical features include mild hepatomegaly and, occasionally, a pulsatile liver that is

tender to palPation.

2. Central hemorrhagic necrosis may be seen in severe heart failure.

a. Pathophysiology is due to hypoxia secondary to hypoperfusion.

b. Pathology. There is a marked "nutmeg-like" appearance, as well as marked sinusoidal

dilatation with parenchymal hemorrhage, atrophy, and necrosis around central veins.

t95


Figure ll-5-8. Ghronic passive congestion of the liver (gross).

Figure ll-5-9. chronic passive congestion of the liver (microscopic).

t94

Pathology

3. Cardiac sclerosis is a sequela of chronic passive congestion and central hemorrhagic

necrosis.

a. Grossly, the liver is slightly smaller with a "pig skin" grain on the external surface.

b. Microscopically, there is delicate fibrosis around central veins fanning out into the

liver parenchyma, causing destruction of central hepatocytes.

4. Infarctions are rare because of the double blood supply (hepatic artery and portal vein).

Occlusion of an intrahepatic branch of the portal vein may cause an infarct of. Zahn, a

sharply bordered regional purple discoloration. Occlusion does not cause an ischemic

infarct.

5. Hepatic vein thrombosis (Budd-Chiari syndrome) is arare syndrome that may be acute

or insidious.

a. Etiology. The Budd-Chiari syndrome may be seen in many unrelated conditions,

including neoplasms invading hepatic veins, polycythemia vera, intrahepatic infec-

tion, paroxysmal nocturnal hemoglobinuria, myeloproliferative syndromes, and

intravascular webs or membranes. All of these syndromes can provoke clotting either

through platelet activation, abnormal platelet function, or activation of the extrinsic

clotting system.

b. Clinical features include abdominal pain with a large, tender liver and ascites.

c. Micropathology is similar to chronic passive congestion and central hemorrhagic

necrosis with fibrosis and rupture at Disse spaces.

6. Portal vein obstruction and thrornbosis

a. Etiology

(l) Extrahepatic causes include abdominal neoplasms (notably renal cell carcino-

ma), pancreatitis, sepsis, and postsurgical conditions.

(2) Intrah€paticcauses include cirrhosis and primary or secondary neoplastic invasion.

b. Clinical features include portal hypertension and splenomegaly.

Hereditary disorders of bilirubin metabolism

l. Gilbert syndrome is a benign autosomal dominant disease characterizedby unconjugat-

ed hyperbilirubinemia. It may be caused by a defect in hepatocellular uptake of uncon-

jugated bilirubin or by a deficiency of glucuronyl transferase. Liver histology is normal.

The disease presents with chronic jaundice that is worse on fasting. Bilirubin rarely

exceeds 6 mg/dl. It occurs in approximately 5o/o of the population, sometimes without a

family history.

2. Crigler-Najjar syndrome

a. Type I shows autosomal recessive inheritance and complete absence of glucuronyl

transferase, causing marked unconjugated hlperbilirubinemia, severe kernicterus,

and death.

Type 2 shows a mild deficiency of glucuronyl transferase. Kernicterus does not develop.

Autosomal dominant inheritance is clear in some families, but in others, the syndrome may

represent a homozygous Gilbert syndrome since other members of the family have classic

Gilbert disease.

Viral hepatitis

1. Hepatitis A (HAV) is a self-limited hepatitis caused by an RNA virus with an incubation

period of approximately 2-6 weeks. Infection is identified by HAv-specific antibodies (IgM

E.

ln a Nubhell

Budd-Chiari syndrome is ahepatic vein obstructionleading to clinical andpathologic features of chroniccongested liver.

Bridge to Microbiology

. Hepatitis A is a picornavirus.It has a naked icosahedralnucleocapsid and single-stranded RNA.

. Hepatitis B is a double-stranded DNA virusclassified as a hepadnavirus.It has an envelopedicosahedral nucleocapsid.

. Hepatitis C is classified as aflavivirus. lt is a positive-strand RNA virus with anenveloped icosahedralnucleocapsid.

. Hepatitis D is caused by thedelta agent-a proteincapsule surrounding low-molecular weight RNA.

. Hepatitis E is classified as acalicivirus. lt is a single-stranded RNA virus with anaked icosahedralnucleocapsid.

t95


if acute, IgG if convalescent). The usual route of infection is fecal-oral transmission by con-taminated food, particularly mollusks. There is no carrier state and no chronic disease(Figure II-5-10).

2. Hepatitis B (HBV) may cause acute hepatitis, a carrier state, chronic active disease,chronic persistent disease, fi.rlminant hepatitis, or hepatocellular carcinoma. It is causedby a DNA virus; the virions are called Dane particles. The incubation period is from l-6months. Tiansmission is through contact with infected blood or other body fluids. It canbe transmitted by sexual intercourse and is frequently transmitted to newborns of infect-ed mothers by exposure to maternal blood during the birth process.

Expoune

l gG ant i - HAV

Fecal HAV

\lgM anti - HAV

2 to 6 weeks 1 lo 2 months 1 to 3 months

Figure ll-5-10. Serologic markers in hepatitis A infection.

Exposure

zIF

(rzt!ozoO

Onsel o fsymptoms f'"o"""+ifJ8i:l":+

zI

GFzUJozoo

Ant i - HBs\ _ -HBSAG

Window

- -.- \-/) < \ A n t i - H B c

- / \ \/ ' \ '

Ant i - HBe

6 months 1 / 2 l o 4months

Figure ll-5-11. serologic markers in hepatitis B infection.

a. Associated antigens include core antigen (HBcAg) and surface antigen (HBsAg).The latter is usually identified in the blood for diagnosis. HbsAg is the earliest *urk-er of acute infection. HBeAg is also associated with the core. Its presence indicatesactive acute infection; when anti-HBeAg appears, the patient is no longer infective(Figure I I -5- l 1) .

b. HBV is associated with hepatocellular carcinoma; HBsAg+ patients have a 200-foldgreater risk of hepatocellular carcinoma than subjects who have not been exposed.

1 t o 3months

In a Nutshell

. HBsAg indicates currentinfection.

. HBeAg indicates infeaivity.

r96

Pathology

c. Antibodies

(t) Antibodies to surface antigen (anti-HBs) are considered protective and usually

appear after the disappearance of the virus.

(2) Antibodies to HBcAg are not protective. They are detected just after the appear-

ance of HBsAg and are used to confirm infection when both HBsAg and anti-

HBs are absent (window).

(3) Antibodies to HBeAg are associated with a low risk of infectivity.

3. Hepatitis C (HCV) is most often mild and anicteric but occasionally severe with fulmi-

nant hepatic failure. It is caused by an RNA virus, which may be transmitted parenterally

(a cause of post-transfusion hepatitis); the route of transmission is undetermined in

40-50o/o of cases.

a. Antibody is detected by enzyme-linked immunosorbent assay (ELISA). The incuba-

tion period is between 2 and 26 weeks with peak onset of illness 6-8 weeks after

infection.

b. Most patients progress to chronic liver disease, specifically chronic persistent hepatitis

or chronic active hepatitis. Cirrhosis is common in patients with chronic active hep-

atitis and occurs in20-25o/o of infected patients. HCV is also associated with hepato-

cellular carcinoma.

4. Delta hepatitis (HDV) is associated with a 35-nm RNA virus composed of a delta anti-

gen-bearing core surrounded by HBV'S Ag coau HDV requires HBV for replication.

Delta hepatitis can cause quiescent HBV states to suddenly worsen. Its transmission is the

same as that of HBV.

5. Hepatitis E (HEV) is caused by a single-stranded RNA virus. The disease is typically self-

limited and does not evolve into chronic hepatitis; it may, however, be cholestatic.

Pregnant \romen may develop firlminant disease. Tiansmission is by the fecal-oral route.

HEV occurs mainly in India, Nepal, Pakistan, and Southeast Asia.

Table l[-s-2.Types of hepatitis.

ln a Nutshell

HAV, HEV: fecal-oralinfections

HBV, HCV, HDV: parenteralinfections

Mode ofTransmission Incubation Carrier State?

Causes ChronicDisease? GenomeHepatitis

Hepatitis A

Hepatitis B

Hepatitis C

Delta hepatitis

Hepatitis E(NANB)

Fecal-oral 2-6 weeks

Parenteral, sexual 1-6 months

Blood transfusion, 2-26 weeksblood products

Parenteral,sexual l-several months

Water-borne, 6 weeksfecal-oral

Yes (50olo of RNAcases)

Yes RNA

No

Yes

No

Yes (5-10%of cases)

ssRNA

DNA

Yes

In associationw/hepatitis B

Not known No ssRNA

197


In a Nutshell

Pathology of Hepatitis

Crossly, enlarged liver;m icroscopically, coagu lativenecrosis with increasedeosinophilia.

Note

HBV and HCV can lead tochronic hepatitis, and maypredispose to hepatocellularcarcinoma.

6. Acute viral hepatitis

a. Clinical features. Acute viral hepatitis may be icteric or anicteric. Symptoms includemalaise, anorexia, fever, nausea, upper abdominal pain, and hepatomegaly, followedby jaundice, putty-colored stools, and dark urine.In HBV patients may have urticaria,arthralgias, arthritis, vasculitis, and glomerulonephritis (because of circulatingimmune complexes). Blood tests show elevated serum bilirubin (if icteric), elevatedtransaminases, and alkaline phosphatase. The acute illness usually lasts 4-6 weeks.

b. Pathology

(1) Grossly, there is an enlarged liver with a tense capsule.

(2) Microscopically, there is ballooning degeneration of hepatocytes and liver cellnecrosis, forming empty regions or acidophilic bodies caused by the coagulativenecrosis of individual cells with karyolysis of nuclei and increased eosinophiliaof the cytoplasm. Acidophilic bodies are frequently engulfed by Kupffer cells.Associated findings are hypertrophy of Kupffer cells and sinusoidal lining cells,an acute inflammatory infiltrate of portal tracts, and evidence of hepatocyteregeneration during recovery (Figure II-5- I 2 ).

Figure ll-5-1 2. Viral hepatitis (microscopic).

7. Chronic hepatitis occurs in 5-10o/o of HBV infections and in well over 50o/o of HCV; itdoes not occur in HAV. Most chronic disease is due to chronic persistent hepatitis. Thechronic form is more likely to occur in the very old or very young, in males, in immuno-compromised hosts, in Down syndrome, and in dialysis patients.

a. Chronic active hepatitis features chronic inflammation with hepatocyte destruction,resulting in cirrhosis and liver failure. Three grades of severity of chronic active hepatitisare currently distinguished. Mild: Minimal mononuclear inflammation confined to theportal areas with no fibrosis or portal enlargement. (Note that the term "chronic persis-tent hepatitis" is being phased out in favor of inclusion in the "mild" category.) Moderate:Active portal inflammation with piecemeal necrosis at the borders of often enlarged por-tal areas. Early fibrosis, but no bridging is noted. Severe: All of the above with advancedfibrosis and bridging or frank cirrhosis.

r98

Pathology

(1) Etiology. HBV HCV HDV, drug toxicity, Wilson disease, alcohol, cr,-antitrlpsin

deficiency, and autoimmune hepatitis are common etiologies.

(2) Clinical features may include fatigue, fever, malaise, anorexia, and elevated

transaminases.

(3) Diagnosis is made by liver biopsy. Patients follow a variable course with high

mortality if bridging necrosis is present.

(4) Pathology shows an excessive portal lymphocytic infiltrate that spreads to adja-

cent liver parenchyma. Other features are piecemeal necrosis; a condensation,

fragmentation, and phagocytosis of hepatocytes; bridging necrosis; a destruction

of adjacent regions (lobules) of hepatocytes; and progressive fibrosis leading to

cirrhosis. In HBV infections, cells with homogeneous cytoplasm may be seen

(ground-glass cytoplasm), representing condensed hypertrophic endoplasmic

reticulum. Variable numbers of acidophilic bodies may be seen.

8. Carrier state for HBV and HCV may be either asymptomatic or with liver disease; in the

latter case, the patient has elevated transaminases.

a. Incidence is most common in immunodeficient, drug-addicted, Down syndrome, and

dialysis patients.

b. Pathology of asymptomatic carriers shows "ground-glass" hepatocytes with finely

granular eosinophilic cytoplasm containing HBsAg particles and "sanded" nuclei,

containing HBcAg, which signi$' active viral replication. Otherwise, the liver has a

normal architecture.

9. Fulminant hepatitis leads to submassive and massive hepatic necrosis.

a. Etiology. HAV HBV HCV delta virus (HDV) superinfection, HEV chloroform, car-

bon tetrachloride, isoniazid, halothane, certain mushrooms, and other drugs

(acetaminophen overdose) all may cause fulminant hepatitis.

b. Ctinical features include progressive hepatic dysfunction with a mortality of 25-90o/o.

c. Pathology

(l) Grossly, one sees progressive shrinkage of the liver as the parenchyma is

destroyed.

(2) Microscopically, there are variable amounts of necrosis within contiguous regions.

Cells undergo coagulation followed by liquefaction necrosis, leaving only a retic-

ulin framework. If the patient survives the initial insult, there is later development

of disorga nized regenerating hepatocytes and macronodular cirrhosis.

G. Cholangitis is inflammation of the bile ducts.

l. It is usually associated with biliary duct obstruction by gallstones or carcinoma, which

leads to infection with enteric organisms. This results in purulent exudation within the

bile ducts and bile stasis.

2. Clinically, cholangitis presents with jaundice, fever, chills, leukocytosis, and right upper

quadrant pain.

H. pericholangitis is inflammation around the bile ducts without intraductal involvement.

There is usually a mononuclear infiltrate, which is associated with sepsis, inflammatory

bowel disease, or pancreatitis. The inflammation may cause fever, mild jaundice, and mod-

erate elevation of alkaline phosphatase.

Clinical Correlate

lnfants with HBV infectedpostnatally or during birthrarely develop active hepatitisbut they often becomechronic carriers. They alsohave an increased rate forhepatocellular carcinoma andhepatic cirrhosis.

Clinical Correlate

Cholangitis = Charcot triad =jaundice, fever, and rightupper quadrant pain.

r99


Note

Sch istoso m o, Ech i n ococcus,and Entomoebc are threeparasitic infections of the liver.

In a Nutshell

Cinhosis is the diffuse fibrosisand regeneration of the liverdue to hepatocellular injury bytoxins, drup, virusel ordeposition of metabolites orminerals (e.g., glycogen storagediseases; Wilson disease)

Clinical Correlate

Cirrhosis and portalhypertension can causenumerous physical examfindings:. Ascites (J albumin

synthesis)

. Varices, hemorrhoids, andcaput medusae (due toportosystemic shunts)

. Splenomegaly

. Cynecomastia, spiderangioma, and palmarerythema (due to impairedestrogen metabolism)

. Dupuytren contracturesand clubbing

. Bleeding diathesis

200

I. \ogenic liver abscesses may be caused by E. coli, Kebsiella, Streptococctts, Staphylococcus,Bacteroides, Pseudomonts, and fungi. Ascending cholangitis is the most common cause.Seeding of the liver due to bacteremia is another potential cause.

l. Parasitic infections

1. Schistosomiasis is caused by different organisms in different parts of the world.

a. Clinical features include splenomegaly, portal hypertension, and ascites. Lesions arecaused by the immune response to ova.

b. Pathology. Giant cell granulomas form in liver parenchyma surrounding ova. Theinflammatory process leads to diffr.rse fibrosis and nodular regeneration. The patternof fibrosis is sometimes called "pipe stem" fibrosis.

2. Amebiasis is caused by Entamoeba histolytica.

a. Clinical features include bloody diarrhea, pain, fever, jaundice, and hepatomegaly.

b. Pathology shows abscesses of the liver parenchyma, which may contain organismsin the necrotic region. Amebiasis is usually associated with amebic dysentery andcolonic ulceration.

K. Drug-induced liver damage may be caused by agents that are direct hepatotoxins, such ascarbon tetrachloride, acetaminophen, methotrexate, anabolic steroids, and oral contracep-tive pills. Alternately, it may be caused by damage resulting from hypersensitivity or ametabolic response to drugs such as phenothiazines, methyldopa, halothane, and isoniazid.

L. Cirrhosis is the diffuse involvement of the whole liver by fibrosis due to hepatocellular injuryfibrosis in the form of dense scars or delicate bands, and nodules caused by fibrous bands andregenerating hepatocftes. These so-called regenerative nodules, which lack the usual archi-tectural landmarks such as ordered sinusoids and a central vein, are hallmarks of cirrhosis.

1. Epidemiology. Cirrhosis is the third leading cause of death in the 25-65-year-old agegroup. Leading types include alcoholic cirrhosis, postnecrotic cirrhosis, biliary cirrhosis,and hemochromatosis-related cirrhosis.


a. Portal hnrertension is most commonly caused by cirrhosis of the liver.

(1) Other causes include posthepatic (e.g., right-sided heart failure, Budd-Chiarisyndrome), prehepatic (e.g., portal vein obstruction), or intrahepatic (e.g., schis-tosomiasis, sarcoid).

(2) Signs and symptoms include ascites (an accumulation of fluid in the peritonealcavity); portosystemic shunts that form hemorrhoids, esophageal varices(which may cause massive hematemesis), periumbilical (caput medusae), andretroperitoneal dilatations, and portosystemic encephalopathy; andsplenomegaly with hypersplenism.

b. Impaired estrogen metabolism and male hlpogonadism may cause female hairdistribution and gynecomastia in males, gonadal atrophy, amenorrhea in females,spider angiomata, and palmar erythema.

c. Other associated disorders include Dupuytren contractures, hypoalbuminemia,peripheral edema,low levels of vitamin K-dependent clotting factors (causing bleed-ing diathesis), rare hepatorenal syndromes, and hepatic encephalopathy.

3. Etiologies. Already mentioned are the chronic hepatidites (HBV, HCV but never HAVHEV) and chronic drug reactions.

Pathology

a. Postnecrotic cirrhosis produces a macronodular pattern.

(1) Etiology. Most cases are secondary to chronic active hepatitis. Postnecrotic cirrho-sis may also arise after exposure to hepatotoxins (o-methyldopa, methotrexate) orafter autoimmune disease (lupoid). Postnecrotic cirrhosis may also be crlptogenicor,less commonly, due to massive hepatic necrosis.

(2) Clinical features include a small, knobby liver with evidence of portal hyperten-sion occurring terminally. There is usually a rapid downhill course once thepatient is symptomatic, with death due to hepatic coma or hepatic failure with-in 3 years. Treatment is unsatisfactory.

(3) Pathology. Grossly, 3-mm to l-cm liver nodules composed of regenerating hep-atocytes separated by fibrous scars are found. Microscopically, broad scars witha mononuclear, inflammatory infiltrate surrounding the nodules of hepatocytesare seen.

b. Biliary cirrhosis

(1) Primary biliary cirrhosis has an autoimmune etiology and causes sclerosingcholangitis and cholangiolitis. It is associated with other autoimmune diseasesand primarily affects middle-aged women.

(a) Clinical features. It often presents with fatigue and pruritus. Elevated alka-line phosphatase discovered on a routine blood test often leads to diagnosis.In more advanced stages, profound hypercholesterolemia is found, signifiedby the appearance of xanthomas. Steatorrhea, caused by fat malabsorption,is another significant sign. Antimitochondrial antibody is present in over90o/o of patients. Definitive diagnosis is by biopsy. Course is slowly progres-sive over 5-25 years.

(b) Pathology varies with stage of the disease. Early on, there is intensemononuclear inflammation around the small portal bile ducts, sometimeswith granuloma formation and bile lakes. Later, scarring and portal-portalbridging fibrosis occurs and small bile ducts disappear.

(2) Second*y biliary cirrhosis is caused by long-standing large bile duct obstruc-tion, producing stasis of bile,leading to inflammation, secondary infection, andscarring. It usually presents with jaundice. Histologically, there is a dilation oflarger bile ducts with or without polymorphonuclear cell infiltration (depending

on if there is cholangitis). With time, portal-portal bridging fibrosis and portalcirrhosis occurs. Early, bile lakes are evident.

(3) Sclerosing cholangitis is a chronic fibrosing inflammatory disease of the extra-hepatic and larger intrahepatic bile ducts. A "beading" pattern is seen on bariumradiographs of the biliary tree. It is associated with inflammatorybowel disease,Hashimoto thyroiditis, and retroperitoneal fibrosis syndromes. Progressivestenosis of larger bile ducts may lead to secondary biliary cirrhosis. There is apredisposition for cholangiocarcinoma.

Hemochromatosis is a disease with autosomal recessive inheritance. Deposits of ironoccur in the liver, pancreas, heart, adrenal, thyroid, parathyroid, and anterior pituitarywith resultant organ dysfunction. It should be distinguished from hemosiderosis,which is a term used to describe iron overload from any cause. An accumulation ofpigment occurs in reticuloendothelial cells, resulting from recurrent hemolysis ortransfusion.

(1) Etiology. Idiopathic hemochromatosis is an autosomal recessive genetic disorder

Clinical Correlate

The prothrombin time(PI), not the PTT, is used toassess coagulopathy due toliver disease, although insevere liver disease, bothare prolonged.

In a Nutshell

Primary Biliary CirrhosisAutoimmune withantimitochondrial antibodies,female predominance, andelevated alkaline phosphatase.

201


Clinical Conelate

Hemosiderin deposits areseen in the liver and pancreasof hemochromatosis patients.

Clinical Correlate

Both hemochromatosis andWilson disease are associatedwith an increased risk ofhepatocellular carcinoma.

ln a Nutshell

Alcoholic Liver Disease. Fatty liver

. Alcoholic hepatitis

. Alcoholic cirrhosis

with severe disease in homozygotes and detectable abnormalities in hetero-zygotes. Organ damage may also be caused by increased intestinal absorptionand iron overload due to transfusions, high iron intake, hemolytic anemia, andthalassemia.

(2) Clinical features of idiopathic hemochromatosis include skin pigmentation, car-diac arrhythmias, diabetes ("bronze"), hepatomegaly,gonadai insufficienry, andarthropathy. There is elevated serum iron, decreased total iron-binding capacity,and increased ferritin. The disease affects men nine times more frequently thanwomen.

(3) Pathology shows micronodular cirrhosis and pigmentation of the liver; pigmen-tation and fibrosis of the pancreas; hemosiderin deposition in the heart, pitu-itary, adrenal, thyroid, parathyroid glands, joints, and skin; and deposition ofboth iron and calcium pyrophosphate in joints,leading to pseudogout. There isa high incidence of hepatocellular carcinoma.

(4) Tieatment is by phlebotomy to prevent these complications. Deferoxamine isalso used.

d. Wilson disease (hepatolenticular degeneration) is an autosomal recessive diseasecharacterizedby inadequate hepatic excretion of copper. Wilson disease causes hep-atitis or macronodular cirrhosis, degenerative changes in the lenticular nuclei of thebrain, and pathognomonic Kayser-Fleischer rings, a deposition of copper in thecorneal limbus.

(1) Clinical features. Wilson disease rarely manifests before age 6. Patients presentwith weakness, jaundice, fever, angiomas, Kayser-Fleischer rings, low serumceruloplasmin, increased urinary copper excretion, and, eventually, portalhypertension. Central nervous system (CNS) manifestations include tremor,rigidiry and disorders of affect and thought. A rare presentation is as acute hep-atitis with severe hemolysis that, without transplant, is likely to be fatal.

(2) Pathology. Early in the disease, fatty changes and inflammation of the liver areseen. In the active stages, patients progress to active hepatitis. Late manifestationsare micro- or macronodular cirrhosis. In the brain, cavitation of the lenticularnucleus is seen, and in the eye, there is copper deposition in Descemet membraneat limbus, forming the Keyser-Fleischer ring.

(3) Treatment is with penicillamine.

e. Alpha,-antitrypsin deficiency is an autosomal recessive disease characterized by defi-ciency of a protease inhibitor, resulting in pulmonary emphysema and hepatic dam-age. It may also cause neonatal hepatitis, childhood cirrhosis (micronodular), or adultcirrhosis (usually macronodular). The pathognomonic finding is periodic acid-Schiff(PAS)-positive cytoplasmic globules within hepatocytes. This represents mutant cx,r-antitrypsin, which is retained within the endoplasmic reticulum of the hepatocyte.

f. Syphilitic cirrhosis causes scarring due to gummas.

g. Other causes include cardiac cirrhosis due to cardiac sclerosis; cirrhosis secondary toinborn errors of metabolism, secondary to infections such as liver fluke or inflammatorybowel disease; and cryptogenic cirrhosis (unknown etiology).

M. Alcoholic liver disease causes faty livea alcoholic hepatitis, and alcoholic cirrhosis, whichare separate though possibly interrelated entities.

1. Epidemiology. Alcoholic liver disease accounts for 60-700/o of cirrhosis in the WesternHemisphere. The male:female ratio is 2:1. There is a possible genetic predisposition.

202

Pathology

2. Clinical features. Fatty change is generally asymptomatic. Alcoholic hepatitis presentswith fever; hepatomegaly; jaundice; elevated aspartate transaminase (AST), alkaline phos-phatase, and alanine aminotransferase (Alf); and possible portal hlryertension. Cirrhosisoften presents with portal hypertension. Patients die due to liver failure, infection, uppergastrointestinal bleeds, hepatocellular carcinoma, encephalopathy, and renal failure(secondary to hepatorenal syndrome).

3. Pathology

a. Fatty liver (steatosis) is reversible.

(1) Grossly, fatty changes appear as a yellow, greasy, enlarged liver.

(2) Microscopically, coalescence of fatty cytoplasmic vacuoles, causing peripheraldisplacement of the nucleus that resembles a lipocyte, is seen. Coalesced cellsmay form fatty rysts (Figure II-5-13). Ultrastructure shows swollen mitochon-dria and proliferation of endoplasmic reticulum among the lipid-laden vacuoles.

b. Alcoholic hepatitis is usually associated with fatty change and is occasionally seenwith cirrhosis. It results from prolonged alcoholic abuse. Pathologic findings includeswelling of hepatocytes, followed by necrosis and polymorphonuclear inflammation,formation of alcoholic hyaline (Mallory bodies) in swollen hepatocytes, cholestasis,and beginning fibrosis. The appearance of fibrosis may be linked to the onset ofcirrhosis (Figure II-5- 14).

Figure ll-5-13. Fatty liver (microscopic).

Note

Steatosis is usuallyasymptomatic and reversible.Fatty vacuoles displacehepatocellular nucleiperipherally.

Note

Mallory bodies may also beseen in Wilson disease,hepatocellular carcinoma, andprimary biliary cirrhosis.Besides history, the otherhelpful feature in distinguishingalcoholic hepatitis from theseother entities is the extremefatty change.

205


lry' w

&w

w

.&*':%q%& eq tu

ffi-e,w* *.#"-:

""#&

* ' *q # . , & ^ - ,

* * . . - 9 * it ' d w f l ' *

w

.*-2.*'

&w iw@w*. # #* ;l'T"t"' '' wh*

Figure l l-5-14. Alcoholic hepatit is (microscopic).

c. Alcoholic cirrhosis. Early stages of disease show a large liver with micronodularformation (Figure II-5-15). Later stages show a small, macronodular liver with a"hobnail" appearance on the surface. Microscopically, Mallory bodies may be present.The end stage resembles postnecrotic cirrhosis. The amount of fat decreases as theamount of fibrous tissue increases.

Figure l l-5-1 5. Micronodular cirrhosis (gross).

N. Benign tumors

1. Liver cell adenoma incidence is increased with anabolic steroid and oral contraceptiveuse. It forms a mass, which may be mistaken for carcinoma or may rupture (especiallyduring pregnancy).

a. Grossly, adenomas are often subcapsular, well-circumscribed round masses that maybe bile stained.

b. Microscopically, they are composed of sheets and cords of hepatocytes with slit-likesinusoidal spaces.

'"w i"&,Y t#^aeL

'M:#i , *W" ;:,..w#,

ffi

204

Pathology

o.

2. Nodular hnrerplasia

a. Focal nodular hlperplasia refers to a solitary nodule that often has a fibrous capsuleand bile ductules. A stellate fibrous core is usually present.

b. Nodular regenerative hyperplasia describes multiple nodules composed of normalhepatocytes with a loss of normal radial architecture (normal architecture is a centralvein surrounded by six portal triads). They are not encapsulated and may be associatedwith FelQ/s syndrome, which is comprised of rheumatoid arthritis, splenomegaly, andneutropenia.

3. Cavernous hemangiomas are large, vascular, endothelial-lined spaces filled with red cells.Radiologically, they must be considered in the differential diagnosis of metastases to theliver.

4. Bile duct adenomas form small nodules that are not bile stained.

5. Cysts may be single (with serous fluid) or multiple (with brown, bile-stained fluid).Multiple cysts may be associated with adult polycystic kidney disease.

Malignant tumors

1. Hepatocellular carcinoma (hepatoma)

a. Epidemiology. Hepatocellular carcinoma comprises 90olo of primaryliver neoplasms.It isstrongly associated with cirrhosis and HBV infection, as well as with oral contraceptives,androgens, and aflatoxin B.

b. Clinical features include tender hepatomegaly, ascites, weight loss, fever, poly-cfthemia, and hypoglycemia. A friction rub may also be heard. Alpha-fetoprotein(AFP) is present in 50-90o/o of patients'serum. (AFP is also found with other forms ofliver disease, pregnanry, fetal neural tube defects, and germ cell carcinomas of theovaries and testes.) Death is due to gastrointestinal bleed and liver failure. Generally,metastases first occur in the lungs.

c. Pathology

(1) Grossly, the tumor may be unifocal, multifocal, or infiltrative, causing a largeliver. It is often bile stained and invades vessels. Pre-existing cirrhosis is usuallyobvious.

(2) Microscopically, well-differentiated tumors are composed of hepatocyte-likecells in a trabecular or pseudoglandular pattern. Rarely, a clear cell variant isseen. If it is associated with HBV infection, ground-glass cells may be present.Occasionally, Mallory bodies are also present. Anaplastic tumors may form pleo-morphic giant cells or spindle cells.

2. Cholangiocarcinomas comprise l0o/o of primary liver neoplasms. In developing coun-tries, this tumor is associated with infection with Clonorchis sinensis (liver fluke) andwith primary slcerosing cholangitis.

a. Clinical features. Patients experience weight loss, jaundice, and pruritus. Fifty percentof tumors metastasize to lungs, bones, adrenals, and brain, exhibiting both hematoge-nous and lymphatic spread.

b. Pathology is that of a sclerosing adenocarcinoma, forming both glandular and tubu-lar structures. Mucus is present; bile is absent. Vascular invasion is not usually seen,although hematogenous metastasis is rather common.

ln a Nutshell

Hepatocellular carcinoma ispredisposed by cirrhosis, HBV,oral contraceptives, andaflatoxin B (fungal toxin).

Clinical Correlate

In well-differentiated tumors,the most important clues arelack of normal trruo-cell thickcords and sinusoids. Thenormal central vein to portaltriad architecture is alsoabsent.

In a Nutshell

Cholangiocarcinoma is cancerof the intrahepatic bile ducts,and is usually anadenocarcinoma. lt can beassociated with infection by theliver fluke Clonorchis srnensrs.

205


Clinical Correlate

In addrtion to liver disease,alcoholia suffer from a variety ofother disorders. lf a que$ionpresents in an alcoholic patient,keep in mind increased incidenceof the following disorders:

Esophagus. Cancer

. Mallory-Weiss tears (aftervomiting)

. Varices (with portalhypeftension)

Stomach. Castritis, reflux

. Peptic ulcer disease

Pancreas. Pancreatitis (#1 cause of

chronic pancreatitis)

. Cancer

Cardiac. Cardiomyopathy (dilated)

Respiratory. Aspiration pneumonia

. Kebsiello pneumonia

. Tuberculosis

Heme. Megaloblastic anemia (folate

deficiency)

. Coagulation defects (liverdysfunction)

. Thrombocytopenia due tocon gestive splenomegaly

. Acquired sideroblastic anemia

Neuromuscular. Wernicke encephalopathy

. Korsakoff amnestic svndrome

. Vestibulopathy

. Peripheral neuropathies

. Acute cerebellar degeneration

. Myopathy (in chronicalcoholism)

. Alcohol withdrawal syndrome;delirium tremens

Acid/Base. Ketoacidosis (increased anion

8ap)

206

P.

3. Hepatoblastoma is a rare, malignant neoplasm of children.

a. Clinical features. Patients have hepatomegaly, vomiting, diarrhea, weight loss, elevat-ed serum levels of AFR and, often, other congenital anomalies (especially renaldefects).

b. Pathology. The epithelial type is composed of embryonal cells in sheets or rosettes.The mixed type is hemorrhagic or bile-stained with mixed epithelial and mesenchy-mal tissue showing calcification.

4. Angiosarcoma is associated with exposure to vinyl chloride and arsenic.

a. Grossly, the tumor produces spongy, hemorrhagic nodules.

b. Microscopically, it is composed of variably shaped blood channels lined by pleomor-phic endothelial cells.

5. Metastic tumors are much more common than primary neoplasms, most commonlycoming from the breast, lung, and colon. Multiple, well-circumscribed nodules in amarkedly enlarged liver are seen (Figure II-5-16). Bile staining of the hepatic parenchymais common if the metastases cause biliarv obstruction.

Figure ll-5-16. Pancreatic carcinoma metastatic to liver (gross).

Reye syndrome is characterizedby fatty change in the liver and edematous encephalopathy.It usually affects children between 6 months and 15 years of age.

1. Etiology is unclear. It is frequently preceded by a mild upper respiratory infection, varicella,or influenza A or B infection. It is also associated with aspirin administration at levels thatare not ordinarily toxic.

2. Clinical features include fever, severe vomiting, change in mental status, convulsions, andcoma. Laboratory data reveal elevated serum ammonia, AST, prolonged prothrombintime, and hypoglycemia. There is a 30o/o mortality in patients with neurologic involve-ment, and there are frequent neurologic sequelae.

Pathology

3. Pathology. The liver shows generalized micovesicuhr fatty chang€ but no hepatocfte In a |{Ubhellnecrosis. Mitochondrial abnormalities may be seen on electron microscopy. The brainshows cerebral edema, which may lead to herniation. Reye Syndrome

: . Fatty liver changes

BluARy DISEASE . vomitins

A. Cholelithiasis (gallstones) ' Encephalopalry

f. Incidence. Cholelithiasis occurs in 2096 ofwomen and 896 ofmen in the United States. It . Preceded by uRl oris rare before age 20, but is seen in 2596 of persons greater than 60 years old. chickenpox.with aspirin

2. Etiologr admlnstraton

a. Cholesterol stones

( 1 ) Pure drcl€st€rol stones are radioluc€nt, solitary, l-5 cm in diameter, yellow, andsmooth, with a glistening radial pattem on cut section.

(2) Cholesterol stones are more common in Northern Europeans and NativeAmericans and are les common in Asians and Blacls.

(3) The typical patient is fat, fem.le, fcrtile (multiparous), and over forty years ofage (the "4 Ft").

(4) Exogenous estrogens, clofibrate, high-calorie diet, obesity, +aPetes Te[itus, Cfini..l Gonelatepregnancy, celiac disease, and increasing age all predispose to cholest€rol stones. .--:;;-;;--"

b. Pignent stones are small, black, multiple, and radiolucent. Pigment stones are clumps When cholelithiasis occurs inof pigment derived from unconjugated bilirubin. There is a high incidence in Asians. a young person, think ofIt is associated witlr hemolytic disease, specifically hereditary spherocytosis and other hereditary spherocgosilchronic hemolytic states; it is not associated with acute hemolysis. sickle cell disease, or other

c. Mixed stones compose 80% of all stones and are associated with chronic cholecysti- chronic hemolytic proces'

tis. They are composed of cholesterol and calcium bilirubinate. Composition deter- :mines color (yellow to black). Those with sufficient calcium content are radiopaque.Mixed stones are usually multiple, faceted and laminated.

3. Pathogenesis. Supersaturation of bile pigment or cholesterol and,/or a decreased amount ,of phospholipid or bile salts predisposes to stone formation.


a. Most stones remain in the gallbladder and are aqrmptomatic.

b. Obstruction of the gallbladder or cystic duct may cause biliary colic, acute chole-cystitis, or hydrops (mucocele of the gallbladder).

c. Obstruction of tle common bile duct may lead to obstructive jaundice and ascendingcholangitis. Pancreatitis and gallstone ileus may also result ftom blockage of theampulla ofVater or distal small bowel, respectively.

B. Acute cholecystitis. Most cases are caused by obstruction of the neck of the gallbladder or !!ecystic duct by gallstones.

cholecyslttis (right upperl. Incidence and risk factors ar€ the same as those for cholelithiasis. . quadrant pain, fevet

2. Pathogenesis. Calculus obstruction is followed by secondary bacterial infectionrnTlVo of I leukocytosis) may resuhfromcases, and by chemical tritation. : superinfection of cholelhhiasis.

207


In a Nutshell

Acalculous cholecystitismay occur with congenitalanomalies, diabetes,or infections.

C.


a. Acute cholecystitis presents with acute onset of right upper quadrant pain, fevettenderness, and leukocytosis.

b. Most cases resolve with medical management. The remainder progress to empyema,gangrenous necrosis, or rupture. Patients exhibit symptoms of acute abdomen andrequire cholecystectomy.

4. Pathology

a. Grossly, patients have an enlarged, erythematous, tense gallbladder. The wall is thick-ened and edematous with a fibrinous exudate on the surface and stones in the lumen.

b. Microscopically, there is an acute inflammatory infiltrate with mucosal ulceration,erosion, and foci of necrosis with hemorrhage; lymphocytes outnumber neutrophils.Rokitansky-Aschoff sinuses are penetrations of the mucosa through the muscularisassociated with chronic inflammation.

c. Empyema of gallbladder describes a lumen filled with pus.

d. Porcelain gallbladder is due to calcium deposition within the wall and correlates witha high incidence of future malignanry.

e. In gangrenous cholecystitis, the mucosa is green-black and necrotic with frequentperforation at the fundus.

5. Acalculous acute cholecystitis refers to cholecystitis without gallstones. It is associatedwith congenital anomalies, diabetes mellitus, polyarteritis nodosa, bacterial infections,helminthic infections (Ascaris lumbricoides), trauma, burns, and surgery.

Chronic cholecystitis is usually not preceded by acute cholerystitis but is always accompa-nied by cholelithiasis.

1. Pathogenesis is unclear. Inflammation is probably due to chemical injury from supersat-urated bile, not to irritation by stones.

2. Pathology

a. Grossly, the wall is thickened by fibrosis, and stones are present in lumen (Figure II-5-17).

b. Microscopically, there is fibrosis with a mononuclear inflammatory infiltrate and out-pouchings of the mucosa into the connective tissue and smooth muscle of the wall.

Cholesterolosis refers to lipid foci deposited in the gallbladder wall ("strawberry" gall-bladder). It is asymptomatic and unrelated to cholelithiasis.

Benign tumors

1. Papillomas are small, pedunculated, branching lesions.

2. Adenomas form small, flat, elevated plaques.

3. Adenomyomas are a proliferation of smooth muscle and glands.

D.

E.

208

Pathology

Figure ll-5-17. Chronic cholecystitis and cholelithiasis (gross).

Malignant tumors

1. Carcinoma of gallbladder

a. Incidence. The disease occurs predominantly in the elderly.

b. Risk factors include cholelithiasis and cholerystitis (in up to 90o/o of patients), porcelaingallbladder, industrial workers (cars, rnetals, fabrics); cholic acid may act as a carcinogen.

c. Clinical features. The disease is asymptomatic until late. It may present with dullabdominal pain, mass, weight loss, and anorexia.

d. Pathology

(1) Grossly, the tumor typically involves the fundus and neck.

(2) Microscopically, 90o/o are differentiated or undifferentiated adenocarcinomas.

e. Prognosis is poor, with a 3o/o 5-year survival rate.

2. Carcinoma of bile ducts (cholangiocarcinoma)

a. Incidence. Men are affected more frequently than women, and patients are usually elderly.

b. Risk factors include chronic inflammation, infections, (e.g., liver flukes), and ulcera-tive colitis. These carcinomas are not associated with gallstones.

c. Clinical features. The disease presents with obstructive jaundice and its associatedsymptomatology (right upper quadrant abdominal pain, hepatomegaly, and distend-ed gallbladder with the possible development of ascending cholangitis).

d. Pathology

(1) Grossly, tumors are usually small, with papillary, fungating, nodular, or infiltrat-ing lesions. Sites of predilection are the distal part of the common bile duct,including the ampulla of Vater, the duodenal papilla, and the confluence of thecommon hepatic and rystic ducts.

(2) Microscopically, adenocarcinoma with abundant proliferation of fibrous stromais found.

In a Nutshell

Callbladder cancer is rare,often asymptomatic, and isusually adenocarcinoma.

Clinical Correlate

Cholangiocarcinoma (cancerof the bile ducts) oftenpresents with obstructivejaundice, right upper quadrantpain, and sometimessymptoms of pancreatitisdue to obstruction ofthe pancreatic duct.

209

Gasbointestinal System

€. Prognosis is usually poor because of ductal, lymphatic, and, to a lesser sdent,hematogenous spread.

NI'TRITIONAT DISORDERSA. Marasmus

I . Defnition. Marasmus is a condition of severe malnutrition or emaciation resultine ftominadequatc calorie intake.

I 2. Clidcal features include'failure to thrive," loss of subcutaneous fat, muscle wasting, anda lower percentile in weight than in height. Bacterial or viral infection may precipitatesuperimposed Kwashiorkor as a result of increased requirements for protein synthesis ofthe immune response.

3. Pathology, There is generalized hypoplasia and atrophy of tissues, and there may be mildanerma,

In a Nubhell B. Kwashiorkor

Marasmus . 1. Definition Kwashiorkor refers specifically to inadequat€ protein intake. It may dwelop. Glorie deficiency despite adequate caloric intake.

. No edema 2. Clinical features include edema, anemia, dermatoses (e.g., pigmentary changes, desqua-mation, dusky erythema), hepatomegaly, hair changes, growth retardation, irritability,

Kwashiorkor apatiy, and low energy.. PrOtein defiCienCy 3. Iaboratorl'values. Serum chemistry shows decreased serum total protein and alburnin.. Edema 4. Pathology. Characteristic pathologic changes include:

a. Atrophy of the villi of small bowel mucosa with associated disaccharide deficiency

b. Fatty liver

c. Mixed anemia exhibiting changes associated with both folate and iron deficiencies

d. Atrophy of the tlrymus and other lymphoid organs

C. Iron deficiency

1. Etiology. Although iron deficiency is caused by dietary insufficiency, rnalabsorption nayalso play a causative role. In the United States, the most common cause of iron deficiencyin adults is blood loss ftom the gastrointestinal tract. In children it is dietary insufficiency.

2. Clinical festures of iron deficiency, all of whic.h are due to the varied metabolic functionsof iron, include:

a, Hnnchromic rnicrocytic anenia

b. Functional folate deficiency

c. Depressed cell-mediated irnrnunity

d. Gastric erosions

D. Zhc deficiency

l. Etiology is usually dietary insufficiency.

2. Clinical feetures include delayed wound healing, short stature, and dirninished axillary,facial, and pubic hair. Zinc deficiency may predispose to alcoholic cirrhosis.

2t0

Gastrointestinal Pharmacology

Many agents used in other areas of pharmacology may be useful in the treatment of gastrointestinaldisorders. This chapter, however, focuses on those drugs that are used primarily in the treatment ofga$rointestinal problems: the gastric antacids, the antisecretory drugs, such as the H, receptorantagonists, the anticholinergic agents, and the proton pump inhibitors; the mucosal protectiveagents, such as sucralfate; and antibiotis used in ulcer therapy. Also included are emetics, laxatives,and antidiarrheal agents, as well as several miscellaneous drugs (e.g., cisapride, metoclopramide).

DRUGS USED IN THE TREATMENT OF PEPTIC UTCER DISEASEDrugs that accelerate healing and prevent relapse or recurrence of peptic ulcers act either bydecreasing gastric acidiry or by enhancing mucosal defense mechanisms. Risk factors that maybreak down mucosal defenses include the use of aspirin or other NSAIDs and the presence ofHelicobacter pylori bacteria in the gastric antrum. Various pharmacologic approaches areemployed.

A. Gastric antacids. Antacids are weak bases that increase gastric pH and, thus, indirectlyinhibit pepsin activity. They work by partially neutralizing gastric acid. They are most oftenused for the treatment of peptic ulcer disease (PUD) and reflux esophagitis. Nonsystemicantacids have a cationic group, which forms insoluble compounds that are relatively poorlyabsorbed. Other antacids (e.g., sodium bicarbonate) do not form insoluble complexes in theintestine and are absorbed; these are systemic antacids that may produce metabolic alkalo-sis. In general, antacids inhibit the absorption of other drugs by forming complexes withthem or ionizing them.

1. Calcium carbonate

a. Pharmacologic properties. Calcium carbonate is a nonsystemic antacid with a rela-tively rapid onset and prolonged duration of action. There is variable absorption ofthe base, which may produce slight metabolic alkalosis.

b. Indications for use. In addition to the treatment of PUD and reflux esophagitis, cal-cium carbonate is used in the treatment and prevention of osteoporosis and as anacid-base buffer in chronic renal failure.

c. Side effects and toxicity include an unpleasant chalky taste, nausea, belching, constipa-tion, hypercalcemia (especially with prolonged use of large doses and with concomitantintake of large amounts of dairy products-the "milk-alkali" syndrome), and renalstones. Calcium ion increases the secretion of gastric acid; that is, it increases secretionof gastrin and HCl. It is not a preferred drug in the treatment of PUD.

Note

NSAIDS and H. pyloripredispose to peptic ulcerdisease; discontinuation ofNSAIDs and eradication ofbacteria with antibiotics areessential to treatment.

Note

All antacids neutralize acid.Their side effects varyaccording to what cation theycontain.

Note

The primary concern withCa2* is that it $imulates acidsecretion, producing an"acid rebound."

2t l


Clinical Correlate

The constipating effect ofaluminum can be offset bymixing it with magnesium,which is a laxative.

Note

H, antagonists inhibith istamine-induced acidsecretion and also decreasegastric and vagally elicited acidsecretion:

Clinical Correlate

Cimetidine has the drawbackof inhibiting the P-450 system,prolonging the half-life ofmany agen6.

212

B.

2. Aluminum hydroxide

a. Pharmacologic properties. Aluminum hydroxide is a nonsystemic antacid and thus isnot absorbed.

b. Side effects and toxicity include constipation; hypophosphatemia, osteomalacia, andproximal myopathy with chronic therapy and low phosphate intake; and encepha-lopathy in patients on dialysis, presumably from aluminum intoxication.

3. Magnesium salts are nonsystemic antacids.

a. Specific agents. Preparations include magnesium hydroxide (milk of magnesia), mag-nesium carbonate, magnesium oxide, and magnesium trisilicate, which may adhere toan uicer and form a protective covering.

b. Side effects and toxicity include diarrhea and hypermagnesemia (in patients withrenal insufficiency).A number of antacids are combinations of magnesium hydroxideand aluminum hydroxide, which results in a balance between the opposing effectsthese antacids have on bowel motility.

4. Sodium bicarbonate

a. Pharmacologic properties. Sodium bicarbonate is a systemic antacid with a relative-ly rapid onset and short duration of action.

b. Side effects and toxicityinclude belching and gastric distention; milk-alkali syndrome(with chronic use and concomitant intake of large amounts of dairy products); andmetabolic alkalosis, especially in patients with renal insufficiency. Sodium bicarbonatemay also exacerbate congestive heart failure and edema from sodium intake. It iscontraindicated in hypertension.

Gastric antisecretory drugs include histamine (H2)-receptor antagonists, anticholinergicagents, and proton pump inhibitors.

1. H2-receptor antagonists are drugs that block parietal cell H2 receptors. They act asreversible, competitive inhibitors of histamine. These drugs inhibit histamine-inducedgastric acid secretion, and also inhibit the acid secretion induced by gastrin and aceryl-choline.

a. Cimetidine

( 1) Pharmacologic properties. Cimetidine contains the imidazole ring of histamineplus a bulkier side chain. Gastric acid secretion is effectively inhibited for 4 hoursfollowing oral administration.

(2) Indications for use include the treatment and prophylaxis of peptic ulcer disease(duodenal and gastric); the ZolTinger-Ellison syndrome (gastrin-secreting isletcell tumor); conditions associated with excessive gastric acid secretion, includinghyperhistaminemia, short bowel syndrome, and systemic mastocytosis; and asprophylaxis against upper gastrointestinal bleeding in acutely ill patients.

(3) Side effects and toxicity include mild gastrointestinal effects such as nausea; cen-tral nervous system (CNS) toxicity, including confirsion, dysarthria, hallucina-tions, and coma (coma is especially likely in the very young or old and in thosewith renal insufficiency); and antiandrogenic effect with prolonged use of highdoses, resulting in glmecomastia or impotence.

(4) Drug interactions. Inhibition of hepatic microsomal enzymes may increaseserum levels of many drugs, including ethanol, warfarin, digitoxin, triryclicantidepressants, phenytoin, carbamazepine, p-blockers, quinidine, theophylline,

(ACh)Histamine Vagal Gastrin

l l lL_](JV

t t l

@*----_r-_--vH+

Pharmacology

2.

methadone, and benzodiazepines. Cimetidine is the only H2-receptor blockerthat significantly inhibits the hepatic cytochrome P-450 system. Reduction ofhepatic blood flow may increase serum levels of morphine, B-blockers, and lido-caine. Antacids decrease cimetidine absorption. Rare side effects include intersti-tial nephritis, drug fever, eosinophilia, thrombocytopenia, and elevated liverfunction tests.

b. Ranitidine

(1) Pharmacologic properties. Ranitidine is much more potent than cimetidine. Iteffectively inhibits gastric acid secretion and does not inhibit hepatic cytochromeP-450 enzymes to the same extent as cimetidine. Ranitidine lacks antiandrogeniceffect and penetrates the CNS less than cimetidine. It is given once or twice a dayfor the treatment of ulcer disease.

(2) Indications for use are similar to cimetidine, but ranitidine is preferred inpatients prone to CNS toxiciry with cimetidine and in patients taking drugsknown to interact with cimetidine.

(3) Side effects include confusion and disorientation.

c. Famotidine has a similar pharmacologic profile to ranitidine but famotidine is morepotent and has a longer duration of action. Dosage must be decreased in patients withrenal insufficienry. The usual dosage is once a day at bedtime.

d. Nrzatidine has a similar pharmacologic profile to ranitidine.

Proton pump inhibitors (omeprazole)

a. Pharmacologl. properties. Omeprazole is a prodrug that diffuses from plasma acrossthe gastric parietal cell cytoplasm into the acid space of the secretory canaliculus. There,it is protonated and converted into an active compound that binds to parietal cellH+-K+-AIPase, inhibiting the final step in the secretion of H+ into the gastric lumen.

b. Indications for use. This proton pump inhibitor is used for the treatment of reflux dis-ease and peptic ulcer disease, especially cases refractory to treatment with H2-receptorblockers. It is particularly usefi.rl for the treatment of Zollinger-Ellison syndrome.

c. Side effects and toxicity include the overgrowth of bacteria; in rats, dose-related gas-tric carcinoid tumors have been seen. The major concern is the uncertain long-termeffect of intense acid suppression.

Anticholinergic agents (muscarinic receptor antagonists) modifr gastrointestinal secre-tory and motor function by inhibiting the effects of vagal nerve stimulation. These agentswere used to decrease gastric acid secretion before the introduction of the H, antagonists.H, antagonists are currently used because they have much greater efficacy and far fewerside effects.

a. Belladonna alkaloids (e.g., atropine) are anticholinergic agents.

b. Synthetic anticholinergic compounds (e.g., propantheline) have the same mecha-nism of action as atropine, but the CNS effect is much less because of the structuralmodification (quaternary ammonium group). General contraindications to the use ofanticholinergics include glaucoma, cardiac disease, and prostatic hypertrophy (when

urinary retention is already a problem).

c. Pirenzepine is a tertiary amine producing the selective antagonism of acetylcholine atthe M1 (muscarinic) receptor. Because of the drug's selectivity, the incidence of sys-temic anticholinergic side effects is minimal at therapeutic doses. This drug is cur-rently used in Europe and is in clinical trials in the United States.

ln a Nutshell

Ranitidine and famotidineare more potent blockersthan is cimetidine and havefewer side effects.

Note

Omeprazole irreversiblyinhibits the parietal cell protonpump. lt is an extremelyeffective acid inhibitor.

Note

Anticholinergia, such asatropine, also inhibit acidsecretion. However, their sideeffects prohibit wide usage.

3.

215


Note

Sucralfate is thought to coatdamaged tissue and helpulcers heal. lt has few sideeffects. lt cannot be given withantacids, H, blockers, oromeprazole.

Clinical Correlate

Misoprostol can be used toprevent gastritis in susceptiblepatients who must takeNSAlDs.

Note

The antibiotia tetracycl ine,metronidazole, andclarithromycin are used totreat H. pylori infection.

C. Mucosal protective agents

1. Sucralfate

a. Pharmacologic properties. Sucralfate is a complex of a sucrose polysaccharide andaluminum hydroxide, which polymerizes upon exposure to low pH of gastric acid.Negatively charged sulfate groups bind electrostatically to positively charged proteinsin ulcerated tissue.

(1) By adhering to damaged ulcer tissue, sucralfate protects the tissue against acid,pepsin, and bile, possibly retarding acidic and proteolytic damage.

(2) It is administered orally, resulting in very little systemic absorption.

b. Indications for use. Sucralfate is used to treat duodenal and gastric ulcers.

c. Side effects and toxicity. There is very low incidence of side effects, which includeconstipation and,less often, diarrhea, nausea, dry mouth, and rash.

d. Drug interactions. Sucralfate requires an acidic environment for activation andshould not be given with antacids, Hz-receptor antagonists, or omeprazole. Sucralfatedecreases the absorption of the antibiotics ciprofloxacin and norfloxacin.

2. Colloidal bismuth compounds bind selectively to an ulcer, coating the ulcer to protect itfrom acid and pepsin. There is possibly some antimicrobial activity against H. pylori.

3. Prostaglandins Ez (PGEz) and 12 (PGI2) inhibit gastric secretion and stimulate secretionof mucus. Misoprostol, a synthetic methyl analog of PGE' has been approved for theprevention of gastric ulcers caused by NSAIDs. The most common side effect is diarrhea.

D. Antibiotics. The role of antibiotics in the therapy of gastrointestinal ulceration is relativelynew. FL pylori may be a causal agent of peptic ulcers. The recurrence rate is much less inpatients receiving antibiotics (tetrarycline, metronidazole) plus an H2-receptor antagonistthan in those receiving only the H2-receptor antagonist. The role played by H. pylori is stillnot clear because most people with the bacterium do not develop peptic ulcers.

EMETICS AND ANTIEMETICSA. Overview. Emetics are drugs that induce vomiting. They are most often used following oral

ingestion of poisons or overdoses. These drugs should not be used in patients with adepressed level of consciousness because aspiration may occur, or in patients who haveingested acids/alkalis because esophageal or gastric damage may occur. They should also beavoided in patients who have ingested CNS stimulants, due to the possibility of seizures, orafter the ingestion of hydrocarbons, because chemical pneumonitis following aspiration mayoccur. Antiemetics are drugs used to treat nausea and vomiting.

214

Pharmacology

loV

Vomitingcenters

Dopamineantagonists

ot

5HT3

A\oSerotoninantagonists

Figure ll-6-1

B. Agents

1. Ipecac

a. Pharmacologic properties. Ipecac produces an emetic reaction by local irritation ofthe gastrointestinal tract and stimulation of the chemoreceptor trigger zone of themedulla. It has greater effrcaq than gastric lavage in emptying the contents of thestomach. It is orally administered, with an onset of action in 15-30 minutes. If emesisdoes not occur, gastric lavage should be used to remove the ipecac.

b. Side effects and toxicity are uncommon with usual doses. Cardiotoxicity is notedwith chronic use (e.g., bulimia). Ipecac should not be given with activated charcoal, asthe latter will absorb it and diminish its action.

2. Apomorphine

a. Pharmacologic properties. Apomorphine is a morphine derivative with little analgesicactivity. It is a dopaminergic agonist that directly stimulates the chemoreceptor triggerzone,leading to emesis. It is administered parenterally (usually subcutaneously), andthe onset of action occurs within 5 minutes.

b. Side effects include respiratory and CNS depression. It is more toxic than ipecac.

3. Dopamine receptor antagonists (prochlorperazine,chlorpromazirre,metoclopramide)

a. Pharmacologic properties. These drugs are antiemetics that act on D, receptors inthe CNS at the chemoreceptor trigger zone.

b. Side effects. These drugs canantiemetic effects.

4. Ondansetron

cause sedation and dystonia in addition to their

a. Pharmacologic properties. Ondansetron is a 5-HT. antagonist used to preventchemotherapy- induced emesis.

b. Side effects are minimal, but may include headaches, constipation, and dizziness.

Note

lpecac initates thegastrointestinal tractand stimulates thechemoreceptor triggerzone -) emesrs.

ln a Nubhell

. Apomorphine directlystimulates dopaminereceptors in the chemo-receptor trigger zone -)

emesis.. Dopamine antagonists such

as phenothiazines act asantiemetia.

215


ln a Nutshell

Bulk-Forming Laxatives. lncrease stool mass and

water content

. "Centle laxatives"

In a Nutshell

Castor oil, senna, andcascara irritate the bowelsand thus increasegastro i ntesti na I motil ity.

2t6

TAXATIVESLaxatives act to promote bowel motility. An orderly classification is hampered because laxative-induced fluid accumulation may be caused by inhibition of ion and water absorption, by stim-ulation of fluid secretion, or by both. Inhibition of cellular energy production or utilization,mucosal injury and activation of adenylate ryclase may be involved in the mucosal action ofthese agents. Long-term laxative abuse may result in spastic colitis, dehydration, and depletionof electrolnes.

A. Bulk-forming laxatives


a. Osmotic effect causes fluid and electrolyte retention in intestinal lumen.

b. Increased fecal mass and softness accelerate intestinal transit, producing action with-in 1-3 days following oral administration.

2. Indications for use. Bulk-forming laxatives are used for symptomatic relief in patientswith diverticular disease and irritable bowel disorders. Bulk-forming laxatives may beprepared from dietary fiber (e.g., nondigestible plant food, grains, bran, fruits, vegetables)or from semisynthetic polysaccharides and cellulose (e.g., methylcellulose, carboxymethyl-cellulose, psyllium).

3. Side effects and toxicity include flatulence, electrolyte imbalances, and, rarely, esophagealor intestinal obstruction; these laxatives should be taken with fluids.

B. Stimulant laxatives are agents that act on the intestinal mucosa and have effects both on thenet absorption of electrolytes and water and on motility. Stimulant laxatives are commonlyinvolved in cathartic abuse.

1. Castor oil

a. Pharmacologic properties. Castor oil is hydrolyzed in the small intestine to ricinoleicacid (active ingredient) and glycerol; ricinoleic acid reduces absorption of electrolytesand fluids and stimulates peristalsis. Onset of action is 1-3 hours following oral admin-istration.

b. Indications for use. Castor oil is not recommended for chronic use because it mayimpair absorption of essential nutrients and exacerbate dehydration and electrolytedisturbances.

2. Bisacodyl

a. Pharmacologicproperties. Bisacodyl is administered orally or rectally. Onset of actionis 6-12 hours after oral administration and less than I hour after rectal administration.

b. Side effects and toxicity include fluid and electrolyte deficiencies, rash, and rectalburning following rectal administration.

3. Anthraquinones

a. Pharmacologic properties

(1) The effect of anthraquinones is limited mainly to the large intestine. They con-tain anthraquinone derivatives, the basis for their laxative action. In the largeintestine, bacterial action (E. coli) causes hydrolysis of the glycosides and oxida-tion of freed aglycones to anthraquinones.

(2) Anthraquinones include cascara and senna. The onset of action is usually6-8 hours after administration.

Pharmacology

b. Side effects and toxicity. Anthraquinones are generally well tolerated when used inrecommended doses.

4. Docusates

a. Pharmacologic properties. Docusates are anionic surfactants, which soften stool byemulsifring water, fat, and feces, having mild laxative effects. The onset of action is1-3 days after administration.

b. Side effects include nausea and abdominal cramps. They should not be used withmineral oil because they promote absorption of the oil.

C. Osmotic laxatives

1. Salt-containing agents

a. Pharmacologic properties. Salt-containing agents are composed of magnesium,phosphate, and sulfate salts. They cause an osmotic effect, resulting in fluid retentionin the gastrointestinal lumen. This indirectly increases motility. Salt-containing agentshave a rapid onset of action (2 hours), with semifluid or water evacuation.

b. Indications for use. They are used for bowel evacuation prior to surgery and otherprocedures.

c. Specific agents include the magnesium salts for oral administration only, magnesiumsulfate, magnesium hydroxide (which also has an antacid effect), and magnesium cit-rate; sodium phosphate (which can be administered rectally as well as orally); potas-sium sodium tartrate; and sodium sulfate.

d. Side effects and toxicity. Patients with renal insufficiency may develop hypermagne-semia with magnesium salts. Sodium salts may exacerbate congestive heart failure.Dehydration may also occur.

2. Nonsalt osmotic laxatives

a. Lactulose is a semisynthetic disaccharide that produces laxative action via osmoticeffect. It increases fecal excretion of ammonia from laxative effect and decreasesammonia production by gut flora. Its onset of action is 1-3 days.

(1) Indications for use. It is used as a laxative and in cases of hepatic encephalopa-thy with portal-systemic shunting.

(2) Side effects and toxicity include nausea, vomiting, flatulence, abdominal dis-comfort, diarrhea, dehydration, and hypokalemia.

b. Other agents include glycerin and sorbitol.

D. Mineral oil

1. Pharmacologic properties. Mineral oil is a petroleum derivative composed of hydrocar-bons. It softens stool and may increase its fluid content.

2. Side effects and toxicity limit its use; they include pneumonitis following aspiration,impaired absorption of fat-soluble nutrients (e.g., vitamin K), and pruritus ani.

Clinical Correlate

Docusates act to soften stoolsand therefore are used afterabdominal surgery and postmyocardial infarction toprevent the patient fromstraining and possiblyrupturing the sutures.

Note

Poorly absorbed salts drawwater into the gastrointestinallumen, producing a stronglaxative action.

ln a Nutshell

Lactulose. Osmotic laxative

. Acidifies stool, trappingammonia as NH4+

. Enhances excretion ofnitrogenous wastes thatbuild up in hepaticinsufficiency

ln a Nutshell

. BranLactuloseMineral oil

J

l-3 days(soft feces)

. PhenolphthaleinSennaCascara

J

6-8 hours (soft or semifluidstool)

. Magnesium sulfateSodium phosphateCastor oil

Jl-3 hours (wateryevacuatron)

217


Clinical Correlate

Opiates decreasegastrointestinalmotility. Loperamideand diphenoxylate are twoopiates that poorly cross theblood-brain barrier andtherefore have fewside effects.

ANTIDIARRHEAT AGENTSDiarrhea is a symptom; accordingly, treatment should be directed to causative factors.Nonetheless, symptomatic treatment can add to physiologic well-being. Many pharmacologicapproaches are available.

A. Synthetic, opioid-like agents. Agents include diphenoxylate and loperamide. Addictionpotential is negligible when administered in recommended dosage range. The onlyrecognizeduse is in the treatment of diarrhea. Atropine is often used in combination with diphenoxylateto discourage abuse, although it probably contributes to the decrease in gastrointestinalmotility and secretions.

B. Adsorbents. Such agents as activated charcoal, hydrated aluminum silicate (kaolin), andpectin adsorb the irritants and mechanically protect the mucosal surface. Belladonna alka-loids may be added to kaolin and pectin mixtures.

C. Protectives, such as bismuth subcarbonate, provide a protective coating over the irritatedsurface because of their consistency.

MISCETTANEOUS GASTROINTESTINAT DRUGSA. Metoclopramide hydrochloride is a dopamine receptor antagonist used as a stimulant of

upper gastrointestinal motility.


a. Metoclopramide hydrochloride increases resting tone and contractility of gastroin-testinal smooth muscle, increases lower esophageal sphincter tone, and may increasecolonic motility.

b. In the CNS, metoclopramide hydrochloride has a direct effect on medullary antiemet-ic chemoreceptors as well as neuroleptic effects.

2. Indications for use include diabetic gastric stasis and postsurgical gastric stasis; treatmentof emesis in cancer chemotherapy; diagnostic and therapeutic procedures, such as aidingin radiographic examination of the upper gastrointestinal tract and endoscopy examina-tion of the small intestine; and gastroesophageal reflux.

3. Side effects

a. CNS effects include restlessness, drowsiness, fatigue, depression and dyskinesias.

b. Gastrointestinal effects include nausea or constipation.

c. There may also be prolactin secretion and a decrease in the absorption time in thestomach of such drugs as digoxin and food, causing hypoglycemia in insulin-dependentdiabetics.

4. Drug interactions. Metoclopramide hydrochloride should not be used in patients takingneuroleptics.

218

SECTION III

Endocrlne System

Endocrine Histology

NotcThe endocrines are a group of diverse tissues and organs that coordinate the activities of othertissues and organs by producing storing and secreting hormones. The hormones are kansported in There is no separatethe blood to target tissues and organs, where they exercise a particular effect or response. Ihis Endocrine Embryologychapter will review the microscoDic structural |eatures of each of the different endocrine tissues and chapter The developmertorgans. of the geographiolly diverse

endocrine glands is covered inthe other organ systems andin the Ceneral Princioles

PlrulrARY GLAND books

A. Overview

1. The pituitary gland or hnrophysis is a bilobed organ that lies at the base of the brainbelow the hypothalarnus in a bony cavity called the sella turcica.

a. The functions of the pituitary gland are controlled by the hypothalamus.

b. The pituitary gland exerts control over otler endocrine glands by the secretion oftropic hormon€s.

2. The pituitary is divided into the adenohypophysis and neurohypophysis based on itsembryologic origins (see Figure III-1-1).

a. The adenohnrophysis arises from an outpocketing of the ectoderm in the roof of theprimitive mouth called Rathke poudr. The adenohypophysis consists of the pars dis-talis, the pars tuberalis, and the pars intermedia. The pars distalis is often referred toas the anterior lobe.

b. The neurohnrophysis is derived from nerve tissue at the base of the brain and growsdownward to take a position that is posterior to the adenohypophysis. The neurohy-pophysis consists of tlre pars nervosa (neural lobe) and the infrrndibulum (neuralstalk). The pars nervosa is often referred to as the post€rior lobe. Glial cells, calledpituicytes, surround the nerve terminals in the neural lobe.

221

Endocrine System

Pars tuberalis

Bridge to Physiology B.

The anterior pituitary iscontrolled by releasinghormones from thehypothalamus, which reachthe pituitary via thehypophysial portal system.

Median eminence

Figure lll-1-1. Anatomic divisions of the hypophysis.

The anterior pituitary functions in the production, storage, and release of various polypep-tide hormones. Under the light microscope, this area appears as clusters or cords of cells ina rich network of fenestrated sinusoidal capillaries. Generally, anterior pituitary cells areclassified as either chromophils, based on their affinity for acid or basic dyes, or chromo-phobes, based on their lack of affinity for these dyes. Chromophils that have an affinity foracid dyes are called acidophils; those with an affinity for basic dyes are called basophils.

1. Acidophils contain large granules in their cytoplasm; the granules stain with eosin and otheracid dyes. Immunologic techniques .ue used to subdivide the acidophils with accuraq.

a. Somatotropes secrete growth hormone (GH) or somatotropin.

b. Mammotropes secrete prolactin. Th.y increase in number and size during pregnancyand lactation.

2. Basophils have been identified by a number of staining techniques, including the periodicacid-Schiff (PAS) reaction for those that contain glycoprotein hormones.Immunohistochemistry is used to identifr subtypes accurately.

a. Gonadotropes are large round cells that secrete follicle-stimulatinghormone (FSH) andluteinizing hormone (tH).

b. Thyrotropes produce thyroid-stimulating hormone ( TSH).

c. Corticotropes produce adrenocorticotropic hormone (ACTH).

3. Chromophobes are cells whose cytoplasm generally remains unstained. They may beeither reserve stem cells or acidophils and basophils that have degranulated during secre-tion.

4. Folliculostellate cells form a network of support-like cells; their function is unknown.

The pars tuberalis surrounds the infundibulum of the neurohlpophysis. It is composed ofhighly vascularized cords of epithelial cells forming a thin sheath around the stalk of theinfundibulum. The function of this region is unknown.

ln a NuBhellAnterior pituitary crllls

I

I

v vChromophils Chromophobes(stain with basic do not stainor acidic dyes)I

l->AcidophilsI l--Somatotrooes-+GH| |

(somatotropin)

| 4Mammotropes--+Prolactitt'->Basophils

->FSHl-+Gonadotrooes-4I L-+LHI

l+ThyrotropeF-+ ISHL+ C o rt i cotrope s----> ACT H

C.

222

Histology

D. The pars intermedia is present in humans during fetal life but is greatly reduced or disap-pears in adults.

1. This portion is referred to as the intermediate lobe.

2. In other mammals, it is composed of cords of weakly basophilic cells that synthesizemelanocyte-stimulating hormone (MSH).

E. Hypothalamohypophysial tract. The median eminence and stalk of the infundibulum andthe pars nervosa contain a tract of unmyelinated axons belonging to secretory nerve cellsthat have their cell bodies in the supraoptic and paraventricular nuclei of the hypothala-mus. These fibers are collectively known as the hypothalamohypophysial tract.

1. The secretorynerve cells produce the polypeptide hormones oxytocin and antidiuretichormone (ADH), or vasopressin, which are packaged into secretory granules and aremoved by axoplasmic transport to the pars nervosa. There they accumulate in nerve ter-minals near capillaries in clumps called Herring bodies.

2. These hormones are secreted by exocytosis upon stimulation of their neurons in the brain.

F. Vascular anatomy of the hypophysis is variable, but typically there are two superiorhypophysial arteries on each side of the organ: the anterior and posterior superiorhypophysial arteries.

1. These vessels supply the median eminence and the stalk of the infundibulum and formprimary looped sinusoidal capillaries that drain into venous trunks of the hypophysialportal system, which supplies the adenohypophysis.

2. The portal system terminates in the sinusoidal capillaries in the anterior lobe and con-ducts neurohormones from the median eminence to the adenohypophysis.

3. The anterior and posterior inferior hypophysial arteries supply the neurohypophysis andform an arterial circle at the junction to the anterior and posterior lobes.

4. The neurohypophysis,like the adenohypophysis, is perfused via sinusoidal capillaries linedwith fenestrated endothelium.


. Oxytocin induces uterinecontractions and stimulatesmilk let-down.

. ADH increases waterresorption in the kidney.The mechanism of actionfor ADH is discussed indetail in the RenalPhysiology chapter ofOrgan Systems Book t(Volume lll).

22t

Endocrine System

Note

The thyroid diverticulum arisesfrom the floor of the pharynxand enters the neck via thethyroglossal duct. This ductusually disappears, but thyroidtissue and cysts may remainas accessory thyroids (e.g., thepyramidal lobe).

In a Nutshell

Thyroid Gland. Two lobes connected

by an isthmus

. Synthesizes T3, T4,and calcitonin

. Tissue composed offollicles whose lumencontains colloid made ofthyroglobulin.

Supraoptic nucleus

Hypothalamic cellsthat producereleasing hormones

Median eminence Hypothalamus

Portal system

Anteriorpituitary gland

Posteriorpituitary gland

Fi gu re I ll-1 -2. The hypothalam ic-pituitary system.

THYROID GTANDA. Overview

1. The thyroid is a lobulated gland that consists of two pear-shaped lateral lobes connectedby an isthmus. It is found in the cervical region anterior and inferior to the larynx. A pyra-midal lobe is frequently present and points upward from the isthmus near the left lobe.

2. The thyroid synthesizes and secretes the thyroid hormones triiodothyronine (T3) andtetraiodothyronine (Tl, thyroxine), which regulate cell metabolism, development,growth, and differentiation. T3 and Ta synthesis and release is stimulated by thyroid-stimulating hormone (TSH) from the adenohypophysis. The gland also releases calci-tonin, which participates in calcium homeostasis.

3. The stroma of the gland is covered by a thin fibroelastic capsule from which connectivetissue septa penetrate, incompletely dividing the gland into lobules.

4. The parenchyma of the thyroid consists of follicles, which are lined by a simple cuboidalepithelium surrounding a central lumen. The follicles are filled with colloid composed ofalarge secretory protein material called thyroglobulin.

a. During development, the epithelial parenchymal cells become clumped and form thefollicles, the cells of which secrete their products into a central lumen called the follic-ular cavity.

b. Between follicles, a reticular stroma contains an extensive capillary bed.

224

Histology

c. Two cell types occur: follicular cells and parafollicular cells.

(1) Follicular cells are the principal thyroid cells. They are simple cuboidal epithe-

lial cells that line the follicular cavity and secrete thyroid hormones. Their api-

cal surfaces face the follicular cavity into which thyroglobulin is released, and

their basal poles rest on a basal lamina. In periods of increased activity, the cells

are columnar; their height declines toward squamous as their activity decreases.

The nuclei of follicular cells are rounded, and the cytoplasm is basophilic and

PAS-positive, indicating the presence of glycoprotein.

(2) Parafollicular cells, or C cells, are separated from the colloid by follicular cells.

These are larger cells, which possess light-staining cytoplasm. The parafollicular

cells are responsible for the secretion of calcitonin, a hormone that lowers blood

calcium levels and is secreted into the capillary bed.

B. Synthesis of thyroid hormones

1. Thyroglobulin is synthesized on membrane-bound ribosomes of the rough endoplasmic

reticulum (RER), where the nascent polypeptide is discharged into the cisternae of the

endoplasmic reticulum.

2. From the endoplasmic reticulum, the polypeptide is transported to the Golgi, where

peripheral sugar residues are added.

3. The finished glycoprotein is secreted into the lumen of the thyroid follicle.

4. The thyroid gland actively extracts and accumulates iodide ions from the blood, which are

used to iodinate the ryrosine residues in thyroglobulin. Iodination of tyrosine residues

in thyroglobulin occurs at the follicular cell surface and is catalyzed by thyroid peroxidase

enzymes localized in the microvillous border.

5. Under stimulation of TSH, endocytosis of the colloid by follicular cells occurs.

6. Endocytotic vesicles fuse with cytoplasmic lysosomes, resulting in hydrolysis of thyroglobu-

lin and liberation of T3 and Ta.

7. Thyroid hormones are released from the basal surfaces of foliicular cells into adjacent

capillaries.

C. Vascular supply. The thyroid is richly supplied by fenestrated capillaries that are closely

apposed to the follicular epithelium.

1. The thyroid is supplied by paired superior thyroid arteries (branches of the external

carotids) and paired inferior thyroid arteries (branches of the thyrocervical trunks).

2. The thyroid has many lymphatic capillaries. [ 'r 4 ,

PARATHYROID GTANDS

' ( - ' l , a a

A. Overview

1. The parathyroids usually consist of four flat and ovoid glands located behind the thyroid

or, occasionally, embedded within it.

2. The stroma of each gland is covered by a delicate connective tissue capsule from which

septa penetrate and divide the gland into incomplete lobules. Richly vascularized, it

contains many reticular fibers.

ln a Nutshell

C cells -+ calcitonin ->

J blood (Ca'.;

ln a Nutshell

Stages of Hormone Synthesis

(l) sv1t!7is of thyroglobulin

(2) Uptake ofcirculatory iodide

(3) Activation of iodideby thyroid peroxidase

(4) lodination of tyrosineresidues in thyroglobulin

Clinical Correlate

Thyroid abnormalities arerelatively common findln gs.Thyroid disease may result inhyperthyroidism, with highcirculating T3 and Ta, ot'hypothyroidism, with lowamounts of T3 and To.

Clinical Correlate

Due to the proximity of theparathyroid glands to thethyroid, thyroid removal mayresult in hypoparathyroidism,which is characterized by lowserum caz* and tetanv.

225

Endocrine System

Flashback toEmbryology

Parathyroid glands are derivedfrom the pharyngeal pouches-the superior glands are derivedfrom the foufth pouch, and theinferior glands are derivedfrom the third pouch.

Clinical Correlate

Hyperparathyroidism. Blood Ca" elevated

' Blood POo'- 1o*.t.0

. Bone becomes decalcified,subject to fracture

Hypoparathyroidism. Blood Ca,. lowered

' Blood PQ,r- elevated

. Bone becomes denser,more mineralized

. Tetany (spastic contractionsof muscles and generalizedconvulsions)

\ -i ) I i i ( r i , r

i . l i , i 1 1 "

In a Nutshell

Adrenalcortex (outside -+ inside)

3. The epithelial parenchymal cells, arranged in irregular cords or clusters, are composed oftwo cell tnres, which may represent different functional states of a single cell type.

a. Chief cells are small polyhedral cells with round nuclei. They are generally arrangedin cords but occasionally occur in clumps. They secrete parathyroid hormone (PTH),which is released into the capillary bed.

b. Oxyphil cells are larger and much less numerous than the chief cells. They appear aseosinophilic cells arranged in three forms: solitary cells, small clumps, or small distinctnodules surrounded by chief cells. The prominent eosinophilic granule-like structuresin their cytoplasm are mitochondria. The function of oxyphil cells is unknown.

B. Parathyroid hormone (PTH) is synthesized and secreted by the parathyroid gland. PTHincreases the serum calcium concentration by increasing bone resorption, decreasing renalexcretion, and increasing gastrointestinal uptake of calcium (via l,25-hydroxy vitamin D).

1. PTH acts initially on osteocftes of bone tissue (osteocytic osteolysis) and, subsequently,on osteoblasts, which recruit osteoclasts (osteoclastic resorption) to resorb calcium frombone matrix and make it available to the circulation.

2. PTH also increases renal excretion of phosphate.

3. Secretion of PTH is controlled byblood calcium and magnesium levels. For example,lowblood calcium levels signal the secretion of PTH from the parathyroid glands. This mech-anism appears to be independent of endocrine or neural inputs.

C. Blood supply of the parathyroids is from the superior and inferior thyroid arteries.

ADRENAT GTANDSA. Overview

1. The adrenals are paired glands, each about 4-6 cm in length. They are located retroperi-toneally, superior to the cranial poles of the kidneys.

2. The stroma of the adrenal gland consists of a thick connective tissue capsule that sendstrabeculae of collagenous and reticular fibers into the glandular tissue.

3. The glandular parenchyma is divided into a cortex that secretes steroid hormones and amedulla that secretes catecholamines.

B. Adrenal cortex contains cells that synthesize and secrete glucocorticoids, mineralocorti-coids, and certain sex steroid hormones. It is formed by three concentric layers of epithe-lioid cells and abundant fenestrated capillaries.

l. Zonaglomerulosa is the outermost narrow zone in which acidophilic columnar-like cellsare arranged in groups surrounded by capillary networks.

a. These cells secrete aldosterone, a steroid mineralocorticoid hormone, whose synthesisand release is controlled principally by angiotensin II and plasma potassium ion (K+)concentration. To a lesser extent, ACTH and atrial natriuretic peptide (ANP), which issecreted from the heart, also stimulate secretion of aldosterone.

b. Aldosterone acts mainly on the distal tubules of the kidney and on the salivary andsweat glands to promote sodium reabsorption. It also acts on the principal cells of thekidney's collecting duct to secrete K+.

Zona -) Zona -tglomerulosa fasciculata

J JMineralo- Clucocorticoidscorticoids (cortisol)

(aldo$erone)

"SALT' "SUCAR"

Tonareticularis

JAndrogens(DHEA)

"SEX"

226

Histology

2. Zonafasciculata is a wide zone with its cells organized in cords, coursing radially inward

from the zona glomerulosa and pointed toward the medulla. A longitudinal mesh of sinu-

soidal capillaries extends the length of the cords.

a. The cells are polyhedral or cuboidal and are often binucleated. They contain a high

lipid concentration.

b. Zonafasciculata cells secrete glucocorticoids, including the principal hormone cortisol,

which have major effects on carbohydrate, protein, and lipid metabolism. This zone also

secretes some androgens and a minimal amount of estrogens.

c. The cells of this zone are stimulated by the secretion of ACTH from the anterior pituitary.

3. Zonareticularis is a small region at the corticomedullary junction in which the cells of

the cords are arranged in irregular networks. This zone secretes dehydroepiandrosterone(DHEA), other l7-ketosteroids, and probably some glucocorticoids as well. It is stimulated

by ACTH. The zona fasciculata and zona reticularis function together as a unit in some

ways (e.g., some sex steroids are made in both fasciculata and reticularis).

C. Adrenal medulla consists of cells that are arranged in anastomosing cords intermingled with

capillaries and venules.

1. These columnar cells are oriented with one end facing a capillary and the opposite pole in

contact with a venule. Preganglionic sympathetic fibers contact each cell at the capillary pole.

2. The cells are known as chromaffin cells because they are colored by oxidizing agents such

as potassium dichromate, which turns them brown due to oxidation of the cate-

cholamines in the cells.

3. The cells produce and secrete the catecholamine hormones epinephrine and norepi-

nephrine, which are stored in their secretory granules. Glucocorticoids produced in the

cortex pass through the medulla and are required by medullary cells for synthesis of cat-

echolamines, especially during stress.

4. The medulla is under sympathetic control, and its hormones function in concert with the

sympathetic flow in the "fight-or-flight" response. In many respects, the medullary cells

function as postganglionic sympathetic neurons.

D. Blood supplyto the adrenals comes from the superior, middle, and inferior suprarenal arteries.

E. Innervation of the adrenal glands is mainly sympathetic and is carried via the splanchnic nerves.

1. These autonomic fibers are the principal means of regulating the release of cate-

cholamines from the medulla.

2. Although the cortex receives some fibers, they do not appear to play an important role in

regulating the release of hormones.

ENDOCRINE PANCREASA. Overview. The islets of Langerhans are rounded clusters of endocrine cells dispersed in the

pancreatic exocrine tissue.

l. There are over one million islets in the human pancreas, constituting approximately l.5o/o

of the volume of the pancreas.

2. Theislets are enclosed in delicate reticular capsules, a few fibers of which penetrate the islets.

B. Cells of the islets are polygonal and are arranged in clusters that are intermingled with sinu-

soidal capillary networks.

Flashback toEmbryology

The cells of the adrenalmedulla are derived fromneural crest cells. The cells ofthe adrenal cortex are derivedfrom mesoderm.

In a Nutshell

Catecholamines(Epinephrine,Norepinephrine):

. t Heart rate

. Vasoconstriction(t cardiac output, t bloodpressure)

. t Blood glucose

Clinical Correlate

Pheochromorytoma is aneoplasm that secretesepinephrine andnorepinephrine. This causessecondary hypertension,increased urinaryvanillylmandelic acid (VMA)levels, and high plasma levelsof catecholamines. lt is treatedwith cr-receptor blockers suchas phenoxybenzamine.

227

Endocrine System

ln a Nutshell

lsleb of Langerhans

o cells p cells

1. When viewed under the electron microscope, these cells have the structure of cells syn-thesizing polypeptides: abundant RER, a prominent Golgi complex, and secretory gran-ules.

2. Using special staining methods, particularly immunohistochemical procedures, threemajor cell types have been identified in the islets.

a. cr (A) cells constitute approximately 20o/o of the cells found in the endocrine pancreas.They synthesize and secrete the polypeptide hormone glucagon, which acts toincrease blood glucose levels. cr cells are found mainly in the periphery of the islets.

b. B (B) cells are the major cell type and constitute approximately 60-800/o of the isletcells. They secrete the hormone insulin, which acts to decrease blood glucose levels.B cells are found mainly in the center of the islets.

c. 6 (D) cells are the least numerous and constitute less than 5o/o of islet cells. Theysecrete the hormone somatostatin, which acts locally to inhibit the secretion of bothinsulin and glucagon. 6 cells are found scattered throughout the islets.

PINEAT GTANDA. Overview

1. The pineal gland or epiphysis is a pedunculated, cone-shaped body that is attached to theroof of the third ventricle by a stalk.

a. It is approximately 5-8 mm in length and is encapsulated by pia mater, except at itspoint of attachment.

b. Connective tissue septa, containing blood vessels and unmyelinated nerve fibers, orig-inate in the pia mater and penetrate the pineal gland to form irregular lobules aroundcellular cords and follicles.

2. Maior cell types of the pineal gland consist of pinealocftes and interstitial cells.

a. Pinealocftes are epithelial-derived cells with large, irregularly shaped nuclei and rel-atively large nucleoli.

b. Interstitial cells are characterized by elongated dark-staining nuclei and are locatedbetween the cords of pinealocytes and perivascular areas. Interstitial cells are compa-rable to glial cells of the brain.

B. Innervation of the pineal gland is by postganglionic sympathetic fibers, which arise in thesuperior cervical ganglion and terminate on pinealocytes.

C. Melatonin, an indoleamine compound, is the principal hormone synthesized by the pinealgland. The precise function of this hormone in humans is unknown. In other mammals, itplays a role in seasonal reproductive rycles; in amphibians, it induces the aggregation ofpigment granules in the melanophores.

Clucagon Insulin

f Clucose J Glucose

, i ^ (G. i t . .

6 cells

II

Somatostatin

II

J Glucagon

J Insulin

1 , . ' ' t . c I

Clinical Correlate

The pineal gland in humanshas been associated with thecircadian rhythm. Seasonalaffective disorder (SAD) andjet lag may result fromdisturbances in this rhythm.

Note

A microscopic feature seen inan aging pineal gland is "pinealsand." This consists of calciumand magnesium phosphatewithin an organic matrix.

228

Endocrine Anatomy

This chapter will highlight the gross anatomy of the thyroid, adrenal glands, and pancreas.

The anatomy of the pituitary is discussed in the Neuroanatomy section of Organ Systems Book t(Volume lll).

I}IYROID GTANDThe thyroid gland is locat€d anterior to the upper trached rings. !!,$9

A. Arterial supply. The superior thyroid artery is a branch of the external carotid artery and The parathyroid glands arethe inferior tlyroid artery is a branch of the thyrocervical trunk ftom the sub-clavian artery. usuaily four in number ThEA single 'thyroidea ima" artery may arise ftom the arch of the aorta or one of its branches. are embedded in the Dosterior

B. Venous drainage. The superior and middle thyroid veins drain to the int€rnal iugular veins surface of the lobes of thebilaterally. The inferior thyroid veins usually form a common tnurk whidr drains to the left thyroid gland.brachiocephalic vein.

C. Lynphatic draimge. The thyroid gland drains primarily to the deep cervical nodes.

ADRENAT GTANDSA- Adrenal glands are paired endocrine glands that lie on the apical poles of the kidnqrc, and

are therefore referred to as suprarenal glands'

B. Arterial supply, Like all endocine glands, the adrenals are very vascular. All oftheir arteriesmay be multiple.

1. The superior suprarenal artery is a brandr of the inferior phrenic art€ry.

2. The rniddle suprarenal artery is a branch of the abdominal aorta.

3. The inferior suprarenal artery is a branch of the renal artery'

C. Venous drainage

1. The right suprarenal vein ihains to the inferior vena cava.

2. The left suprarenal vein drains to the left renal vein.

D. Lyrnphatic drainage goes to the superior lumbar (lateral aortic) nodes.

E. Imervation

1. The preganglionic sympathetic fibers travel in the splanchnic nerves and the celiac plorus.

2. Postganglionic sympathetic cell bodies form the substance of the adrenal medulla.

229

Endocrine System

PANCREASA. The Pancreas lies retroperitoneally behind the stomach in the transpyloric plane

(Figure III-2-1).

Right suprarenalgland

Right kidney

TailBodyNeckHead

Pancreas

Duodenum

Figure lll-2-1. Relations of the pancreas.

B. The Pancreas is cane-shaped, with a head, body, and tail. The uncinate process, which hooksaround the superior mesenteric vessels, is continuous with the head of the pancreas.

C. Both main and accessory ducts lead from the pancreas. The main duct (of Wirsung) and thecommon bile duct open into the second part of the duodenum at the ampulla of Vater. Theaccessory duct (of Santorini) usually opens independently at a secondary papilla.

Clinical Correlate

Pancreatic cancer is insidiousand may or may not causejaundice, depending onwhether or not the tumorblocks the bile duct system.Cancers of the head of thepancreas are more likely toproduce faundice than those ofthe body;the latter, therefore,may not be diagnosed untilthe tumor is large enough tocause back pain.

zto

Endocrine Physiology

The endocrine system is composed of various glands and secretions whose primary roles are

metabolic regulation, growth promotion, maintenance, communication, and reproduction. This

chapter will focus on the major hormones controlling these processes as well as their interactions

with other organ systems. Since the endocrine system is closely associated with the nervous system,

specific neurotransmitters, including dopamine, serotonin, epinephrine, and norepinephrine will be

discussed in relation to their regulatory roles in hormone secretion.

REGUTATION AND ORGANIZATION OF THE ENDOCRINE SYSTEMA. Organization of the endocrine system

1. The pituitary glurd (hypophysis) is an unpaired organ that lies just beneath the brain and

is connected to it by the infundibulum. It is composed of the anterior pituitary and the pos-

terior pituitary.

a. The anterior pituitary (adenohlpophysis) is derived embryologically from somatic

ectoderm and is devoid of innervation.

b. The posterior pituitary (neurohypophysis) is derived from neural ectoderm. The pars

nervosa of the posterior pituitary is supplied with nerve tracts directly from the

hypothalamus.

2. The hypothalamic-hypophysial portal blood system is the capillary system that con-

nects the brain and the anterior pituitary. It originates in the median eminence region of

the hypothalamus. The anatomic relationships are shown in Figure III-3-1.

a. Releasing factors (RFs) and releasing hormones (RHs) are released close to the cap-

illary loops of the hypothalamic-hypophysial portal blood system and travel to the

anterior pituitary via the portal blood system. Upon reaching the anterior pituitary,

the RHs stimulate the release of hormones. These hormones, in turn, travel to spec-

ific endocrine glands and cause the synthesis or release of specific hormones.

2tl

Endocrine System

Dorsal medial nucleusDorsal hypolhalamic area

Paravenlricular nucleus

Laleral hypolhalamic area

Anterior hypothalamusVenlromedial nucleus

Mamrllary body

Preoptic area

Supraoplic nucleus

Suprachiasmatic nucleus

Optic chiasm

Arcuale nucleus

Median eminence

Superior hypophysial arterySupraoptic andparaventracularnuclei nerva lract Long portal vessels

Secondary portal plexus

Anterior pituitary(Adenohypophysis)

Inferior hypophysial artery

Figure lll-3-1. Anatomic relationships among the hypotharamus,hypothalamic-hypophysial portal blood system, anterior pituitary,

and posterior pituitary.

b. Corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH),thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone(GHRH) are hypothalamic hormones that stimulate pituitary function. CRH controlsthe release of ACTH; GnRH stimulates the release of LH and FSH; and TRH stimulatesthe release of TSH and prolactin. GHRH stimulates growth hormone secretion.

c. Somatostatin inhibits both TSH and growth hormone, whereas dopamine inhibitsprolactin secretion.

Neurosecretory cells of the hypothalamus have axons that pass through the infundibularstalk and terminate either in the pars nervosa or close to the capillary network in themedian eminence. Oxytocin and antidiuretic hormone (ADH) are produced by thehypothalamus. They travel via nerve tracts to the pars nervosa, are stored there, and arereleased under appropriate physiologic stimulation.

Neurotransmitters involved in hypothalamic neurohormone secretion are epinephrine,norepinephrine, dopamine, serotonin (5-hydroxytrlrytamine, 5-HT), acetylcholine(ACh), and y-aminobutyric acid (GABA). Several peptidergic neurotransmitters (i.e.,neurotensin, substance R enkephalins, endorphins) also affect neuroendocrine functionby their effects on hypothalamic hormones and on monoaminergic neurotransmitters.

Poslerior pituitary{Neurohypophysis)

ln a Nutshell

Hypothalamic-Releasin gHormones. TRH

. CRH

. CnRH

. CHRH

. PRH

Hypothalamic InhibitoryHormones. SOmatOStUlin /r:t '1a', !

. Prolactin inhibitory factor(dopamine)

3.

4.

252

Physiology

B. Regulation of the endocrine system. There are five distinct mechanisms by which theendocrine system functions. Note that most of the hormones discussed in the followingexamples are described in greater detail later in this chapter.

1. Feedback not involving the hypothalamic-hypophysial axis. The simplest type ofendocrine control occurs when a hormone acts on specific cells and promotes a change inthe extracellular fluid, which, in turn, regulates the output of the original hormone. Forexample, parathyroid hormone (PTH) is a peptide produced by the parathyroid glandsthat regulates the concentration of calcium (Cuz*) in the blood, as shown in Figureril-3-2.

Figure lll-3-2. Feedback regulation of serum calcium (Ca2*)and parathyroid hormone (PTH). (+) = stimulation; (-) = inhibition.

a. The concentration of serum Ca2+ in the bloodstream drops (step I in the above fig-ure) which stimulates the secretion of PTH from the parathyroid (step 2).

b. PTH travels to its target organs (i.e., kidney, bone, and indirectly to the gut) to stimu-late Ca2+ absorption and raise the serum Ca2+ level (step 3).

c. As the concentration of serum Ca2+ rises in the bloodstream, PTH secretion from theparathyroid is inhibited (step 4).

2. Endocrine control involving a hormone precursor. A hormone precursor is releasedinto the bloodstream and is then converted to an active substance. This system is used tostimulate the secretion of aldosterone from the adrenal cortex.

a. Angiotensinogen, an inactive hormone precursor, is secreted into the bloodstream bythe liver.

b. In the blood, the renal enryme renin converts angiotensinogen to another hormone,angiotensin I.

c. In the capillaries of the lung, angiotensin I is converted to angiotensin II by the actionof angiotensin-converting enzyme (ACE).

d. Angiotensin II stimulates the production of aldosterone by the adrenal cortex.

e. Aldosterone acts on the kidney and alters electrolyte secretion, which, in turn,leads toa decrease in renin production by the kidney.

3. Endocrine control involving a dietary precursor. This type of endocrine control occurswhen a hormone precursor is derived from the diet or is synthesized within the organism.

ln a Nutshell

Angiotensinogen (liver)

J e renin (JC apparatus)

Angiotensin I

J e ACE (lungs)

Angiotensin ll

J

Aldosterone (adrenal cortex)

Parathyroidhormone

2!'

Endocrine System

This precursor goes through successive transformations in several additional sites beforebecoming biologically active. For example, vitamin D can be either synthesized in the skinfrom 7-dehydrocholesterol or ingested in the diet. It then undergoes successive hydroxyla-tions in the liver and kidney to form l,25-dihdroxycholecalciferol (1,25[OH]rDr), the activeform of the hormone.

4. Endocrine control involving the hypothalamic-hypophysial axis. This type of control isillustrated in Figure III-3-3.

a. Gonadotropin-releasing hormone (GnRH) is produced in hypothalamic neurons.These neurons terminate in proximity of the capillary network in the median emi-nence region of the hypothalamus.

b. After being picked up by this capillary system, GnRH is transported via the hypotha-lamic-hypophysial portal blood system to the anterior pituitary where it promotes thesynthesis and release of luteiniztnghormone (tH) and follicle-stimulatinghormone(FSH).

c. LH travels via the bloodstream to the testis, where it stimulates the production andrelease of testicular steroids (androgens). The androgens, in turn, travel via the bloodto the hypothalamus to inhibit the secretion of GnRH, thus functioning in a negative-feedback loop.

Hypothalamus

Shoft-loopfeedback to

hypothalamus

LH (_) Anterior pituitary

Long-loopfeedback tohypothalamusandrogens) Long-loop

feedback topituitary(androgens)

Testis

Figure lll-3-3. Negative feedback system involvingthe hypothalamic-hypophysial-testicular axis.Both long-loop and short-loop feedback systems

are shown; (+) = stimulatory effects; (-) = inhibitory effects;LH = luteinizing hormone; GnRH = gonadotropin-releasing hormone.

LH

LH

(+

214

Physiology

d. Alternately, androgens act directly on the pituitary to decrease the release of LH or FSHby altering the sensitivity of the pituitary cell to GnRH. This is known as directfeedback (pituitary) as compared to indirect feedback (hypothalamic).

e. LH could travel via retrograde blood flow from the pituitary to the hypothalamus toinhibit the synthesis or release of GnRH.

(1) The effect of LH on the target gland and of the target gland secretions on thehypothalamic-pituitary unit is referred to as long-loop feedback.

(2) The effect of LH on the hypothalamus is referred to as short-loop feedback.

5. The interaction between the nervous and endocrine systems is seen with the release ofoxFtocin in a lactating woman.

a. If the breast is prepared hormonally for lactation, the suckling of an infant sends neu-ral impulses from the breast to the spinal cord, up into the brain, and eventually, todiscrete nuclei of the hypothalamus.

b. These impulses stimulate the paraventricular nucleus of the hypothalamus to syn-thesize and transport oxytocin to the pars nervosa and also to cause the release of oxy-tocin from the pars nervosa.

c. Oxytocin then travels via the bloodstream to the breast, where it causes contraction ofthe breast myoepithelial cells, resulting in milk let-down.

d. The afferent part of the arc is nervous, which stimulates the synthesis, transport, andrelease of oxytocin. The efferent part of the arc is endocrine, which is the effect of oxy-tocin on the breast to induce milk let-down (Figure III-3-4).

Paraventricular nucleus

Paraventriculo-hypophysialnerve tract

Anterior pituitaryPosterior pituitary

AfferentOxytoci

(neural)

ln a Nutshell

Overall Orytocin Effects. Contraction of

myoepithelial cells inmammary glands and milklet-down

. Stimulant of uterinecontractions; is often usedto induce labor

T,isuckrins/t \b*

Milk let-down

Efferentstimulus

Figure lll-3-4. Neuroendocrine reflex arc in oxytocin release.

2t5

Endocrine System

Note

Normal groMh requiresnormal levels of:. Nutrition

. C H

. lcF-t

. Thyroid hormone

. Cortisol

. lnsul in

Clinical Correlate

The major diseases associatedwith CH are pituitary dwarfism(insufficient CH secretion),gigantism (excessive CHsecretion before growth platesare fused), and acromegaly(excessive CH secretion aftergrowth plates are fused). Theyare discussed in detail in theEndocrine Pathology chapterof this book.

ln a Nutshell

Control of GH Secretion

Hypothalamus

/ \Somatostatin

olY

(+)

ANTERIOR PITUITARY HORMONESThe hormones synthesized and secreted by the anterior pituitary are assigned to three basicgroups according to their chemical structure.

A. Straight-chain peptides containing disulfide bridges (somatomammotropic group)

1. Growth hormone (somatotropin, GH)

a. Structure. Growth hormone is a protein containing two internal disulfide bridges. Itshares similar structural and biologic function with prolactin (PRt) and humanplacental lactogen (hPt).

b. Function. Growth hormone stimulates growth in childhood. It acts as an anabolicand anticatabolic agent. It promotes growth in most body tissues and regulates cell sizeand number. Growth hormone stimulates the production of somatomedins (insulin-like growth factor, IGF) in the target tissues, which mediate many of growth hor-mone's key growth actions. Like the insulin receptor, the IGF receptor has tyrosinekinase activity.

c. Metabolic effects

(1) Increases protein synthesis with a decrease in blood urea and urinary nitrogen.It also increases protein synthesis in chondrocftes (increases linear growth) withincreased conversion of proline to hydroryproline. Iean bodymass is increased.

(2) Decreases sensitivity to insulin; diabetogenic effect.

(3) Increased lipolysis results in increased free fatty acids in the bloodstream.Metabolically, this spares glucose and protein from being burned as fuel (anti-catabolic effect).

d. Pattern of secretion. GH is released in pulses throughout the day. The most consis-tent period of secretion occurs approximately one hour after the onset of sleep. GH isreleased following stress, hypoglycemia, vasopressin or r-dopa injection, during exer-cise, and during sleep.

e. Control of secretion

(1) GHRH stimulates the production and secretion of growth hormone.

(2) Somatostatin blocks the secretion of growth hormone from the anterior pitu-itary. Recall that besides the hypothalamus, somatostatin is also produced in thepancreas and in other tissues.

(3) Somatomedins exert negative feedback by inhibiting GH secretion from theanterior pituitary and promoting somatostatin release from the hypothalamus.

(a) Both GHRH and GH inhibit their own release by feeding back on the hypotha-lamus and anterior pituitary respectively.

2. Prolactin (PRt) is secreted from the acidophilic mammotrophs of the adenohypophysis.

a. Prolactin is required for milk synthesis in the mammary gland.

b. Prolactin is controlled primarily by an inhibitory hypothalamic system. Dopamineinhibits prolactin release by a direct action on the mammotroph and possibly also byreleasing a prolactin-inhibiting factor (PIF). The pituitary secretes copious amounts ofprolactin when removed from its hypothalamic inhibitory system. Prolactin inhibits itsown release by increasing the release of dopamine from the hypothalamus.

GHRH

Y.)(+)

Anterior rPituin" l-T u' I

Somatom edins <-Irbbues -+ Somatomedi ns

216

Physiology

c. TRH stimulates prolactin release. Although inhibition by dopamine is the major reg-ulator of prolactin, chronically elevated TRH levels can contribute to hyperpro-lactinemia.

d. Chronically elevated prolactin inhibits GnRH production and secretion.

e. Causes of hyperprolactinemia include:

(1) Pituitary tumors

(2) Dopamine antagonists, such as most antipsychotics

(3) Primary hypothyroidism (increased TRH)

B. Glycoproteins composed of cr and B subunits include LH, FSH, and thyroid-stimulatinghormone (TSH). LH and FSH act on the ovaries and the testes. TSH maintains and stimu-lates thyroid follicles to produce thyroxine (Ta) and triiodothyronine (Tr).

1. All are composed of two polypeptide chains called o and B subunits.

a. The o subunit is similar in structure in FSH, LH, and TSH.

b. The B subunit conveys the biologic specificiry of the hormone, but both the u and Bsubunits are needed for biologic activity.

c. Human chorionic gonadotropin (hCG), secreted by the placenta, has a B subunit thatis almost identical to that of LH.

2. The biochemical arrangement of these glycoproteins' subunits permits dissociation ofintact TSH, LH, FSH, and hCG into their respective cr and B subunits. These subunits canbe recombined under appropriate conditions to form hybrid molecules with an cr subunitfrom one molecule and a B subunit from another molecule.

C. Straight-chain peptides and polypeptides (corticotrophs)

l. Overview

a. B-lipotropin (B-LPH) and melanocyte-stimulating hormone (MSH) are secretedfrom the pars intermedia of the adenohypophysis; adrenocorticotropin (ACTH) issecreted from the pars distalis.

b. Pro-opiomelanocortin (POMC) is a hormone precursor synthesized in the hypotha-lamus. It is hydrolyzed in the anterior pituitary to ACTH, p-lipotropin (B-LPH), and

B-endorphin.

2. ACTH

a. ACTH maintains the size of certain adrenal cortical cells and stimulates them to pro-duce glucocorticoid hormones.

b. ACTH also has the ability to stimulate pigment cells (because of its structural similar-ity to MSH). Therefore, hyperpigmentation is seen in patients suffering from excessiveACTH production, either in Addison's disease, a form of adrenal insufficienry inwhich ACTH production is elevated, or following adrenalectomy in which ACTH pro-duction is elevated as a result of lack of negative feedback.

c. ACTH secretion can be inhibited by adrenal corticosteroids.

d. ACTH is discussed in greater detail in the section on the adrenal cortex.

3. MSH stimulates melanocytes (pigment cells).

a. MSH is produced by the corticotropin (chromophobe) cells found in the pars inter-media. Increases in pigmentation are seen in patients with MSH-secreting tumors.

In a Nutshell

Pituitary ClycoproteinHormones

. TSH, LH, FSH

. cr subunit is common toTSH, LH, and FSH

. B subunit conveys thespecificity of the hormone

Note

TSH is discussed in greaterdetail in reference to the thyroidgland later in this chapter. FSH,LH, and hCC are discussed inthe Reproductive Physiologychapter of this book.

Clinical Correlate

Cushing diseose is due tohypersecretion of ACTH froman adenoma of the anteriorpituitary.

Cushing syndrome can bedue to multiple causes, suchAS:

. Adrenal corticaladenoma/carcinoma

. Ectopic ACTH productionby nonpituitary tumors,most commonly small cellcarcinoma of the lung

. Corticosteroid medication

257

Endocrine System

ln a Nutshell

Endorphins and enkephalinsare endogenous opioidagonists. They act asneurotransmitters and bind toopioid receptors. Morphineand other opioid analogs bindto these receptors and act asanalgesics.

In a Nutshell

Anterior Pituitary Hormones. Crowth hormone (CH)

. Prolactin

. Luteinizing hormone (LH)

. Follicle-stimulatinghormone (FSH)

. Thyroid-stimulatinghormone 0SH)

. Adrenocorticotropichormone (ACTH)

' Melanoqrte-stimulatinghormone (MSH)

. B-lipotropin (B-LPH)

P 1 - . , . , , , . , - r ' , h c v x , ' , , i

, l ' - f t ;

. f - . r r r i 1 - r r

b. Control of MSH secretion in humans is not understood, but it can be inhibited byadrenal corticosteroids.

a. p-lipotropin (B-LPH) is derived from the carboxy terminal fragment of POMC. Otherthan being a possible precursor for other hormones, the only known effect of p-LPH isweak lipolytic action.

5. A class of opiate-like peptides known as enkephalins and endorphins are derived fromPOMC, and are fragments of B-LPH.

a. Endorphins help regulate the limbic system by binding to specific opiate receptors,resulting in effects on pain mechanisms, behavior disorders, and narcotic addiction.

b. Enkephalins are endogenous pentapeptides that bind to opiate receptors in the brain.Enkephalins produce transient analgesia and inhibit electrically evoked contraction incertain tissue preparations. They bind opiate receptors and are found in nerve end-ings, thereby modifring the nervous system response to sensory information such aspain and emotional behavior.

POSTERIOR PITUITARY HORMONESA. Overview. The pars nervosa receives direct nerve supply from hypothalamic neurons and

stores hormones produced from those neurons. Varicosities (Herring bodies) on the neuronsextending into the posterior pituitary from the hypothalamus contain stainable neurosecre-tory granules similar to those found in the supraoptic and paraventricular nuclei.

B. Biosynthesis of ADH (vasopressin) and oxytocin. The supraoptic nucleus (SON) andparaventricular nucleus (PVN) of the hypothalamus supply unmyelinated axons that tra-verse the basal hypothalamus to terminate in both the median eminence and posterior lobeof the pituitary.

1. ADH and oxytocin are produced in separate cells;both types of cells are distributed with-in the SON and PVN.

2. Granules identified in the cell body, axon, and terminals contain either ADH or oxytocin, acorresponding carrier protein (neurophysin), and, probably, a larger precursor molecule ormolecules.

3. The neurosecretory cells that make up the SON and PVIrI generate action potentials thatregulate the release of the hormone products from the nerve terminals.

4. Converging inhibitory and excitatory afferents from other brain regions regulate neu-rosecretion to achieve neuroendocrine control. Neuronal depolarization results in therelease of the entire granule contents into the perivascular spaces, where diffrrsion into theblood rapidly occurs.

5. The posterior lobe stores and releases oxytocin, ADH, and their associated neurophysins.

a. Nicotine is a potent stimulus for release of ADH and its neurophysin, unless ADH isinhibited with large amounts of ethanol.

b. Estrogen stimulates the release of oxytocin and its neurophysin.

2t8

Physiology

C.

Table III-3-1. Regulation of ADH secretion.

ProducelncreasedADH ProduceDecreasedADHSecretion Secretion

t Set,t- osmolarityVolume contractionPainNauseaHypoglycemiaNicotine, opiates,antineoplastic drugs

J Serum osmolariwEthanolcx-agonistsAtrial natriuretic factor (ANF)

Physiologic secretion of ADH (Table III-3-1) depends primarily on the changes detected byosmoreceptors and baroreceptors. Osmoreceptors respond to small changes in the extra-cellular fluid osmolarity; baroreceptors respond to changes in blood pressure (and volume).

1. Osmoreceptors. Osmotic changes are sensed by neural cells in the hypothalamus. Adecrease in serum osmolarity leads to inhibition of ADH release, whereas an increase inserum osmolarity stimulates ADH secretion. The primary site of action of ADH is thekidney. ADH acts to increase permeability of the distal tubules and principal cells of thekidney's collecting ducts, thus causing water reabsorption.

2. Baroreceptors are found in three anatomic locations: the left atrium, the carotid sinus,and the aortic arch.

a. Left atrium. These are low-pressure receptors, which respond to small reductions incentral blood volume that are not associated with systemic hypotension. The impuls-es are transmitted via the vagus nerve.

b. Carotid sinus and aortic arch. These are high-pressure receptors. The carotid sinusimpulses are transmitted via the glossopharyngeal nerve, while the aortic archimpulses are transmitted via the vagus nerve. Both of these receptors tonically inhib-it ADH. With diminished stretch (decreased pressure) there is a reduction in the fir-ing rate, resulting in ADH secretion.

c. A small change (as little as 1olo) in plasma osmolarity results in ADH release; in con-trast, it takes a decrease in blood pressure of )10olo to cause an increase in ADH secre-tion. However, the response of ADH secretion is much greater to a volume (and there-fore pressure) change than to an osmotic change. Volume receptors override osmoticreceptors in situations such as hyponatremia and blood loss.

d. Volume contraction also stimulates thirst by the release of angiotensin II.

3. Other causes of increased ADH secretion include nausea, severe hypoxemia, hlpo-glycemia, and pain. Drugs that stimulate ADH secretion include nicotine, opiates, and cer-tain antineoplastics.

ADH effects on the kidney

1. When ADH is absent, the water permeability of the collecting ducts is low and there isessentially no reabsorption of water from tubular fluid in the ducts. This results in excre-tion of hypotonic urine.

2. During antidiuresis, ADH increases the water permeability of the renal collecting ductsand distal tubules, allowing osmotic equilibration of tubular fluid with the hypertonicmedullary interstitium. The result is decreased urine volume and conservation of bodywater. The urine is hypertonic.

Bridge to Cardiovasculal

The mechanism of actionof baroreceptors is discussedin greater detail in theCardiovascular Physiologychapter of Organ SystemsBook t (Volume lll).

D.

2t9

Endocrine System


Certain drugs, such as lithiumand demeclocycline, inhibitrenal response to ADH,resulting in an acquirednephrogenic diabetesinsipidus. Demeclocycline isused in the treatment ofchronic SIADH.

Bridge to Reproductive

Oxytocin is discussed ingreater detail in theReproductive Physiologychapter of this book.

In a Nutshell

Control of GlucocorticoidSecretion

HypothalamusJ

CRHJ(*)

Anterior pituitaryJ

ACTHl(+)

Adrenal cortexl(+)

Cortisol

(-)

3. Diabetes insipidus. Absence of ADH secretion or lack of a renal response to ADH resultsin either central (neurogenic) or nephrogenic diabetes insipidus, respectively. Either typeof diabetes insipidus causes a decrease in renal reabsorption of water, an increase in serumosmolariry and generation of a dilute (hypotonic) urine.

a. In central diabetes insipidus, ADH plasma levels are reduced; the converse is true innephrogenic diabetes insipidus.

b. Exogenous ADH is beneficial in central diabetes insipidus but has no effect in nephro-genic diabetes insipidus.

4. Excess ADH secretion, typically by a tumor, results in SIADH, or the syndrome of inap-propriate ADH secretion. SIADH causes increased water retention, hypo-osmolariry andhyponatremia, concurrent with hypertonic urine excretion.

E. Oxftocin

1. Secretion is stimulated by infant suckling. Dilation of the cervix during labor and orgasmare also stimuli for oxftocin secretion.

2. Physiologic effects

a. Milk let-down occurs due to the contraction of the myoepithelial cells in the mam-mary gland.

b. Causes uterine contraction; can be used to induce labor late in pregnancy.

ADRENAT GTANDSA. Zones of the adrenal cortex

1. The outer zolna glomerulosa is chiefly concerned with biosynthesis of the mineralocorti-coid aldosterone. Its size increases with salt restriction and is also affected by potassiumIevels, angiotensin, and to a lesser extent, ACTH.

2. The two innermost zones of the cortex-the zonafasciculata (produces glucocorticoids)and the zolna reticularis (produces androgens)-are controlled by pituitary ACTH.

B. Products. The major steroids secreted by the adrenal cortex include: corticosteroids, miner-alocorticoids (primarily aldosterone), and androgen precursors (primarily dehy-droepiandrosterone, DHEA).

C. Adrenal cortical secretion except for mineralocorticoids is controlled by ACTH. Thesecretion of hypothalamic CRH and subsequently ACTH can be suppressed if the concen-tration of cortisol in the plasma is high, or it can be enhanced if cortisol concentration is low.

D. ACTH

l. Origin. As noted earlier, all of the corticotropin-related peptides are derived by selectiveproteolytic cleavage from pro-opiomelanocortin (POMC).

a. Primarycleavage. The corticotropic cells cleave POMC into ACTH, B-LPH, and an N-terminal fragment.

b. Secondary cleavage of ACTH yields a-MSH and the corticotropin-like intermediatelobe peptide (CLIP). Secondary cleavage of B-LPH results in B-endorphin and y-lipotropin.

2. Synthesis and storage. The human pituitary contains approximately 250 pg of ACTH, whichis synthesized and stored in corticotropic cells. The storage granules are basophilic and peri-odic acid-Schiff (PAS) positive because of the glycoprotein content of the POMC precursor.

240

Physiology

3. Action. ACTH stimulates the conversion of cholesterol to pregnenolone. ACTH affectsthe cortex in a manner typical for polypeptide hormones: It interacts with a cell-surfacereceptor, and this interaction increases the intracellular concentration of cyclic adenosinemonophosphate (cAMP).

E. Steroidogenesis

l. Cholesterol is the precursor of the steroid hormones. It is available from animal fats inthe diet and by biosynthesis in many organs, including the adrenal cortex.

2. Immediate sources of cholesterol for steroid synthesis are:

a. The free and esterified cholesterol associated with the lipoproteins of plasma

b. The free and esterified cholesterol stored in adrenal lipid droplets

c. The cholesterol synthesized by the adrenal itself

d. In humans, the cholesterol of plasma low-densitylipoprotein (tDt) appears to be thepreferred substrate. Cells of the adrenal cortex have LDL receptors, and uptake of LDLis stimulated by ACTH.

3. The adrenal handles normal steroid production by using free cholesterol from plasma orthe labile tissue pool but draws on steroid cholesterol esters as a reserve when rapid syn-thesis is required.

a. Simultaneously with the increased contribution from stored cholesterol esters, entryof cholesterol from the plasma is accelerated under stimulation from ACTH so that inthe long term, plasma cholesterol remains the major substrate for steroid synthesis.

b. ACTH is also involved in the side-chain cleavage of cholesterol.

4. Synthetic pathways are summarized in Figure III-3-5.

5. 2f -B-hydrolase deficiency is the most common enzyme deficiency of the adrenal cortex.It is discussed in the Endocrine Pathology chapter.

Dehydro-epiandrosterone(DHEA)

1 3 p-hydroxy-I steroid dehy-

Y drogenase

ZonaReticularis

IesfesandOvaries

cellmembrane

CholesterolACTH stimulates------> | cnobsterol desmolase

this reaction V 17 u-hvdroxvtase 17,20 -tyasePregnenolone

' ' - 17-hydroxY----€3 p-hydroxysteroid I nregnenolonedehydrogenase Y

Progesterone21 p-hydrorylat"

/

1 1 -DeoxycorticosteroneI| 11 p-hydrorylaseY

CorticosteroneAngiotensin tt --------+l atdosteronestimulates

{ sVnthase

this reactionAldosterone

Zona Glomerulosa

\\ 17,20 -tyase

1 7-Hydroxyprogesterone #

| 21 p-hydroxylase| (most common

Y 'aeficiency)

11-DeoxycortisolI

| 11 p-hydrorylase

YGortisol

Zona Fasciculata

Androstenedione

:Y

V

Testosterone

IY

V

Estradiol

In a Nutshell

Mechanism of SteroidHormone Action

Steroid hormone

-..,},..^

Hormone binds to receptor innucleus or cytoplasm andexposes the DNA binding siteon the receptor

IV

DNA transaiption in nucleus

IV

mRNA translation incytoplasm

IV

New proteins synthesized

Figure lll-3-5. Pathways in steroidogenic cells.

241

Endocrine System

Clinical Correlate

Therapeutic uses of syntheticglucocorticoids include.

. A$hma/allergicrhinitistreatment

. Relief of inflammation

. Therapy for congenital adrenalhyperplasia

. Dexamethasone suppressiontest to diagnose Cushing'ssyndrome

. Therapyfor lo, 2", or 3oadrenocortical insufficiencv

. Transplant rejection

F. Biologic actions of adrenal cortical hormones (corticosteroids)

1. Glucocorticoid effects are involved in intermediary metabolism, inflammation, immuni-ty, wound healing, and muscle and myocardial integrity. These actions are predominant-ly mediated by cortisol or other glucocorticoids.

2. Mineralocorticoids are involved in salt, water, and mineral metabolism; these effects arepredominantly mediated by aldosterone.

G. Glucocorticoids

1. Glucocorticoid activities. Glucocorticoids promote the conversion of protein to carbo-hydrate (gluconeogenesis). They also reduce the sensitivity of cells to insulin and increaseglucagon release from the pancreas.

a. Glucocorticoids increase protein breakdown and lipolysis.

b. Anti-inflammatory effects. The inflammatory reaction is inhibited by glucocorti-coids. The arterioles fail to dilate frrlly, the capillary permeability is not increased frrlly,and deposition of fibrin around the inflamed area is diminished. Glucocorticoids:

( 1) Inhibit release of arachidonate from membranes by blocking phospholipase Ar.This inhibits the synthesis of prostaglandins and leukotrienes that are involvedin the normal inflammatory response.

(2) Inhibit release of histamine from mast cells.

(3) Inhibit production of IL-2 and proliferation of T lymphocytes.

c. Normal levels of glucocorticoids are permissive for growth and maintenance of ade-quate blood pressure.

2. Clinical use of glucocorticoids

a. For replacement therapy in individuals with adrenocorticol hypofunction (e.9.,Addison disease).

b. To suppress undesirable inflammatory reactions.

c. To minimize the immune response to a variety of antigens, including transplantedorgans.

d. All glucocorticoids with anti-inflammatory activity can also suppress ACTH secretion.Although this effect is usually undesirable, it is the basis of treatment of patients whohave congenital adrenal hyperplasia.

3. Steroid withdrawal

a. The administration of glucocorticoids inhibits the release of CRH and, thus, sup-presses both the synthesis and release of ACTH.

b. This, in turn, causes atrophy of the adrenals and the ACTH-releasing cells of theanterior pituitary. As long as exogenous steroid is given, the patient remains healthy.

c. When steroids are stopped or the patient becomes ill, the demand for additional steroidcannot be satisfied by the atrophied adrenals.

d. After chronic therapy with high-dose glucocorticoid, 6 months are required for nor-mal ACTH secretion to occur, while 6 to 9 months are required to regain normal cor-tisol secretion. If the steroid treatment has been minimal in amount, or if large doseshave been given for less than I month, the pituitary-adrenal axis remains intact andno special precautions need be taken. Suppression of ACTH and endogeneous corti-sol secretion can also be somewhat reduced by administering the glucocorticoid on

242

Physiology

alternate days and by administering the majority of the dose in the morning. Use ofACTH rather than glucocorticoids is one way around the problem of steroid with-drawal (e.g., in patients with rheumatoid arthritis). ACTH has advantages oversteroids, but the need for daily intramuscular injections is a drawback and long-termACTH preparations can cause allergic reactions.

H. Mineralocorticoids

1. Aldosterone activity. Aldosterone promotes renal Na+ retention, which in turn promoteswater retention if ADH is present. It also promotes K+ and H+ ion excretion by the kid-ney. It is synthesized in the zona glomerulosa.

2. Targettissues

a. It increases active Na+ reabsorption, K+ secretion, and H+ secretion in the renal dis-tal tubule and collecting duct. In the presence of ADH, water is reabsorbed passively,following the sodium.

b. There is decreased Na+ secretion in the sweat glands.

c. Na+ (and water) absorption is increased in the colon.

3. Regulation of mineralocorticoids

a. Renin-angiotensin system

(1) Renin is released from the kidney juxtaglomerular apparatus cells in response todecreases in arterial blood pressure, extracellular fluid (ECF), plasma volume, orECF sodium; it is also released in response to increased sympathetic nervous sys-tem tone.

(2) Under the influence of renin, circulating angiotensinogen is converted toangiotensin I. Angiotensin-converting enzfme (ACE) converts angiotensin I toangiotensin II, a potent hypertensive (vasoconstrictive) agent. This occurs main-ly in the lung.

(3) Angiotensin II acts directly on the zona glomerulosa to increase aldosteroneproduction from corticosterone (see Figure III-3-5).

b. K+ control is also important. Increased plasma K+ directly stimulates aldosterone syn-thesis by zona glomerulosa cells.

c. The anterior pituitary also plays a minor role in mineralocortoid regulation.

(1) ACTH stimulates aldosterone synthesis transiently with no negative feedbackcontrol. It stimulates synthesis, but the release is primarily controlled byosmoregulators.

(2) GH maintains normal responsiveness until there is diminished responsiveness ofglomerulosa cells to GH after a long-term absence of anterior pituitary stimulation.

I. Disorders of the adrenal cortex

1. Adrenal insufEciency (Addison disease) is characterizedby weakness, fatigue, anorexia,gastrointestinal problems, hypotension, and hypoglycemia. In addition, Na+ wasting andK+ retention occur, leading to hyponatremia, hyperkalemia, dehydration, and acidosis.Primary insufficiency results when cortisol synthesis is inhibited directly, as in a defi-ciency of biosynthetic enzymes. In primary insufficienry, ACTH levels are elevated andsevere pigmentation is seen. In secondary insufficiency, ACTH is inhibited and, thus,cortisol production is not stimulated. Secondary adrenocortical insufficiency is mostcommonly due to chronic exogenous glucocorticoid therapy.

Bridge to Cardiovascular

The role of angiotensin-converting enzyme (ACE)inhibitors in the treatment ofhypertension and congestiveheart failure is discussed in theCardiovascular Pharmacologychapter of Organ SystemsBook t (Volume lll).

In A Nutshell

Addison Disease. Also called l' adrenocortical

insufficiency

. Most commonly due toautoimmune adrenal atrophy

. Characterized byhypotension, increased skinpigmentation, decreasedserum Na., Cl-, glucose,HC0,-, and increasedSCTUM K-

. Discussed in greater detailin the Endocrine Pathologychapter

24t

Endocrine System

Clinical Correlate

Excessive gl ucocorticoidsecretion is called Cushingsyndrome. Clinicalmanifestations include:

. Truncal obesity

. "Moon" facies

. Hypertension

. Osteoporosis

. Protein depletion

. Clucose intolerance

. Muscle wasting andweakness

. Purple abdominal striae

Flashback to Embryology

Other neural crest derivativesinclude sensory andautonomic ganglia andmelanocytes.

Note that in contrast to themedulla, the adrenal cortexis derived from mesoderm.

t.

2. Adrenocortical excess (Cushing syndrome)

a. Cushing disease is caused by excessive pituitary ACTH secretion.

b. Ectopic ACTH production

c. Adrenal adenoma and carcinoma, which are ACTH independent

d. Clinical evaluation requires recognition of ACTH-dependent and independent caus-es. One of the common causes of adrenocortical excess is iatrogenic, resulting fromchronic glucocorticoid therapy.

e. The physiologic consequences of excessive cortisol exposure include obesity, facialplethora, hirsutism, menstrual disorders, and hypertension.

3. Hypoaldosteronism results in hyperkalemia (K+ retention), metabolic acidosis (H+retention), hlponatremia (Na+ depletion), and hypotension (plasma volume loss).

4. Hlperaldosteronism results in hypokalemia (K+ depletion), hypernatremia (Na+ reten-tion), metabolic alkalosis (H+ depletion), and hypertension. Note that increased levels ofANP (atrial natriuretic peptide), stimulated by the increased plasma volume, increase sodi-um and water excretion, providing an "escape" from continued increases in plasma volumeand blood pressure.

a. Primary hyperaldosteronism (Conn syndrome). The majority of patients (approxi-mately 90o/o) have adrenocortical adenomas. It is characterizedby decreased serumrenin.

b. Secondary hnreraldosteronism. Elevation of aldosterone results from the stimula-tion by angiotensin II due to excess renin production; the condition is characterizedby increased renin levels.

The adrenal medulla is a specialized neural crest derivative responsive to cholinergic nervestimulation. Epinephrine and a little (<10olo) norepinephrine are synthesized and stored inthe adrenal medulla and released into the blood.

Catecholamine release involves movement of storage granules to the cell periphery bymicrofilaments, where the contents are exocytosed. Epinephrine and norepinephrine arestored in different cell types.

1 .

244

Physiology

TA\- cHc_cH-NHetUJ |

- PhenYlalanine\-/ cooH

I

I Phenylalanine hydrorylaseY

rA>c Hc-cH - NH2 Tyrosine'o-\/

- loorr

I Tyrosine hydrorylase

Ho-{A-F CHc-cH-NHrt ( ' t | -

| -

D o p aHo-\z cooH

''t, DOPA decarboxYlase

HO 1A)- CHz- CH2- NH2. l ( ) l

- D o p a m i n eHO-V

''t, DoPamineP-hYdrorylase

no-AFcHoH-cH2-NH2. l ( ) l Norepinephr ine,o_*v;

I Phenylethanolamine-N-

* methyltransferase

HO-<ATCHOH- CH.--N-Hl ( ) l , Ep inephr ine

HO+/ -cHs -r - ' - ' - -

Figure lll-3-6. Structures and synthetic pathway in catecholamineproduction from phenylalanine.

2. C-atecholamine degradation is catalped by catechol-O-methyltransferase (COMT) ormonoamine oxidase (MAO), limiting the duration and magnitude of their action.Termination of the local action of catecholamines is also accomplished by neuronal reuptake.

3. Catecholamine synthesis (Figure III-3-6)

a. Epinephrine is synthesized from phenylalanine, tyrosine or both, with each step in theprocess catalyzedby a specific enzyme.

b. The main site of synthesis is in the adrenal medulla, but catecholamines are alsoformed in postganglionic sympathetic neurons (norepinephrine) and select CNS neu-rons (e.g., dopamine in substantia nigra).

245

Endocrine System

4. Catecholamine activity

a. Catecholamines stimulate both cr- and B-adrenergic receptors. o-receptors typicallymediate smooth muscle contraction (e.g., skin, iris, arterioles), while B-receptors medi-ate smooth muscle relaxation (e.g., bronchi, arterioles in skeletal muscles) and cardiacstimulation (heart rate, contractility).

b. Biologic effects include increased heart rate, cardiac output, blood pressure, pupildiameter; selective effects on blood flow in different organs; increased oxygen use,blood sugar, and respiration rate.

5. Catecholamine overproduction and underproduction

a. Overproduction is mainly associated with tumors (e.g., neuroblastoma, ganglioneuroma,pheochromocytoma). The most common features include hypertension, hlperme-tabolism, and hyperglycemia. Diagnosis is made by measuring urinary levels of cate-cholamine metabolites such as homovanillic acid (HVA) and vanillytmandelic acid(vMA).

b. Underproduction is usually a result of adrenal destruction or surgical removal.

THYROID GTANDA. Biosynthesis of thyroid hormones. The thyroid gland synthesizes and releases two

principle hormones: triiodothyronine (Tl) and tetraiodothyronine (Tl, thyroxine). Theprocess of thyroid hormone biosynthesis and secretion is shown schematically inFigure lll-3-7 . All steps described are stimulated by TSH.

l. Thyroglobulin (TG) is a glycoprotein synthesized by the thyroid follicular cell and secret-ed into the colloid space (follicular lumen).

2. TG is released into the lumen via exocrtosis. Iodination occurs at the follicular cell sur-face.

a. Before iodination can occur, iodide must be taken up by the thyroid cell and oxidizedto iodine. Iodide uptake, or trapping, takes place at the base of the cell via activetransport, using energy from an iodide pump.

b. Oxidation of iodide to iodine occurs at the apex of the follicular cell and involves aperoxidase enzvme system (thyroid peroxidase). The oxidized species of iodine isthen extruded from the cell by exocytosis and is added to the TG present in the colloid.The products of iodination, the iodotyrosines 3-monoiodotyrosine (MIT) and3,5-diiodotyrosine (DIT), are contained within the iodinated TG molecule.

Clinical Correlate

The thyroid gland isdependent on iodine.Coiter can occur incertain geographic areaswhere iodine is deficientin the diet.

246

Physiology

Extracellular Space Foll icular Cell Foll icular Lumen

Endop|asmic--}Go|gi. . . .-+Thyrog|obulin--.--+Exocytosis->TGreticulum apparatus

lodide pump +lodide +Oxidized via(active transport) peroxidase

Secretion

3. Formation of Ta involves oxidative coupling of two DIT molecules, whereas synthesis ofT3 requires oxidative coupling of one MIT and one DIT molecule. These reactions are alsocatalyzed by thyroid peroxidase.

4. Re-uptake of iodinated TG from the follicular lumen into the cell occurs via endocftosis.Under appropriate physiologic stimuli, iodinated TG is digested by lysosomal enzymes torelease MIT, DIT, T:, and Ta.

5. The Ta and T3 can then be secreted into the extracellular space. MIT and DIT normallydo not escape into the circulation but are deiodinated in the thyroid cell.

6. The tyrosine residues and iodide are then recycled or "salvaged" for synthesis and iodina-tion of additional TG.

7. Note that iodinated TG classifies as a prohormone since, prior to proteolysis, it consists ofphysiologically inactive iodothyronines. TG is found in the peripheral plasma of euthy-roid subjects, but most of it remains sequestered in the colloid.

a. Conditions associated with damage to the thyroid gland (thyroiditis and thyrotoxico-sis) elevate circulating TG levels.

b. Although the regulation of TG is not yet completely understood, it appears thatexogenously administered T3 and T4 decrease serum TG levels, and stimulators of thy-roid gland function increase them.

B. Metabolism of thyroid hormones

1. Ta leaves the peripheral circulation with a half-life of 6-7 days, whereas T3 has a half-lifeof approximately I day.

2. Inthe peripheral plasma, T4 and T3 are bound to plasma proteins. Approximately 99o/o of thecirculating thyroid hormones are protein bound, and only lo/o are free and biologically active.

a.T+ and T3 are bound to thyroxine-binding globulin (TBG). Ta binds much moreavidly to TBG than does T3, which accounts for the longer half-life.

',?S^)

T3

T4

) llHiisl;(l

.h".Jl-TG = thyroglobulin-containing iodotyrosines (MlT and DIT) and iodothyronine(Ts,T+); MIT = 3-monoiodotyrosine; and DIT = 3,5-diiodotyrosine.

Figure lll-3-7. Biosynthesis and secretion of thyroid hormones by the thyroid follicular cell.

In a Nutshell

Thyroid Hormone Synthesis

. Synthesis of thyroglobulin 0C)

. lodide trapping (base of cell,active transport)

. Oxidation of iodide to iodine(apex of cell); iodineexocytosed from follicularcell into colloid

. lodination of TC tyrosineresidues in colloid to form 3-monoiodotyrosine (M lI) and3,5-diiodotyrosine (DlT)

. Coupling of MIT and DIT toform T, and trruo DITmolecules to form To

. Re-uptake of TG into the cell;proteolysis to release MlT,DlT, T,, and T,

. Secretion of T, and To intoextracellular space

247

Endocrine System

Note

Peripheral 5Ldeiodinaseis inhibited by:. Prolonged fasting or severe

illness

. Propranolol

. Clucocorticoids

. Propylthiouracil

C.

b. Thyroxine-binding prealbumin (transthyretin) and albumin also bind T, and T' butwith considerably less affinity than TBG.

3. Both T, and T, are metabolized by peripheral tissues along similar metabolic pathways.

4. Peripheral monodeiodination of T, (i.e., the removal of one iodine molecule) and thesubsequent formation of T, occurs in many tissues, with the pituitary, liver, and kidneysexhibiting the highest reaction rates.It can proceed along two alternate pathways yieldingmetabolically active T, or relatively inert reverse T, (rTr).

5. Circulating T3 originates primarily from peripheral conversion of Tr.

a. Thirty-five percent of Tn secreted by the thyroid is converted by peripheral tissues to Tr.

b. The sources of rT3 in the circulation are similar. Both T, and rT, are monodeiodinatedto 3,3'-diiodothyronine (Tr), and the tyrosine and iodide can be recycled to the thyroidgland.

c. Two separate deiodinating enzymes are involved (S-deiodinase and 5'-deiodinase) anddeiodination is a controlled rather than a random process. Thus, the production ofactive thyroid hormone can be regulated not only at the thyroidal but also at theperipheral level.

( 1) Inhibition of the 5'-deiodination pathway with relative overproduction of rT, atthe expense of T, has been observed in starvation and in euthyroid patients witha variety of nonthyroidal diseases. This may represent an adaptive attempt by theorganism to conserve energy during times of stress. These patients have normallevels of Tn and TSH.

(2) High rT, and low T, levels are also observed during fetal life.

(3) Pharmacologic inhibition of 5'-deiodination of serum Tn can be achieved with thep-blocker propranolol, glucocorticoids, propylthiouracil (see below), and certainradiocontrast agents, causing the serum T, to fall and the serum rT, to rise.

Mode of action of thyroid hormones

1. No one mechanism accounts for all aspects of thyroid hormone activity; there are differ-ent modes of action in various tissues and even during different stages of development.

2. The model now widely accepted describes the direct action of thyroid hormones on thenuclear chromatin.

a. Thyroid hormone receptors, located on the histone (non-DNA) fraction of the chro-matin have been isolated. These receptors are structurally similar to steroid hormonereceptors, but are present in the nucleus whether or not thyroid hormones are present.

b. Thyroid hormones, specifically T, more than Tn, enter the cell nucleus and bind tonuclear receptors. This complex then promotes the transcription of required genes.

c. The end result of thyroid hormone binding to the nuclear chromatin receptor is pro-tein synthesis.

d. Thyroid hormones also have extranuclear binding sites,located on membrane and mito-chondrial areas. This extranuclear binding is implicated in thyroid-hormone-mediatedamino acid transport under conditions when protein synthesis has been blocked.

248

Physiology

D. Extrathyroidal regulation of thyroid hormone secretion. The thyroid axis consists of thehypothalamus, the hypophysis, and the thyroid gland, associated in a classic negative feed-back system.

1. Thyrotropin-releasing hormone (TRH). The hypothalamus synthesizes and releasesTRH, which acts directly on the pituitary and stimulates the secretion of TSH.

2. Thyroid-stimulating hormone (TSH). In response to TRH, the anterior pituitary releas-es the thyrotropin, TSH. TSH is a glycoprotein that stimulates the thyroid gland to secreteboth Tn and T' which then inhibit further TSH release by negative feedback. TSH exertsa trophic action on the thyroid gland, maintains its structure, and promotes blood flow.All aspects of thyroid gland function, such as increased iodine transport, increased organ-ic binding and coupling, increased proteolysis of TG, increased secretion of Tn and T' andaccelerated metabolism, are controlled by TSH. TSH binds to a receptor on the plasmamembrane of the thyroid cell and elevates the intracellular cAMP concentrations.

3. The relationship between the thyroid and the pituitary is reciprocal.

a. Hypophysectomy causes thyroid atrophy, reduces thyroid blood flow, and decreasesthyroid secretion of T, in serum. If TSH is administered to hypophysectomized sub-jects, the effects are reversed.

b. If the thyroid is removed or fails to function, there is an increase in the size and weightof the pituitary gland, causing a goiter. Following thyroidectomy, so-called "thyroid-ectomy cells "appear in the pituitary, and in long-term hypothyroidism, destructivepituitary enlargement can occur. The administration of T, prevents these pituitarychanges.

4. Final feedback of the hypothalamic-pituitary-thyroid axis (Figure III-3-8)

a. The major product of the thyroid gl*d, Tn, is carried in the peripheral plasma boundprimarily to TBG. Monodeiodination of T, to T, occurs in the peripheral plasma, andespecially in the liver, kidney, and pituitary gl*d. Both hormones act peripherally ontheir target organs and also exert their negative feedback effect on the pituitary gl*d.

b. Thyroid hormones reduce the pituitary responsiveness to TRH, inhibiting furthersecretion of TSH. This inhibition of TRH-induced TSH release by thyroid hormone isseen during TRH testing.

c. Thyroid hormones also exert a negative feedback on TRH synthesis.

Note

T, binds to the thyroidreceptor with l0 times theaffinity of To. Therefore,intracellular T, is responsiblefor thyroid hormone effeGand negative feedback.However, circulating To isconsidered the major sourceof negative feedback, since itdiffuses into pituitary andhypothalamic cells and isimmediately deiodinated to Ti.

249

Endocrine System

T+ Ts

Figure lll-3-8. Diagram of the final feedback of theTRH = thyrotropin-releasing hormone; TSH

Hypothalamus

Pituitary gland

gland

hypothalam ic-pituitary-thyroid axis.= thyroid-stimulating hormone.

(-)

Note

lodide = l-

lodine = lz

thyroid peroxidase

2l -+ lz

This reaction occurs in thethyroid follicular cell membraneand is inhibited by propyl-thiouracil.

E. Intrathyroidal regulation. In addition to extrathyroidal regulation, regulatory systemswithin the follicular cells monitor the size of the intraglandular organic iodine pool.

1. Autoregulatory mechanisms

a. Changes in intrathyroidal organic iodine are associated with reciprocal changes in thetrapping and organic binding (iodination) reactions, as well as in the sensitivity of thefollicular cell to a given level of TSH.

b. These intrathyroidal autoregulatory mechanisms maintain a constant level of thyroidhormone production during periods of iodine deficiency and excess. Iodide deficien-cy is rare in the United States because iodide is traditionally added as a supplement totable salt.

2. Effects of iodide on thyroid function. The thyroid gland uses approximately 100 pg ofdietary and internally rerycled iodide each day.

a. When the amount of acutely ingested iodide exceeds a critical level, there is a suddeninhibition of organic binding (Wolff-Chaikoffeffect). This inhibition is usually tran-sient because an adaptive decrease in iodide pump activity limits further entry ofiodide into the cell.

b. Iodide has important effects on the sensitivity of the follicular cell to TSH. Iodideloading dampens and iodide depletion increases the intracellular accumulation of

250

Physiology

cAMP in response to TSH. The modulating effects of iodide on sensitivity to TSH,iodide transport, and organic binding protect the constancy of the intrathyroidalorganic iodine pool.

c. Large doses of iodide inhibit thyroid hormone release and decrease the vascularity ofthe gland, and are used as adjunct therapy for hyperthyroidism.

F. Assessment of the thyroid function. Direct measurement of thyroid hormones in the bloodby radioimmunoassay (RIA) under basal conditions as well as after pharmacologic stimu-lation and suppression makes it possible to detect and treat thyroid dysfunction at an earlystage.

1. Tests

a. Total serum T4 (TT4) and totd serum Tt (TTl) can be measured by RtA methods.The antibodies used are highly specific and sensitive.

b. Free T3 and Ta. Techniques to measure free T3 and Ta are now available as well.

c. Serum TSH

(1) Elevated serum TSH concentration measured by RIA is used to discriminatebetween primary hypothyroidism (thyroid origin and, therefore, increased plas-ma TSH concentration) and secondary hypothyroidism due to pituitary orhypothalamic disease (decreased TSH).

(2) Patients with early thyroid failure (subclinical hypothyroidism) have elevationsof serum TSH before serum Ta levels fall below the normal range.

(3) In patients with hyperthyroidism, TSH is suppressed as a result of Ta feedbackto the pituitary.

(4) Conventional TSH-RIA methods (TRH stimulation) have detection limits:euthyroid subjects cannot be distinguished from hyperthyroid patients orpatients taking suppressive doses of Ta. Through administration of TRH, TSHlevels are stimulated to increase above the detection limit in euthyroid patients,whereas hyperthyroid patients have no response (flat) or a blunted response.

(5) Sensitive TSH assays are now widely available that are able to distinguish betweeneuthyroid and hlperthyroid patients.

d.Tr resin uptake (RT3U) test. The results of this test are compared with the resultsobtained for standard control sera from euthyroid individuals with normal quantitiesof thyroid hormone-binding proteins. The results of the unknown serum are dividedby those obtained for the control serum in the same assay.

Patient's RT3 value

Mean euthyroid RT3 value

Clinical assessment of thyroid function should include the measurement of the total Taconcentration by RIA and the determination of some parameter of the Ta-bindingcapacity of the serum proteins (THBR). From these two measurements, free Ta can bereliably estimated (FT4I). This suffices to diagnose hyper- or hypothyroidism in mostpatients.

z.

Note

RIA (radioimmunoassay) is amethod to measurehormone concentration.

. A serum sample withunknown hormoneconcentration is mixed witha known quantity ofantibody to the hormoneand a known amount ofradiolabeled hormone.

. The radiolabeled hormoneand the unknown amountof unlabeled hormonecompete for antibodybinding sites. When there ismore unlabeled hormonein the sample, there is lessradiolabeled hormone thatcan bind to the antibody(more free radioactivehormone).

. A curve can be prepared:

aoundfiree lllabeled l\

hormone |

\-

Unlabeled hormone

The ratio of boundfreehormone will be highestwhen there is no unlabeledhormone present tocompete for antibody.

The ratio of boundfireehormone will be lowe$when the quantity ofunlabeled hormone is thehighest.

251

Endocrine System

G. Thyroid hormone activities

1. Thyroid hormone regulates overall metabolic rate and maturation, including:

a. Basal metabolic rate and core temperature

b. Appetite

c. Normal maturation rate, including onset of puberty

2. Thyroid hormone is permissive for the effects of other hormones on many body systems.It is required for normal development and functioning of those systems, including:

a. Growth

b. Immune system and wound healing

c. GI motiliry

d. CNS

e. Cardiovascular, e.g., heart rate and cardiac output

f. Skin, connective tissue

H. Thyroid disorders

1. A goiter is a hlpertrophied thyroid gland and results from chronic stimulation of thegland; goiters can occur with hyperthyroidism or hypothyroidism.

a.Any condition causing chronically elevated TSH can cause a goiter, such as I-deficiency in the diet, or inhibition of gland function by a goitrogen.

b. The antibodies responsible for Grave's disease stimulate the TSH receptors of thegland, causin g hlpertrophy and hyperthyroidism.

c. Goitrogens. Any chemical or agent that causes a goiter is referred to as a goitrogen.There are two major types: those that inhibit iodine transport and those that inhibitbinding and coupling processes.

(1) Inhibitors of iodine transport include the monovalent anions thiocyanate andperchlorate. These agents promote rapid discharge of inorganic iodide, therebyproviding a means of readily distinguishing between "free" and "bound" iodinestores within the gland. Their clinical utility is limited by their toxiciry.

(2) Inhibitors of binding and coupling. The most widely used agents that affectorganic binding and coupling processes and inhibit thyroid hormone formationinclude the thioamides, propylthiouracil (PTU), and methimaz.ole.Interferencewith iodination and coupling reduces the synthesis of thyroid hormones. In aeuthyroid individual, this stimulates TSH secretion and leads to hyperplasia ofthe thyroid gland (goiter). PTU also blocks the peripheral conversion of Tn to T'but has no effect on the peripheral action of Tr.

2. Hyperthyroidism

a. Hyperthyroidism is most often due to excessive production of thyroid hormone in theabsence of TSH stimulation (tT' tT., JTSH); it is rarely due to excessive productionof TSH (secondary hyperthyroidism: tT4, TT3, tfsff) or excessive TRH production( tertiary hyperthyroidism) .

b. Classic symptoms include irritability andappetite, tremor, sweating, and tachycardia.

nervousness, weight loss with increased

c. The most common cause of hyperthyroidism is Graves disease, an autoimmune dis-ease that also causes a diffi.rse goiter and exophthalmos. Graves disease is discussedalong with other causes of hyperthyroidism in the Endocrine Pathology chapter.

252

Physiology

3. Hypothyroidism

a. Hypothyroidism can be classified as either primary (defect in thyroid gland: JTn, JT'ttsFl), secondary (defect in pituitary TSH secretion: JT' JT' JtsFI), or tertiary(very rare defect in hypothalamic TRH secretion). Rare cases are due to peripheralthyroid resistance (partial T, receptor defect: tTn, tT' normal TSH).

b. Classic symptoms include decreased heart rate, weight gain (often accompanied bydecreased appetite),lethargy, constipation, dry and coarse skin and hair, and cold sen-sitivity.

c. Autoimmune thyroiditis and destruction of the thyroid gland is the most commonnoniatrogenic cause in adults (discussed along with other causes in the EndocrinePathology chapter).

MINERAL HOMEOSTASIS AND BONE REMODELINGThere are two hormones of major importance in mineral homeostasis and bone remodeling:parathyroid hormone (PTH) and the active form of vitamin D, 1,25(OH)2D3, which is secretedby the proximal convoluted and straight tubules of the nephron. A third hormone, calcitonin, issecreted by the thyroid parafollicular cells and inhibits bone resorption and thereby decreasesserum Ca2* and phosphate.

A. Parathyroid hormone (PTH)

l. Structure and biosynthesis

a. PTH is secreted from the chief cells of the parathyroid gland and ectopically bycertain tumors.

b. Precursor forms are produced and then modified by a series of cleavages and translo-cation steps. This occurs in specialized subcellular organelles of the chief cells andeventually leads to the formation of PTH.

c. In the endoplasmic reticulum, the initial amino acids of a preproparathyroid hormoneare cleaved to form proparathyroid hormone (proPTH).ProPTH then moves withinmembrane channels of the endoplasmic reticulum to the Golgi apparatus, where theamine (NHz) terminal hexapeptide is removed.

d. The final product, PTH, is incorporated into secretory granules, transported to theperiphery of the cell, and released into the extracellular space upon physiologic stimuli.

2. Regulation of secretion

a. The major regulator of PTH secretion is plasma Ca2* levels.

(1) J Plasma Ca2+ +1 PTH

(2) t Plasma Ca2+ +J PTH

b. Increased levels of 1,25 (OH)rD? will decrease PTH.

3. Functions of PTH

a. PTH maintains plasma Ca2+ and phosphate levels to ensure the optimal functioningof a variety of cells.

b. PTH functions as a trophic hormone by stimulating the synthesis of 1,25(OH)zDrfrom 25(OH)D3 in the kidney.

c. In the major sites of PTH action (the kidney, bone, and, indirectly, the intestine), thenet result of PTH action is an increase in plasma Ca2+ and a decrease in plasmaphosphate.

25t

Endocrine System

In a Nubhell

PTH Actions. lncreases bone resorption,

releasing both Ca2* andphosphate from bone

. lncreases calciumreabsorption in the distalnephron, decreasingcalcium excretion

. Inhibits phosphatereabsorption in theproximaltubule andincreases phosphateexcretion (phosphatu ria)

. Increases Ca2* absorptionfrom the inte$ine indirectlyby $imulating renalproduction of 1,25-dihydrorycholecalciferol(1,2s [0H]2D3)

. Overall effect lncreasesplasma calcium, decreasesplasma phosphate

254

4. Effects on bone

a. It induces osteoblasts to pump Ca2+ into the ECF. The long-term effect of PTHpromotes osteoclastic activity (bone resorption) and triggers formation of moreosteoclasts while inhibiting the formation of osteoblasts.

b. PTH allows C*+ efflux from small available pools to the ECF.

c. PTH also increases the rate of skeletal remodeling by promoting bone resorption viaactivation of osteocytic osteolysis.

5. Effects on the kidney. PTH acts directly to promote Ca2+ tubular reabsorption andphosphate excretion.

a. Approximately 50-650/o of Caz+ is reabsorbed in the proximal tubule and approxi-mately 20-30o/o is absorbed in the medullary loop of Henle. This reabsorption is notunder hormonal control. In the cortical distal nephron, under the influence of PTH,the remaining 15-20o/o of the Caz+ is reabsorbed. The results of these actions aremaintenance of high Ca2+ and reduced phosphate concentrations.

b. The mechanism operates between the bone and kidney.

(1) PTH stimulates release of both Ca2+ and phosphate from bone.

(2) Uncorrected, this mechanism would cause precipitation of calcium phosphatecrystals. However, PTH also promotes phosphaturia, reducing the precipitationof these ions.

c. PTH increases the urinary excretion of hydroryproline-containing peptides.Hydro4;'proline is a nonessential amino acid found almost exclusively in collagenand, therefore, can indicate the amount of bone remodeling occurring.

6. Effects on the intestine

a. As noted, PTH promotes the conversion of 25(OH)D3 to 1,25(OH)2D3 (1,25-dihy-droxycholecalciferol) in the kidney.

b. This sterol then acts on the intestinal mucosa to increase Ca2+ and phosphateabsorption.

7. Mode of PTH action

a. PTH binds to the membrane-bound PTH receptor, and the guanyl nucleotide regula-tory protein is stimulated to bind guanosine triphosphate (GTP).

b. GTP binding to the guanyl nucleotide regulatory protein converts the membrane-bound receptor to a low-affi"ity state, inducing dissociation of PTH and the formationof a Gsa-adenylate ryclase complex, leading to activation of this enzfme and theincreased production of intracellular cAMP.

c. This intracellular cAMP message is the means by which PTH exerts it action on targettissues.

8. Parathyroid disorders

a. Primaryhnrerparathyroidism is caused by hypersecretion of PTH from the parathy-roid (usually secondary to an adenoma). As would be expected, the result is hypercal-cemia and hypophosphatemia.

b. Secondaryhyperparathyroidism is caused by hypersecretion of PTH due to hypocal-cemia (usually secondary to chronic renal failure).

Physiology

c. Hypoparathymidism is caused by insufficient secretion of PTH. The result ishypocalcemia and hyperphosphatemia.

d. Pseudohypoparathyroidism is a rare disease caused by PTH tfiget-tissue resistanc€.This disorder is characterized by hypocalcemia in the setting of elevated PTH.

B. cholecalciferols (vitamin D) Note

r. vitamin D can be either ingested in the diet or manufactured in the skin through ultra- ylTT,l.D-]t-::: :l^t} jil;violet light activatiotr of 7-dehydrocholesterol ( Figure III-3-9 ).

soluDle vmmlns' along wmvitamins A, E, and K.

a. Liver enzymes conv€rt vitamin D to 25(oH)Dr. This conversion at the liver is regu-lated by a feedback system involving th€ liver level of25(OH)D, itself.

b. Under the stimulus of PIII and low serurn phosphate' the 25(OH)D3 m€tabolit€ isconvert€d in the proximal tubule of the kidney to 1,25(OH)rD., which is the activeform of vitamin D.

2. Regulation of enzyrne activity

a. The kidney enzyme (25[OH]D-fo-hydroxlase) introduces an OH at the cr positionof carbon l of the A ring.

b. The hydroxylation occurs in the proximal convoluted and straight tubules of thekidney nephron.

c. Regulation of 1,25(OH)2D3 is under very tight control. The renal output of1,25(OH)2Dj re{lects individual Ca'' requirements.

3. Regulators of 1,25(OH)'D, levels include:

a. Decreased serum calcium increases 1,25(OH)'D, indirectly by increasing serum PTH

b. PTH stimulates la-hydrorylase in the hdney cells; 1,25(OH)rD, inhibits PTH secretion

c. 1,25(OH)2D, itself inhibits the 1(r enzfm€

d. Decreased phosphate intake and hypophosphatemia increase 1,25(OH)rD,

e. An increase in phosphate intake or hyperphosphatemia will decrease 1,25(OH)2D3

255

Endocrine System

7- Dehydrocholesterol

St<in I

Ultraviolet light

v

<_- Diet

Cholecalciferol(vitamin D3)

25(OH)D3(Conversion takes place in liver)

1 ,25(OH)2D3CHz (Conversion takes place in proximal

tubule of kidney under stimulationby parathyroid hormone)

OH

Figure l l l-3-9. Formation of 1,25(OH)zDg.

4. Effects on intestine. The major actions of 1,25(OH)zD: facilitate Ca2+ absorption fromthe intestine. Phosphate transport can accompany that of Ca2*,but vitamin D stimulatesa distinct phosphate transport system in the intestine.

a. 1,25(OH)2D3 interacts with an intestinal receptor for regulation of a Ca2+-bindingprotein (calbindin-D).

b. The amount of calbindin-D in the intestinal mucosa is positively correlated with therate of transport or absorption. Increased transport of both minerals at the intestineis directed by physiologic levels of 1,25(OH)zD:.

c. The movement of both Ca2+ and phosphate is active against an electrochemical gradient.

I

256

Physiology

d. 1,25(OH)2D3 acts at the intestinal brush-border membrane, altering properties of the

microvillar surface, allowing entry of these ions into the cell.

e. The result is increased serum Ca2+ and phosphate concentrations, permitting nor-

mal skeletal mineralization and other physiologic functions affected by these ions.

5. Effects on bone

a. The two most striking changes in bone in advanced vitamin D deficiency(rickets/osteomalacia) are:

(1) Failure of the normal mineralization of bone matrix, leading to the accumula-

tion of unmineralized osteoid

(2) Decrease in osteoclast count and bone resorption surface in relation to the con-

centration of circulating PTH

b. Normal calcification requires vitamin D acting directly on bone.

( 1) One action of vitamin D is an increase in the osteoclast count on the endosteal

bone surfaces. This change, requiring the presence of PTH, precedes the increase

in Ca2+ and phosphate in the ECF, indicating that vitamin D has a direct action

upon bone.

(2) In bone as in the intestine, the important metabolite of vitamin D is

1 '25(OH)zDE.

c. The action of vitamin D to cause a dissolution of bone seems paradoxic, considering

that the sterol promotes normal bone mineralization. However, the bone resorption

provides Caz+ andphosphate for new bone formation. The osteoclastic resorption of

bone is normally in equilibrium with osteoblast-mediated formation of new bone.

(l) 1,25(OH)zD:-induced stimulation of bone growth and mineralization is not

mediated through a direct effect on osteoblasts.

(2) 1,2;(OH)zD: stimulates bone mineralization indirectly by providing minerals

for incorporation into bone matrix through increased intestinal absorption of

Ca2+.

6. Effects on the kidney

a. Ninety-nine percent of the reabsorption of Ca2+ by the kidney occurs if vitamin D is

deficient.

b. The 1,25(OH)zD3 stimulation of the renal reabsorption of calcium is of questionable

importance.

7. Mode of vitamin D action

a. 1,25(OH)2D3 acts at the molecular levels in a manner similar to steroids.

b. 1,25(OH)2D3 interacts noncovalently but stereospecifically with an intracellular

receptor protein.

c. The steroid receptor associates with the genome and new RNA encoding protein to

enhance a spectrum of biologic responses or mediate a selective repression of gene

transcription.

C. Calcitonin is secreted by C cells found primarily in the thyroid and secondarily in the

parathyroids and thymus tissue.

1. Increased serum Ca2+ is a stimulus for secretion of calcitonin. Calcitonin decreases bone

resorption and decreases serum Ca2+.

Clinical Correlate

Some factors that result inrickets (children) andosteomalacia (aduls):. Malnutrition

. Intestinal malabsorption

. lnadequate exposureto sunlight

. Liver diseases, with impairedconversion of vitamin D. to2s(0H)D3

. Renal disease, with impairedsynthesis of the active formof vitamin D (1,25[0H], D.)

Note

PTH and vitamin D regulateplasma calcium (andphosphate) levels and affectbone metabolism. Calcitoninalso affects bone metabolism,but does not regulate plasmacalcium levels on a daily basis.

257

Endocrine System

In a Nutshell

PTH

Vit D

Calcitonin +

t Serum Ca2*J Serum

phosphate

t Serum Ca2*, , t \ ^| )erum

phosphate

J Serum Ca2*

J Serumphosphate

2. Ten percent of thyroid cancers are medullary and are accompanied by elevated circulat-ing levels of calcitonin; its measurement is diagnostic and indicative of effective thera-peutic action.

3. Calcitonin can be used in the treatment of osteoporosis.

a. Since postmenopausal osteoporosis is characterized by bone resorption in excess offormation, calcitonin is administered to inhibit further bone resorption.

b. Although calcitonin deficiency is not seen in postmenopausal osteoporosis, the thera-py is still considered a pharmacologic antiresorptive treatment.

D. Control of Ca2+ and phosphate homeostasis and skeletal remodeling

1. The major controlling factor of PTH secretion is the serum Ca2+ level, which is held rel-atively stable and is inversely related to the serum pTH level.

2. The changing serum Ca2+ level is monitored by a sensitive feedback system.(Figure III-3-10).

lOsteocyticosteolysis

CaZ+/POq3- releasedor remodelingoccurs

Figure lll-3-1 0. The feedback mechanism controlling Ca2+ concentration.([+] = stimulation [-] = inhibit ion; [t] = increase; [J] = decrease)

a. A decrease in the serum Ca2+ (<10 mg/dl) is monitored by the calciostat in the chiefcells of the parathyroid gland to stimulate the secretion of prH.

b. PTH travels to the bone, where the process of osteolytic osteolysis causes bone break-down and remodeling with an increase in serum ca2+ and phosphate.

c. PTH acts on kidney tubules to promote Ca2+ reabsorption and phosphate excretion.The kidney stimulates conversion of 25(oH)D, to 1,25(OH)2D3.

d. 1'25(OH)rD, then travels to the intestine, where promotion of absorption of bothCa2* and phosphate occurs. 1,25(OH)rD, also travels to the bone where, together withPTH, it causes remodeling.

e. 1,25(OH)rD, directly inhibits secretion of PTH from chief cells operating in a nega-tive feedback loop.

Parathyroid chief cells

25(OH)D3

1,25(OH)2D3tOa2* reabsorptionleOos- excretion

258

Physiology

PANCREATIC HORMONESA. Overview

1. Islets of Langerhans are the functional units of the endocrine pancreag there are approx-imately I million islets.

2. There are four cell types in the pancreatic islets -+ four hormones'

a. c cell -+ glucagon

b. P cell -+ insulin

c. 5 cell -l somatostatin

d. PP(F) cell -+ pancr€atic polypePtide

3. Islet cells contain gap iunctions that link them together, possibly allowing cell-cellcommunication.

4. Islets are innervated by both the sympathetic and paraqrmPatletic systems. F{S.!__l,if!_a,Aig-y

B' Insulin The metabolic effects of

1. Insulin is secreted by p cells in response to incr€ased blood sugar. insulin and glucagon are

2. synthesis fl:iff*:l';'^lt1ffJ';'a. Synthesized as prqrroinsulin; cleavage of the IO0-amino-acid N-terminal signal pep- chapter in the Biochemistry

tide leaves proinsulin. seclion of the General Principles

b. Wthin proinsulin, residues 1-30 will form the B chain, and residues 66-86 will form Book I (Volume l)

the A chain of insulin. Residues 31-65 form the "connecting peptide" (C-peptide).

The two regions forming the A and B chains form two disulfide bridges in the proin-sulin molecule.

c. In the conversion of proinsulin to insulin, two pairs of basic amino acids are cleavedfrom either end of the connecting peptide, leaving one molecule eac.h of insulin andC-peptide-these are secreted in equimolar amounts.

d. Measwement of circulation C-peptide indicates p-cell secretory actiYit)'. Note thatorogenously administered insulin will not contribute circulating C-peptide'

3. Secretion

a. Stimulatory a8€nts

(1) Hyperglycemia (tlreshold >l mg/ml)

(2) Amino acids (especially Arg)

(3) Fatty acids, esPecially long chain (16-18 C)

(4) Gastmintestinal hormones, GIP, gastrin, sefietin (oral dose of glucose -) greaterproduction of insulin tlnn via IV because of these hormones)

(5) GH, cortisol

(6) Acetylcholine (parasympathetic stirnulation)

(7) Sulfonylureas (used to treat noninsulin-dependent diabetes mellitus)

259

Endocrine System

b. Inhibitory agents

(1) Hypoglycemia

(2) Somatostatin

(3) Norepinephrine

(4) Epinephrine

c. When stimulated by glucose, secretion is biphasic.

(1) Initial burst for 5-15 minutes from secretion of already formed granules

(2) More gradual and sustained release of newly synthesized insulin

(3) Secreted in fed-state-hormone of nutrient abundance

d. Primary target cells for insulin are liver, skeletal muscle, and adipose tissue.

4. Insulin receptor

a. Heterotetramer with two u-p subunits held together by disulfide bonds

( I ) cx-Subunits are extracellular proteins and contain insulin binding sites.

(2) p-Subunits are transmembrane proteins and have tyroxine kinase activity.

b. Insulin binding to the receptor causes autophosphorylation of intracellular portionsof the B-subunits-this activates the tyrosine kinase portion of the B-subunits tophosphorylate intracellular proteins and initiate a cascade of protein-protein interac-tions that results in activation of a variety of cellular Ser-Thr kinases.

5. Metabolic effects of insulin

a. Glucose transport

(1) Insulin promotes uptake of glucose from blood into cells.

(2) A specific family of carriers are involved to facilitate glucose diffrrsion across cellmembranes = GLUT 1 to GLUT 6 (GLUT = glucos€ transporter).

(3) Different carriers are expressed in different tissues and at different stages of fetaldevelopment.

(4) GLUT 4 is the insulin-stimulated transporter in skeletal muscle and adipose tissue.

(5) Insulin promotes translocation of GLUT 4 transporters from inactive intracellularpools (smooth ER) to plasma membrane-therefore, increased glucose uptake.

b. Glycogen synthesis

(l) Activates glycogen synthase by promoting its dephosphorylation

(2) Inactivates glycogen phosphorylase by promoting its dephosphorylation

(3) Net result is to increase conversion of glucose to glycogen in liver and muscle

c. Glycolysis

(1) Promotes glycolysis by increasing glucose uptake

(2) Also activates the enrymes glucokinase, phosphofructokinase, pyruvate kinase,and pyruvate dehydrogenase of the glycolytic pathway

260

Physiology

d. Gluconeogenesis

(1) Increases fructose 2,6-bisphosphate, leading to increased phosphofructokinase

activity

(2) Decreases gluconeogenesis

e. Lipogenic and antilipolytic effects

(1) In adipose tissue and liver, insulin promotes lipogenesis by increasing produc-

tion of cr-glycerol phosphate and fatty acids (stimulates fatty acid synthase) nec-

essary for triglyceride formation.

(2) In adipose tissue, insulin inhibits breakdown of triglycerides by inhibiting a

hormone-sensitive lipase that is activated by other hormones such as

epinephrine and glucocorticoids.

(3) Increases activity of lipoprotein lipase, which enhances fatty acid uptake from

blood into adipocytes or other tissues.

f. Protein synthesis and degradation

(1) Stimulates amino acid uptake by liver, muscle, and adipose tissue by stimulat-

ing amino acid transport system

(2) Increases activity of protein synthesis initiation factors that promote transla-

tion; increases ribosome synthesis.

(3) Inhibits protein degradation by decreasing lysosomal activity.

g. Hypokalemia. Insulin increases cellular uptake of K+. This effect can be used thera-

peutically-patients with hyperkalemia can be treated by giving insulin in combina-

tion with glucose.

C. Glucagon

1. Secreted by o cells in response to decreased blood sugar.

2. Synthesis

a. Synthesized as preproglucagon in c cells of the islets and also by cells of the gastroin-

testinal tract and some brain cells.

b. Primary regulator of secretion is a decrease in blood sugar below -1 mg/ml.

c. Like insulin, glucagon secretion is stimulated by amino acids (especially Arg) and

inhibited bv somatostatin.

3. Secretion

a. Stimulatory agents

(1) Hypoglycemia

(2) Amino acids

(3) Acetylcholine

(4) Norepinephrine

(5) Epinephrine

(6) ccK

25r

Endocrine System

b. Inhibitory agents

(1) Hyperglycemia

(2) Fatty acids, ketones

(3) Somatostatin

(4) Insulin

4. Metabolic effects of glucagon are exerted primarily in the liver. Glucagon binds to one ormore tfpes of cell surface receptor coupled to G-proteins and promotes increased cAMPvia adenylate ryclase or increased cytosolic Caz+.

a. Glycogenolysis

(1) Promotes glycogen breakdown by phosphorylating phosphorylase B, which isthen converted to phosphorylase c[

(2) Inactivates glycogen synthase

b. Gluconeogenesis is increased by increased transcription of mRNA coding for theenzpe phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme in gluconeoge-nesis.

c. Glycolysis is decreased by inhibition of pyruvate kinase.

d. Ureagenesis

(1) Glucagon enhances the conversion of amino acids to glucose, leading toincreased ammonia.

(2) Glucagon increases activig of urea rycle enzfmes to aid in the disposal of theammonia.

e. Lipolysis and ketogenesis

(1) Promotes lipolysis in the liver (small effect since few lipids are stored in liver).

(2) Allows fatty acids to enter mitochondria for oxidation to ketones. Ketones are afuel source that spares blood glucose for other tissues, such as brain, that requireglucose.

D. Insulin/glucagon ratio (I/G)

1. Net metabolic status is determined by the relative levels of insulin and glucagon.

2. llc ratio:

a. In fed-state = 30

b. Overnight fast = 2

c. Prolonged fast = 0.5

E. Somatostatin

1. Secreted by the islet delta cells

Z. Inhibits both insulin and glucagon secretion when given exogenously; probably plays aparacrine role in regulating insulin and glucagon

3. Somatostatin secretion is increased bv:

a. Hyperglycemia

b. Glucagon

c. Amino acids262

Physiology

F. Diabetes mellitus

1. Symptoms include ftequent urination (polyuria), increased thirst (polydypsia)' increased

food consumption (po\phagia), and weight loss.

2. Criterion for diagnosis is elev-ated blood glucose after ovemight fast (tfPically >140 mg/t ).

3. Insulin-dependent diabetes mellitus (IDDM, ryPe f )

a. Characterized by an inability of p-cells to produce ad€quste amounts of insulin

b. Most commonly caus€d by an autoimmune disorder in which p cells are destroyed

c. kss common is a mutation of the gene for preproinsulin

d. Genetic and environmental factors may also determine susceptibility to dwelopment of

type I diabetes.

e. Tieatment is insulin rqtlacement and matching of insulin, diet' and exercise (exercise,

like insulin, increases glucose uptake into cells).

4. Noninsulin-dependent diabetes mellitus (NIDDM, tyPe 2)

a. Characterized by an impairment of target cells to respond to insulin; may also have

some decreased secretory response in tlte pancreas itself.

b. ln most type 2 diabetes, s€rum insulin i6 normal or elwated; the fundamental defect is

often in th€ receptor or a PostrecePtor defect (not well understood).

c. There is a strong genetic component to the development of tfpe 2 diabetes; autoimmu-

nity does not play a significant role.

d. Many type 2 diabetics are overweight; weight loss can decrease the severity of the

disease.

e. Tre.tmenl Drugs of the sulfonylurea class aPPear to Prom*. T:*11:3.':.]'"::-5i:t Bridge !o pharmacologytissues and correct the sluSSish pancreatic p-cell response to normalize msulln secretron. - - -:?: - '

5. Complication of diabetes rnellitus The sulfonylureas are

a. Acute discussed in greaterdetail in the Endocrine

( 1 ) With poor control, tfPe I diab€tics €'.hibit hyperglycernnr' glucosuria' dehydra- PharmacoloSy chapter.tion, and ketoacidosis.

(2) The drop in fluid volume may comprornise cardiovascular frrnction-may lead to

circulatory failure.

(3) Excessive ketone formation leads to metabolic acidosis and electrolyte imbalanccs(renal elimination of ketones may deplete Na+ or K+ from blood since they areexcreted as the ketone salts).

b. Chronic

( I ) Large vessels show changes sirnilar to atherosclerosis.

(2) Microcirculation exhibits a thickening of basement membranes, leading todecreasing delivery of nutrients to and removal of waste ftom tissues' which, inturn, leads to tissue damage.

(3) Deterioration ofblood flow to the retina can lead to retinopathy and blindness.

(4) D€terioration of blood flow to the extremities can lead to possible amputation.

(5) Deterioration of renal blood flow leads to kidney failure.

(6) Peripheral and autonomic neuropathy

26'.

Endocrine Pathology

Endocrine pathology is primarily concerned with the hypothalamic-pituitary-end organ axis.Knowledge of the complex homeostatic feedback mechanisms affecting the hypothalamus andpituitary is critical to making an accurate diagnosis of hyper- or hypofunctioning of the endocrineglands or organs. In general, hyperplasia of glands implies an excess of stimulating hormone, whileadenomas and carcinomas may arise completely independently of normal regulatory hormonesecretion. Hyperplasias are almost always functional. In contrast, adenomas vary in the amount offunctional product they secrete; moreover, their responses to regulatory hormone vary considerably.Carcinomas are usually the least functional and are usually independent of regulatory hormonalinfluence.

HYPOTHATAMUS AND PITUITARY GTANDA. Lesions of the hnrothalamus

1. Destructive lesions include tumors such as craniopharyngiomas, gliomas, hamartomas,and inflammatory conditions (e.g., sarcoidosis).

2. Craniopharyngiomas arise from ectodermal remnants of Rathke pouch, forming the mostcommon pituitary tumor in children. Pathology shows stratified squamous epitheliumwith areas of keratinization and rysts. Lamellar bone deposits and calcium may be seen.Malignant transformation is rare. The tumor may be detected on x-ray by its opaque cal-cifications.

B. Anterior pituitary hyperfunction

1. Etiology. Most cases of anterior pituitary hyperfunction are caused by adenomas, whichusually secrete prolactin, growth hormone, or adrenocorticotropic hormone (ACTH).

2. Clinical syndromes correspond to the hormone secreted.

a. Hnrerprolactinemia (amenorrhea-galactorrhea syndrome) results from elevatedserum prolactin associated with pituitary adenomas (prolactinoma). It is the mostcommon pituitary tumor. In women, it results in amenorrhea and galactorrhea; inmen, this tumor may result in galactorrhea and infertility. Other causes of elevatedprolactin, such as reserpine, phenothiazines, estrogens, or a hlpothalamic lesion,should be ruled out.

b. Excess growth hormone

( 1) Gigantism occurs if there is excessive GH secretion before the growth plates arefused (i.e., before the end of puberty). Excessive skeletal growth may result inheights close to 9 feet tall.

Flashback to Physiology

The hypothalamus producesgroMh hormone-releasinghormone (CHRH),somatostatin, dopamine,gonadotropi n-releasi n ghormone (CnRH),corticotropi n-releasin ghormone (CRH), antidiuretichormone (ADH), thyrotropin-releasing hormone (IRH), andoxytocin.

Clinical Correlate

A pituitary tumor may impingeon the optic chiasm,producing a bitemporalhemianopsia (loss ofperipheral visual fields). Makesure to perform a visual fieldtest if you suspect this tumor(or any brain neoplasm).

265

Endocrine System

Note

Hyperplasia or tumors of thepituitary are associated withMEN type l. The MENsyndromes are discussed atthe end of this chapter.

In a Nutshell

Diabetes Insipidus (Dl). Polydipsia. Polyuria. Large volumes of dilute

(hypotonic) urine. High serum osmolality. Hypernatremia

Central Dl responds toexogenous ADH therapy;nephrogenic Dl does notbecause renal receptors donot respond to ADH.

266

(2) Acromegaly occurs if there is excessive secretion after closure of the epiphysealplates. There is a gradual coarsening of facial features (i.e., thick lips, protrudingjaw, large tongue) and enlargement of the hands and feet. It may be associatedwith diabetes mellitus, hypertension, osteoporosis, and other symptoms associ-ated with space-occupying lesions in the pituitary region, such as visual fielddefects.

c. Cushing disease is caused by ACTH-secreting tumors. Lesions are usually small andrarely cause mass effect. Cushing disease is discussed later in this section.

3. Pathology of pituitary adenomas

a. Gross findings range from microadenomas (5-10 mm) to large masses (10 cm) thatmay invade surrounding structures.

b. Microscopic findings reveal uniform cells in nests, sheets, or cords in a fibrous stroma.

(1) Eosinophilic adenomas usually produce growth hormone and are often large.

(2) Chromophobe adenomas have few stainable granules and often produce pro-lactin.

(3) Basophilic adenomas have periodic acid-Schiff (PAS)-positive granules andoften produce ACTH.

C. Anterior pituitary hypofunction is usually manifested as panhypopituitarism, resultingfrom the destruction of at least 75o/o of the adenohypophysis.

1. Clinical features include symptoms of hypothyroidism, hypoadrenalism, and hypogo-nadism. Growth hormone deficiency in children results in primary dwarfism with nor-mal limb and skull proportions.

2. Etiology

a. Sheehan syndrome is due to hemorrhagic or ischemic infarction of the pituitaryfollowing postpartum hemorrhage with excessive bleeding or shock. It may presentwith failure to lactate in the postpartum period.

b. Empty sella syndrome is due to atrophy of the pituitary. The sella is enlarged on skullx-ray and may mimic a pituitary neoplasm. Surprisingly,it is usually asymptomatic.

c. Nonsecreting-chromophobe adenomas may present with hypopituitarism or symp-toms of a space-occupying lesion.

d. Tirberculosis (TB), sarcoid, irradiation, and metastases from other neoplasms may alsocause panhypopituitarism.

D. Posterior pituitaryhypo- and hyperfunction

1. Diabetes insipidus (DI) is due to insufficient or absent antidiuretic hormone (ADH).

a. Etiology. Disorders involving the hypothalamus or neurohypophysis (e.g., malignan-

ry, meningitis, TB, sarcoid, postsurgical trauma to base of skull) may all cause centraldiabetes insipidus. Nephrogenic diabetes insipidus is caused by a lack of renalresponse to ADH.

b. Clinical features include polydipsia and polyuria with excretion of large volumes ofdilute urine, even during states of dehydration.

c. Laboratory results show high serum osmolality and sodium with hemoconcentra-tion due to loss of free water. Patients with central DI will respond to administrationof exogenous ADH, while patients with nephrogenic DI will not.

Pathology

2. The syndrome of inappropriate ADH secretion (SIADH) is due to inappropriate, exces-sive ADH secretion unrelated to serum osmolaliw.

a. Etiology. SIADH may result from:

(1) Malignancies associated with ectopic ADH production (usually oat cell lungcancer)

(2) Central nervous system (CNS) disturbances (e.g., skull fracture, subarachnoidhemorrhage, stroke)

(3) Drug use (e.g., chlorpropamide, carbamazepine, thiazide diuretics)

(4) Certain pulmonary diseases (e.g., TB or lung abcess).

b. Clinical features include fluid retention, weight gain, and lethargy. There is a range ofCNS disturbances, including seizures and coma.

c. Laboratoryrestrlts show lowserum osmolaliry hnronatremia, and hypertonic urine.

ADRENAT GTANDSA. Adrenal cortical hyperfunction

1. Cushing syndrome is caused by cortisol excess.

a. Etiology. Cushing syndrome may take one of four distinct forms, depending on itscause. They are summarized in Figure III-4-1.

( 1) Pituitary Cushing syndrome (approximately two-thirds of the cases of Cushing).Pituitary or hypothalamic dysfunction is the most common noniatrogenic cause.It is caused by basophilic adenomas, referred to as Cushing disease, or morecommonly, by multiple corticotroph microadenomas. Pituitary Cushing syn-drome is characterized by bilateral adrenal hyperplasia and elevated serumACTH. The diagnosis is established when the administration of high-dosedexamethasone suppresses ACTH secretion, causing decreased serum cortisoland decreased urinary l7-hydrorycorticosteroid (l7-OHCS) excretion; in normalindividuals, low-dose dexamethasone suppresses ACTH secretion.

(2) Adrenal Cushing syndrome is usually caused by an adrenal adenoma. It ischaracterizedby lowserumACTH and failure of dexamethasone suppression ofcortical secretion.

(3) Ectopic Cushing syndrome is caused by ectopic secretion of ACTH, most com-monly by bronchogenic cancer, but also by pancreatic neoplasms and thymo-mas. It is characterized by bilateral adrenal hlperplasia and failure of dexam-ethasone suppression.

(4) Iatrogenic Cushing syndrome is rather common and is caused by exogenousadministration of glucocorticoids or ACTH.

b. Clinical features usually result from excess cortisol but may also be due to excessaldosterone, corticosterone, or adrenal androgens. The syndrome is most common inwomen in the 2040-year-old age group. Patients exhibit hnrertension, abnormalglucose tolerance (frank diabetes 20o/o), truncal obesity, muscle wasting in theextremities, moon facies, buffalo hump, cutaneous striae, osteoporosis, hirsutismand amenorrhea in women, weight gain, edema, weakness, fatigue, susceptibility toinfection and personality disturbances. Children show growth retardation, delayedskeletal maturation, and precocious puberty if associated with adrenal androgens.

ln a Nutshell

SIADH. Fluid retention

. Weight gain

. Lethargy

. Low serum osmolality

. Hypertonic urine

. Hyponatremia

267

Endocrine System

Cushing Syndrorne

t CortisolHypertension

Truncal obesityIv

IV

PituitaryCushing

IV

Pituitaryadenoma(Cushingdisease)

I

tt ecrnfrom pituitary

IV

Adrenalhyperplasia

IV

Suppressionof ACTH with high-dose dexamethasone

AdrenalCushing

+Adrenaladenoma

IIIv

J ecrn

IvEctopicACTH

IV

Bronchogenic cancer(or otherneoplasm)

IIv

T ecrHIIV

Adrenalhyperplasia

IZ Suppressionwith dexamethasone

+Iatrogenic

I*

Exogenousadministration ofACTH or cortisol

Z Suppressionwith dexamethasone

Figure lll-4-1. Summary of Gushing syndrome and its effects.

c. Pathology

(1) In the pituitary, Crooke hyaline degeneration of basophils results from pro-longed feedback inhibition by cortisol.

(2) In the adrenals, there is bilateral cortical hlperplasia, adrenal cortical adenoma,or, rarely, carcinoma in Cushing syndrome due to primary causes. Nodularhyperplasia or atrophy of the adrenal cortex is seen with exogenous ACTH orglucocorticoids, respectively.

2. Primary hyperaldosteronism (Conn syndrome) is due to increased aldosterone secre-tion, producing sodium retention, increased total plasma volume, increased renal arterypressure, and inhibition of renin secretion.

a. Etiology. An adrenal adenoma secreting aldosterone is the most common cause. Othercauses include idiopathic hyperaldosteronism, in which bilateral cortical nodular hyper-plasia of the zona glomerulosa is seen, or, rarely, adrenal carcinoma, glucocorticoid-suppressible hyperaldosteronism, or congenital bilateral zona glomerulosa hyperplasia.

b. Ctinical features include sodium retention, extracellular fluid expansion, and potassi-um depletion with diastolic hypertension, weakness, fatigue, polprria, polydipsia, andheadache.

268

Pathology

c. Laboratoryvalues reveal hypokalemia, low renin levels, metabolic alkalosis, hlper-natremia, and (fcrr adenomas) failure to suppress aldosterone with salt loading.

d. Pathology usually shows a single benign adenoma, which is a well-circumscribed,encapsulated, small lesion composed of lipid-laden clear cells.

3. Secondary hyperaldosteronism

a. Etiology. The causes are decreased renal blood flow or perfusion pressure, edematousstates with sodium retention, renin-producing neoplasms, and Bartter syndrome,which is characterizedby juxtaglomerular cell hyperplasia, hyper-reninemia, hyperal-dosteronism, and failure to thrive; it is often associated with low blood pressure.

b. Laboratory values include high renin levels, hypernatremia, and hypokalemia.Secretion of aldosterone is triggered by elevated renin-angiotensin levels.

4. Congenital adrenal hyperplasia (CAH)

a. Etiology. CAH is usually due to a congenitalenzyme deficienry of adrenal steroid syn-thesis resulting in cortisol deficiency and marked enlargement of the adrenals.

b. Types. The three most common forms all cause virilism and are called adrenogenitalsyndromes.

(1) 2l-hydroxylase deficiency causes simple virilizing CAH (SOotol. There is normalaldosterone function and impaired cortisol production.

(2) The salt-losing syndrome is due to 2l-hydrorylase deficiency associated withaldosterone deficiency.Infants present with vomiting, dehydration, hyponatrem-ia, and hyperkalemia.

(3) ll-Hydroxylase deficiency causes excessive androgen production and buildupof 11-deoxycorticosterone (strong mineralocorticoid), causing virilization,hypertension, and hypokalemia.

c. Clinical features of adrenogenital syndromes are virilization in women, sexual precociryand premature epiphyseal closure.

d. Pathology of all types shows diffirse or nodular bilateral adrenal cortical hyperplasia.

B. Adrenal cortical hypofunction

l. Acute adrenocortical insufficiency can be caused by:

a. Rapid withdrawal of exogenous steroids in patients with chronic adrenal suppression

b. Stress (e.g., trauma, surgery, infection), Addison disease, or chronic adrenal suppres-sion caused by administration of exogenous corticosteroids

c. Adrenal apoplexy, such as in the Waterhouse-Friderichsen syndrome: a massive,sudden adrenal hemorrhage usually associated with meningococcal septicemia

2. Chronic or primary adrenocortical insufficiency (Addison disease)

a. Etiology. Tuberculosis was once the most common cause. The most common etiolo-gy today is idiopathic (probably autoimmune). Other possibilities include infections(e.g., fungal, Waterhouse-Friderichsen syndrome), iatrogenic causes, metastases,adrenal hemorrhage, and pituitary insufficienry.

b. Pathogenesis. To produce clinical insufficienc,f,90o/o of the adrenal gland must benonfunctional.

ln a Nutshell

Hyperaldosteronism

t rua-J K .

Metabolic alkalosis

vWillsee J renin

l ' (Connsyndrome)

IY

T Aldosteronesecretion by

adrenal gland;usually

adenoma

2"

YT Aldosterone

due to Iperfusion orother causeof t reninsecretion

IV

Will see 1 renin

269

Endocrine System

Note

Pigmentation of the skin inAddison is due to ACTH alsohaving a weak stimulatoryeffect on melanorytes. ACTHand melanoryte-stimulatinghormone (MSH) share aminoacid sequences.

Mnemonic

The Rule of los forPheochromocytoma. l0o/o extra-adrenal

. l0o/o bilateral

. l0o/o malignant

. l0o/o affect children

. l0o/o familial

c. Clinical features are due to insufficient cortisol and aldosterone secretion, leading toweakness, weight loss, anorexia, nausea, vomiting, hypotension, skin pigmentation,hypoglycemia with prolonged fasting, inability to tolerate stress, and abdominal pain.

d. Laboratoryvalues show decreased serum sodium and chloride with metabolic acido-sis and increased serum potassium. Low serum cortisol and urinary 17-OH CS andlow l7-ketosteroids, before and after ACTH administration, should also be measured.ACTH levels are high.

e. Pathology shows bilateral atrophied adrenal glands. In the idiopathic lrpe, there arelymphocytic infiltrates and zones of fibrosis surrounding islets of remaining epithelialcells.

3. Secondary adrenocortical insufficiency

a. Etiology. Causes include metastases, irradiation, infection, and infarction, affectingthe hypophysial-pituitary axis and resulting in decreased ACTH.

b. Clinical features. Secondary insufficiency usually produces less mineralocorticoidmalfunction and less pigmentation.

C. Adrenal neoplasms

l. Adrenal adenomas

a. Clinical features. Adrenal adenomas are mostly asymptomatic and nonsteroid-producing. Steroid-producing adenomas may produce Conn syndrome, Cushingsyndrome, or virilization in women. They may also occur with multiple endocrineneoplasia (MEN) syndromes.

b. Pathology. Adrenal adenomas are usually small and unilateral, yellow-orange on cutsection, and poorly encapsulated. When adrenal adenomas are large, hemorrhage,

rystic degeneration, or calcification maybe seen. Nonsteroid-producing adenomas areusually composed of lipid-filled cells; steroid-producing tumors are often mixed withlipid-filled cells and compact cells.

2. Adrenal carcinomas

a. Clinical features. Adrenal carcinoma is relatively rare and usually very malignant.Greater than 90olo are steroid-producing (often more than one steroid).

b. Pathology. The tumors are often large and yellow with areas of hemorrhage, rysticdegeneration, and necrosis.

3. Pheochromocytoma

a. Etiology. Pheochromocytoma is a neoplasm of neural crest-derived chromaffin cellsthat secrete catecholamines, resulting in hnrertension.

b. Incidence. The highest incidence is in children and in adults age 30-50. Ten percentare familial, i.e., are associated with MEN IIa and MEN III (aka IIb), neurofibromato-sis, or von Hippel-Lindau disease.

c. Clinical features are related to catecholamine release. Parorysmal or constant hlper-tension is the most classic symptom. Also, sweating, headache, arrhythmias, palpita-tions, and nervousness may be seen in any combination.

d. Laboratory values show elevated urinary catecholamines and catacholaminemetabolites (e.g., homovanillic acid, HVA, and vanillylmandelic acid, VIvIA).

270

Pathology

e. Pathology. Ten percent of tumors are extra-adrenal, l0o/o are bilateral, and 10olo aremalignant. Tirmors are well defined and fibrous, creating a lobulated appearance. Thecut surface is light brown, often with areas of hemorrhage and necrosis. Cells arestained with chromium salts (chromaffin reaction) and have a basophilic cytoplasmwith secretory granules.

4. Neuroblastoma is the most common malignant extracranial solid tumor of childhood.Amplification of the N-myc oncogene is a characteristic of neuroblastoma. The morecopies of the oncogene, the more aggressive the tumor.

a. Clinical features. Ttrmors grow rapidly, metastasize widely (especially to bone), andproduce elevated urinary catecholamines. The prognosis is better if patients are lessthan 1 year old. Tumors may regress in young infants. The presence of ganglion cellsalso improves prognosis.

b. Pathology. Neuroblastoma occurs most frequently in the adrenal medulla but mayalso arise in the cervical, abdominal, and thoracic sympathetic chain. The tumors arelobulated with a gray cut surface, showing areas of necrosis, hemorrhage, and calcifi-cation. Microscopically, malignant small cells are often seen in a rosette patternaround nerve fibrils.

THYROID GTANDA. Overview of hyperthyroidism

1. Etiology. Hyperthyroidism may be seen most often in Graves disease, toxic multinodulargoiter, and toxic adenoma. Thyroiditis, thyroid carcinoma, and iodine ingestion are lessfrequent causes.

2. Pathogenesis is due to increased circulating levels of the thyroid hormones triiodothyro-nine (Tr) and thyroxine (Tr), causing a hnrermetabolic state.

3. Clinicat features

a. Cardiac symptoms include tachycardia, cardiac palpitations, cardiomegaly, occasionalcardiac arrhythmias (usually atrial fibrillation), and cardiomyopathy.

b. The skin is warm, flushed, and moist due to vasodilatation.

c. The eyes show a wide stare with upper lid retraction and lid lag. Exophthalmos is char-acteristic of Graves disease, due to swelling of extraocular muscles and periorbital tissues.

d. Patients also show increased sweating, heat intolerance, hyperactivity, nervousness,tremor, weight loss, diarrhea, oligomenorrhea, and myopathy.

e. Propranolol, a nonselective beta blocker, may be given to alleviate the sympatheticnervous system symptoms.

f. Thyrotoxic storm is a severe hypermetabolic state characterizedby tachycardia, fever,cardiac abnormalities, and coma. Twenty-five percent of cases are fatal.

4. Diagnosis is based on low TSH and elevated Tn. Low TSH is most important.

B. Overview of hypothyroidism

1. Etiologies

a. Congenital thyroid dysplasia or hypoplasia

b. Hypothalamic or pituitary disease

NoIe

You are much more likelyto see a pheochromocytomacase on the USMLE thanyou ever are to see one inyour clinical practice.

Clinical Correlation

Clinical diagnosis ofhyperthyroidism may bedifficult in pregnancy, which isan intrinsically hypermetabolicstate and is often associatedwith mild degrees ofthyromegaly. In addition, theincrease in TBG that resultsfrom the high estrogen levelselevates the total serum T4,but not the free serum T4.

271

Endocrine System

Note

In contrast to primaryhypothyroidism, secondary(pituitary gland failure) andtertiary (hypothalmic failure)hypothyroidism have low(or normal) TSH levels.

C.

c. Thyroid conditions causing goiter including iodine deficiency and Hashimoto(autoimmune) thyroiditis

d. Surgical or radiation destruction of gland

e. Peripheral resistance to thyroid hormone

2. Clinical features depend on the age group.

a. Infants lacking sufficient thyroid hormone develop cretinism. The major effects areon skeletal and CNS development (i.e., short stature, retarded bone age, epiphysealdysgenesis, and mental retardation). Once apparent, the syndrome is irreversible. Theinitial presentation includes failure to thrive, feeding difficulties, constipation, andsomnolence. Children develop protuberant abdomens, wide-set eyes, dry rough skin,broad nose, and delayed epiphyseal closure. Neonatal screening for elevated TSH isessential for early detection.

b. Older children show short stature, retarded linear growth, and delayed onset ofpuberty.

c. In adults, hypothyroidism causes lethargy, weakness, fatigue, decreased appetite,weight gain, cold intolerance, hair loss, dry skin, constipation, apathy, myopathy,psychosis, metrorrhagia (irregular uterine bleeding), and accelerated atherosclerosiswith elevated serum cholesterol. Mpredema, a syndrome associated with severehypothyroidism, shows periorbital puffiness, pale doughy skin due to accumulation ofhydrophilic mucopolysaccharides, sparse hair, cardiac enlargement, cardiomyopathy,pleural effrrsions, anemia, and thickened facial features.

3. Diagnosis of primary hypothyroidism is based on an elevated TSH and low To.

Graves disease

1. Incidence. Graves disease peaks in the third and fourth decades and is five times morecommon in women. There is a familial predisposition, and it is associated with otherautoimmune diseases, such as pernicious anemia and Hashimoto thyroiditis. The inci-dence of Graves disease is increased in HLA-DR3- and HlA-B8-positive individuals.

2. Pathogenesis is autoimmune, resulting from production of thyroid-stimulatingimmunoglobulin (TSI) and thyroid growth immunoglobulin, two autoantibodies thatcause glandular hyperplasia and hormone production by binding to TSH receptors.

3. Clinical features are present in varying combinations.

a. Thyrotoxicosis has symmetric glandular enlargement.

b. Ophthalmopathy is characterized by lid lag, retraction of the upper lid, proptosis,periorbital edema, and stare. It results from inflammatory infiltration and edema ofextraocular muscles and periorbital tissues. It does not always respond to antithyro-toxicosis treatment.

c. Dermopathy is characterized by thickened edematous nodules or plaques on thelower extremities and is present in 10olo of Graves patients.

4. Pathology

a. Grossly, there is a diffi.rse, moderate symmetrical enlargement of the gland.

b. Microscopically, hypercellulariry producing small follicles with little colloid and pap-illary infoldings into the lumen, is seen. The stroma exhibits increased vascularity andvariable lymphocytic infiltrate. These changes are not associated with an increasedincidence of thvroid cancer.

272

Pathology

D. Hashimoto thyroiditis is a chronic lymphocytic thyroiditis featuring goitrous enlargementof the thyroid gland produced by lymphocytic and plasma cell infiltrates, with the eventu-al development of hypothyroidism.

1. Etiology is autoimmune. There may be autoantibodies to the TSH receptor, T' Tn,microsomes, and thyroglobulin.

2. Incidence. Hashimoto thyroiditis is the most common type of thyroiditis and is the leadingcause of goitrous hypothyroidism in the United States. The highest incidence is in middle-aged women, and there is a higher incidence in patients with a family history of Hashimotoor other autoimmune diseases (e.g., Graves disease, Sj6gren syndrome, systemic lupuserythematosus). The incidence of Hashimoto thyroiditis is increased in HLA-DR5 andHLA-BS individuals.

3. Clinical features include painless goiter. Hypothyroidism develops, along with malaise,fever, a decreased Tn, and elevated TSH.

4. Pathology. The gland is enlarged, usually symmetric, and firm. It contains a lymphocft-ic and plasma cell infiltrate with occasional germinal centers. Acini are partly atrophic,with little colloid and variable fibrosis, increasing as the disease progresses. Follicularepithelium is transformed into Htirthle cells characterized by an eosinophilic granularcytoplasm.

Diffrrse nontoxic goiter is used to describe diffirse enlargement of the gland in euthyroidpatients.

1. Incidence

a. Endemic goiters have a high incidence in certain geographic regions (e.g., mountain-ous regions or regions far from the ocean). They are caused by iodine-deficient dietsor increased intake of goitrogens (e.g., calcium, fluorides).

b. Sporadic simple goiter is less common. The incidence in women is much greater thanin men.

2. Pathogenesis. There are variable abnormalities with thyroid hormone synthesis, resultingin compensatory hypertrophy and hyperplasia of follicular epithelium.

3. Pathology. The gland becomes hyperplastic, then accumulates colloid asymmetrically.

Multinodular goiter develops from chronic diffirse goiters; it may be toxic or nontoxic andmay become very large (Figure III-4-2).

E.

In a Nubhell

Hyperhyroidism(J TSH, t T3,

1rJ

IV

. l H R

. Skin moi$and flushed

. Lid lag

. Sweating

. Heatintolerance

. Weight los

l-lypdyroidlsn(t TsH, J Ty

JTJ

IV

. Getrnismin children

. Lethargyin aduh

. Fatgue

. Weight gain

. Coldintolerance

275

Endocrine System

lP*"i

:

Et',-ru

Figure lll-4-2.Thyroid: multinodular goiter, microscopic.

1. Clinical features. Glandular enlargement may cause stridor, dysphagia, and even superi-or vena cava syndrome (mass effect). Fifty percent produce thyrotoxicosis. These tumorsmust be differentiated from thyroid cancer, particularly asymmetric tumors in euthyroidpatients.

2. Pathology. Glands may be as large as 2 kg and nodular with areas of hemorrhage, scar-ring, and calcification. They are usually asymmetric with areas of colloid-filled acini.

G. de Quervain granulomatous subacute thyroiditis

1. Etiology is probably viral.

2. Incidence. It is the second most common form of thyroiditis with the incidence inwomen greater than in men. The disease peaks in the second to fifth decades.

3. Clinical features. Symptoms often begin following a viral syndrome, most commonlymumps and coxsackievirus. The course lasts several weeks with a tender gland, a goiter in30o/o of patients, fevet malaise, and dysphagia. Early in the course, the patient may havemild symptoms of thyrotoxicosis; latet patients are usually euthyroid, and the disease fol-lows a self-limited course.

4. Pathology

a. Grossly, there is moderate irregular enlargement of the gland.

b. Microscopically, degeneration of follicular epithelium causes leakage of colloid fromfollicles, which initiates an inflammatory response with foreign body giant cells, histi-ocytes, and granuloma formation. The degeneration of epithelial cells is presumablydue to a viral infection, but a specific etiology is usually not demonstrated.

H. Riedel thyroiditis is a rare disease characterized by connective tissue proliferation, causingdestruction of the thyroid gland and fibrosis of surrounding structures.

1. Incidence is greatest in middle age, and greater in women than in men.

2. Ctinical features. Fewer than 50olo of patients are hlpothyroid. They may present withstridor, dyspnea, dysphagia, or a painless lump.

,;;TW ' ',.:%ili

u'rr,,i

274

Pathology

I .

3. Pathology

a. Grossly, the gland is firm and hard, nodular, and irregular; size varies.

b. Microscopically, complete fibrous replacement of the gland is seen. It may mimic car-cinoma.

Congenital thyroid conditions

1. Agenesis or dysgenesis are frequent causes of cretinism.

2. Thyroglossal duct or cyst may communicate with the skin or base of the tongue. It isformed from nests of incompletely descended midline thyroid tissue.

3. Ectopic thyroid nests are usually at the base of the tongue. Prior to removal, it must bedocumented that the patient has other functioning thyroid tissue.

Tumors. Thyroid nodules are very common (F7o/o adults in the U.S.), but thyroid cancer isuncommon (less than 2 cases per 1,000 nodules). There is a higher incidence of neoplasia insolitary nodules and in younger patients.

1. Adenomas. Follicular adenoma is the most common.

a. Clinical features. Adenomas may cause pressure symptoms, pain, and, rarely, thyro-toxicosis.

b. Pathology. There are usually solitary lesions less than 3 cm in diameter that are wellencapsulated and compress adjacent thyroid parenchyma. There is a sharp demarca-tion from surrounding thyroid with a variable amount of colloid, interstitial connec-tive tissue, and acinal size.

2. Cysts make up lV25o/o of solitary nodules and usually represent rystic degeneration offollicular adenomas.

3. Carcinomas represent neoplasia of follicular cells (i.e., papillary, follicular, or anaplasticcancer) and/or parafollicular cells (i.e., medullary cancer). Risk factors include radiationand a genetic predisposition.

a. Papillary carcinoma is the most common type. The incidence is higher in women.

(1) Pathology. Grossly, there is a papillary branching pattern, which may be rystic orsolid. Microscopi..lly, there is a single layer of tumor epithelium on a fibrovascu-lar stalk. Nuclei have a characteristic ground-glass appearance. Forty percent oftumors contain psammoma bodies.

(2) Clinical features. Spread to local nodes is common. Hematogenous spread israre. Resection is curative in most cases. Radiotherapy with iodine tlt (131I) isalso effective for metastases.

b. Follicular carcinoma makes up 20o/o of thyroid cancers and is more malignant thanpapillary cancer.

(1) Patholog''. Tumors are occasionally encapsulated, with penetration through thecapsule. They show an adenomatous pattern with development of acini or folli-cles that are lined by large cells compared to those lining normal follicles. Colloidis sparse.

(2) Ctinical features. Local invasion and pressure causes dysphagia, dyspnea,hoarseness, and cough. Hematogenous metastasis to lungs or bones is common.The prognosis depends on the extent of metastases. The overall 5-year survivalis 60010.

\

In a Nutshell

. Papillary carcinoma +lymph node metastases

. Follicular carcinoma +hematogenous meta$ases

275

Endocrine System

Note

Lab Abnormalities inPrimary Hyperpara-thyroidism

. t P T H

. t ca,r

. J Phosphate

. t Alkaline phosphatase

Clinical Correlate

Osteitis fibrosa cystica, alsoknown as von Recklinghausendisease of bone, occurs as aresult of chronic primaryhyperpa rathyroid ism.Cy$icchanges in bone occur due too$eoclastic resorption. Fibrousreplacement of resorbed bonemay lead to a "brown tumor,"a non-neoplastic tumor mass.

Note

Lab Abnormalities inSecondary Hyperpara-thyroidism

. t P T H

. J Car.

. I Phosphate

. t Alkaline phosphatase

Clinical Correlate

DiCeorge syndrome is alsoassociated with absence of thethymus due to a commonembryologic defect. Tetanyoccurs shortly after birth dueto congenital absence of theparathyroid glands. Cardiacstructural defects and immuno-deficienol are also noted.

276

c. Anaplastic carcinoma is rapid growing, aggressive, and has a poor prognosis. It is rel-atively uncommon and affects older patients (60-80 years old).

(1) Pathology. Tumors are usually bullq and invasive. They are composed of undif-ferentiated, anaplastic, and pleomorphic cells.

(2) Clinical features are early, widespread metastasis and death within 2 years.

d. Medullary carcinomas arise from parafollicular cells (C cetls). They are uncommon,and a minority are associated with MEN IIa and MEN III (IIb) syndromes. They arecomposed of nests of cells in an amyloid stroma made of calcitonin. The tumorssecrete calcitonin.

PARATHYROID GLANDSA. Primary hyperparathyroidism

1. Etiology

a. Parathyroid adenoma is the most common cause, usually involving a single gland.

b. Parathyroid hyperplasia shows diffrrse enlargement of all glands, usually composedof chief cells.

c. Parathyroid carcinoma is very rare. It is characterized by a high mitotic rate, localinvasion, and metastases.

d. MEN I and MEN IIa include tumors or hyperplasias of the parathyroids.

2. Clinical features. Patients with elevated serum calcium are often asymptomatic. Theymay present with bone abnormalities secondary to elevated parathyroid hormone (e.9.,osteomalacia, osteitis fibrosa cystica, subperiosteal resorption). Hypercalcemia may causemetastatic calcification (e.g, kidney stones).

B. Secondary hyperparathyroidism

1. Etiology. Secondary hyperparathyroidism is usually caused by chronic renal failure, leadingto decreased Ca2+ absorption, which in turn results in a feedback loop and increasedPTH. Vitamin D deficiency and malabsorption are less common causes.

2. CLinical features show soft tissue calcification and osteosclerosis. Mild-to-moderatehypocalcemia is characteristic.

C. Hypoparathyroidism

1. Etiology. Common causes are removal of glands during thyroidectomy, idiopathic,radioactive iodine therapy for Graves disease, metastatic cancer, and DiGeorge syndrome.The idiopathic form may be familial and autoimmune.

2. Clinical features include hypocalcemia, hyperphosphatemia, irritabiliry anxiefy, neuro-muscular excitability, tetany, intracranial calcifications, lens calcification, dental abnor-malities, and cardiac conduction defects.

D. Pseudohypoparathyroidism

i. Etiology. Pseudohypoparathyroidism is an autosomal recessive disorder resulting in akidney unresponsive to circulating PTH.

2. Clinical features include skeletal abnormalities such as short stature, and shortenedfourth and fifth carpals and metacarpals.

Pathology

E. Hypercalcemia is defined as a persistent serum calcium over 10.4 m/dl.

1. Etiology. Hlpercalcemia may be caused by metastatic disease to bone, such as myeloma orepithelial neoplasm, vitamin D intoxication, sarcoidosis, primary or secondary hlper-parathyroidism, the milk alkali syndrome, or Paget disease of bone.

2. Clinical features. Renal stones are often seen; hlperparathyroidism is also usually associat-ed with hypercalciuria and with hypophosphatemia. Alkaline phosphatase activity is usu-ally elevated. Patients may experience an altered sensorium, often first noticed as drowsi-ness.

3. Pathologic features in bone range from obvious metastases to osteoclast tunneling throughbony trabeculae in hyperparathyroidism.

ENDOCRTNE PANCREAS (rSrETS OF LANGERHANS)A. Diabetes mellitus is caused by inadequate or abnormal insulin secretion, causing impaired

glucose utilization, irnd resulting in hyperglycemia, glycosuria, and characteristic systemicpathology.

1. Types

a. Insulin-dependent (tt'pe l) diabetes mellitus (IDDM). There is an abrupt onset withpatients prone to ketoacidosis, insulin dependence, and severe metabolic derangements.

b. Noninsulin-dependent (t)"e 2) diabetes mellitus (NIDDM). This disease constitutesmost cases of idiopathic diabetics. It is characterized by peripheral insulin resistance andlater, abnormal insulin secretion. Most patients have central obesitywith an onset of dis-ease usually after age 40. These patients are not prone to ketoacidosis.

c. Secondary diabetes may be caused by destruction of pancreatic islet cells from inflam-mation, hemochromatosis, tumor, surgery or hormonal disease.

2. Pathogenesis

a. IDDM shows a marked, absolute insulin deficienry resulting from diminished p-cell

mass. It it therefore characterizedby lowserum insulin levels. There are three etiologictheories; in many cases of IDDM, all three mechanisms may be operative.

(l) A viral infection (e.g., mumps, coxsackievirus B, rubella, CMV mononucleosis)may lead to destruction of B cells. A subgroup of adult-onset diabetics with isletcell antibodies and HIA-DR3 are at increased risk to become insulin dependent.

(2) There is clearly a genetic predisposition because of increased susceptibility withcertain HLA haplotypes.

(3) Autoimmune response. Eighty percent of patients with IDDM have anti-islet cellantibodies. Relatives of patients with IDDM often have similar antibodies, and thisincreases their risk of developing the disease. Autoantibodies to islet cells mayprecede the development of the disease.

b. MDDM is characterized by mild-to-moderate insulin deficienry and is not associatedwith a specific HLA haplotype. There are two theories:

(1) Insulin resistance, the impaired ability of tissues to react to circulating insulin,results from a decrease in the number of cell-surface insulin receptors, forunknown reasons.

(2) Delayed or inadequate insulin secretion may develop, probably due to isletexhaustion.

Mnemonic

Hypercalcemia (MISHAP)

Malignancy!ntoxication5arcoidosisHyperparathyroidismAlkali syndromelaget disease

277

Endocrine System

3 . Clinical features

a. Predisposing factors are obesiry pregnancy, trauma, infections, and stress.

b. Presentation. Both IDDM and NIDDM may present with polydipsia, polyuria,polyphagia, weight loss, and muscle weakness. Laboratory values may show hnrer-glycemia, glycosuria, and hyperlipidemia.

c. Acute metabolic complications

(1) Diabetic ketoacidosis (DKA) may occur in insulin-dependent diabetics. It leads toan oversupply of glucose, fueled by high rates of protein catabolism, lipolysis inadipose tissue, and fatty acid oxidation in liver. The accelerated rate of fatty acidoxidation produces acetyl-CoA faster than it can be burned by the TCA cycle, andthe liver conserves the excess acetyl-CoA by synthesuing ketones. Metabolic aci-dosis results from the accumulation of the ketones. The high level of blood glucoseleads to dehydration via an osmotic diuresis. Tieatment with insulin normalizesthe metabolism of carbohydrate, protein, and fat. Fluids are given to correct thedehydration.

(2) Hyperosmolar nonketotic coma occurs in patients with mild adult-onset dia-betes when blood glucose levels exceed approximately 600 mg/dl. It is not clearwhy ketoacidosis does not occur in these patients, but it appears that lipolysisoccurs to a much lesser extent than in DKA, thereby producing fewer ketones.The treatment of hyperosmolar nonketotic coma is identical to the treatmentof DKA.

d. Late complications of diabetes. Patients with long-standing diabetes of either typemay develop a series of long-term complications.

( I ) Atherosclerosis causes strokes, myocardial infarcts, and gangrene, frequently ofthe toes.

(2) Nephropathy causes proteinuria, hypertension, and edema, and it may lead torenal failure.

(3) In the Kimmelstiel-Wilson syndrome, intercapillary glomerulosclerosis withhypertension and edema lead to proteinuria, beginning approximately 20 yearsafter the onset of disease.

(4) There is a predisposition to infections (tuberculosis, pyelonephritis, pneumonia,skin infections).

(5) Neuropathy is usually a distal, symmetric polyneuropathy ("stocking-glove" dis-tribution) but may be a mononeuropathy. In addition to this peripheral neu-ropathy, diabetics can also have autonomic neuropathy.

(6) Retinopathy may lead to blindness.

Pathology is characterized by a thickening of basement membranes by homogeneous orlaminated periodic acid-Schiff (PAS)-positive hyaline. Microangiopathy occurs withthickening of capillary basement membranes, causing increased leakage of plasmaproteins.

a. In the pancreas, visible abnormalities may or may not be present. They may include:

( 1) Decrease in number and size of islets

(2) Islet-cell hyperplasia early in IDDM

(3) Lymphocytic infiltrate of islets

Clinical Correlate

Diabetics are also a high-riskgroup for the followinginfections:

. Klebsiello pneumonia

. Sinus mucormycosis

. Malignant otitis externa(Pseu donon os oerug inoso)

. Chronic osteomyelitis

4.

278

Pathology

(a) Hyalinization of islets

(5) Glycogen accumulation and degranulation of B cells

b. Atherosclerosis begins within 5 years of onset, regardless of age. Widespread lesionsare prone to calcification, ulceration, and overlying thrombosis, and lead to ischemia( stroke, myocardial infarction) or aneurysms.

c. Arteriolosclerosis is characteized by a severe thickening of arteriole walls in everytissue, frequently by hyaline material.

d. Kidneys show severe involvement, leading to renal failure. Pathologic findings arecharacterizedby arteriolosclerosis, glomerular pathology (diffrrse glomerulosclerosis,nodular glomerulosclerosis, exudative lesions), and bacterial infection (pyelonephri-tis, papillitis).

e. Peripheral neuropathy, the most common defect, affects both motor and sensorynerves as a result of damage to Schwann cells and myelin, mainly in the lower extrem-ities. It is often associated with autonomic neuropathy, causing bladder and boweldysfunction, gastric atony, impotence, cardiac arrhythmias, and, possibly, suddendeath.

f. Retinopathy is related to duration of disease. Diabetic retinopathy is the fourth lead-ing cause of blindness.

(1) Nonproliferative retinopathy is characterizedby microaneurysms, with leakageresulting in exudates, edema, and hemorrhage; such a finding is diagnostic ofdiabetes. Hard protein exudates are seen in deep retinal layers, and "cotton wool"spots appear due to microinfarcts in the superficial retina.

(2) Proliferative retinopathy is characterized by neovascularization. It may causetraction bands resulting in retinal detachment and vitreous hemorrhage.

g. Diabeticxanthomas are yellow nodules on the elbows and knees resulting from lipid-filled macrophages in the dermis.

5. Prognosis

a. NIDDM decreases life span by approximately 8 years. There is a much higher mortal-ity from IDDM.

b. Causes of death in decreasing frequency are:

(1) Myocardial infarction

(2) Renal failure

(3) Stroke

(4) Ischemic heart disease

(5) Infections

B. Islet-cell tumors (Figure III-4-3)

1. B-cell tumors. Insulinomas most commonly occur between the ages of 30 and 60.

a. Pathogenesis. B-cell tumors produce hlperinsulinemia, causing hypoglycemia.

b. Clinical features. Patients experience episodes of altered sensorium (i.e., disorientation,dizziness, diaphoresis, nausea, tremulousness, coma) that are relieved by glucose intake.

279

Endocrine System

Bridge toGastrointestinal

Zollinger-Ellison syndrome isdiscussed in greater detail inthe Castrointestinal Pathologychapter of this book.

In a Nutshell

. MEN | + anterior pituitary,parathyroids, adrenal cortex,and pancreas

. MEN lla + adrenal medulla(pheochromorytoma) andparathyroids

. MEN lll -+ adrenal medulla(pheochromocytoma),thyroid (medullarycarcinoma), and mucosalneur0mas

c. Pathology. Most tumors are solitary, well-encapsulated, and well-differentiatedadenomas of various sizes. Ten percent are malignant carcinomas.

Figure lll-4-3. lslet-cell adenoma (microscopic).

2. Zollinger-Ellison syndrome is due to a gastrinoma and is often associated with MENtfpe I.

a. Pathogenesis. Tumors of pancreatic islet cells secrete gastrin, causing gastric hyper-secretion of acid.

b. Clinical features include intractable peptic ulcer disease and severe diarrhea.

c. Pathology. Sixty percent are malignant. Most tumors are located in the pancreas, with10olo in the duodenum.

MUTTTPTE ENDOCRTNE NEOPTASTA (MEN)Multiple endocrine neoplasia shows familial, autosomal dominant inheritance with incompletepenetrance. It is characterizedby benign and malignant tumors of the APUD (amine precursoruptake and decarborylation) cell system.

A. MEN I features tumors of the parathyroids, adrenal cortex, pituitary gland, and pancreas,and is associated with peptic ulcers and Zollinger-Ellison syndrome.

B. MEN IIa features tumors of the adrenal medulla (pheochromocFtoma), medullary carcino-ma of thyroid, and parathyroid hyperplasia or adenoma.

C. MEN III (also called MEN IIb) features medullary carcinoma of the thyroid, pheochromo-cftoma, and mucosal neuromas.

D. Clinical features show varied presentations that may include peptic ulcerations, hypo-glycemia, hyperparathyroidism, hypertension, and Cushing syndrome.

OVARY AND TESTISThe pathology of these endocrine organs is discussed in the Reproductive Pathology chapter inthis book.

280

Endocrine Pharmacology

Many synthetic and semisynthetic hormones and hormone antagonists are used for diagnosis andtreatment of endocrine and nonendocrine disorders. This chapter will discuss these importantendocrine drugs.

HYPOTHALAM I C-PITU ITARY HORMON ESThe hypothalamic-pituitary system is important for regulating the secretion of peripheral hor-mones, which control growth and development, metabolic function, and reproduction.

A. Hypothalamic hormones

1. Growth hormone-releasing hormone (GHRH) stimulates somatotrophs in the anteriorpituitary to secrete growth hormone.

a. Indications for use. GHRH is available for diagnosis and therapeutic use in patientswith growth hormone deficienry and is effective in specific types of dwarfism.

b. Side effects and toxicity.It causes pain at the injection site.

2. Somatostatin (growth hormone release-inhibitinghormone, GHIH) is produced in thehypothalamus, in other areas of the central nervous system (CNS), pancreas, gastroin-testinal tract, and thyroid.

a. Physiologic effects

(1) Somatostatin reduces the secretion of growth hormone, gastrin, secretin, vaso-active intestinal peptide, cholecystokinin (CCK), glucagon, insulin, calcitonin,parathyroid hormone (PTH), renin, and thyroid-stimulating hormone (TSH).

(2) It acts through cell membrane receptors to reduce calcium influx into the cells.

b. Indications for use. Somatostatin's duration of action is too short to be clinicallyusefrrl. Octreotide, a synthetic somatostatin analog, is longer acting; given subcutan-eously, it controls excessive hormone secretion in acromegaly glucagonoma, andinsulinoma.

3. Thyrotropin-releasing hormone (TRH)

a. Physiologic effects. TRH increases the secretion of TSH (thyrotropin) and acts on cellmembrane receptors to increase the activity of adenylate ryclase.

b. Regulation of secretion. Secretion is regulated by levels of thyroid hormones in a neg-ative-feedback loop.

Note

Somatostatin, groMhhormone release-inhibitinghormone (CHIH), andsomatotropin release-inhibiting hormone (SRIH)are all names for thesame hormone.

Clinical Correlate

Octreotide is used clinically totreat ga$rointestinal bleedingand intractable diarrhea.

In a Nutshell

TRH stimulates the secretionof thyroid hormones byincreasing cyclic adenosinemonophosphate (cAMP).

281

Endocrine System

Note

Leuprolide can be used toinhibit FSH and LH release.

Bridge toNeruous System

See the Central NervousSy$em Pharmacology chapterof Organ Systems Book I

flolume lll) to review therole of bromocriptine inthe treatment of Parkinsondisease.

In a Nutshell

Oxytocin stimulates uterinecontractility to:

. lnduce labor

. Control postpartumbleeding

4. Corticotropin-releasing hormone (CRH)

a. Physiologic effects. CRH acts on the anterior pituitary to increase the secretion ofadrenocorticotropic hormone (ACTH). It binds to cell membrane receptors toincrease levels of cyclic adenosine monophosphate (cAMP). The release of ACTH iscalcium dependent. CRH also stimulates the release of B-endorphin.

b. Indications for use. A synthetic CRH is available for diagnostic studies of pituitaryfunction.

5. Gonadotropin-releasinghormone (GnRH or LH-RH) is produced in the arcuate nucle-us of the hypothalamus, which controls the release of follicle-stimulating hormone (FSH)and luteinizinghormone (LH).

a. GnRH (gonadorelin), when administered in a pulsatile manner (similar to endoge-nous secretion patterns), stimulates release of FSH and LH and is useful in the diag-nosis and treatment of hypogonadism.

b. Continuous dosing. When administered in continuous, steady doses, gonadotropinrelease is inhibited. Leuprolide and other GnRH analogs (i.e., nafarelin, goserelin,histrelin) are given in continuous doses to produce a chemical castration in adultswith prostate cancer, polyrystic ovary syndrome, uterine fibroids, and endometriosis.Leuprolide is given subcutaneously or intramuscularly. Patients usually worsen slight-ly before improving because hormone levels (e.g., testosterone) initially increase dur-ing the first week of therapy.

6. Prolactin-inhibiting hormone (PIH)

a. Physiologic and pharmacologic effects. Dopamine has been identified as a PIH. It isnot useful in the treatment of CNS abnormalities because of the peripheral side effectsand the failure of dopamine to cross the blood-brain barrier effectively. It is also notused to alter prolactin secretion.

b. Bromocriptine, a dopaminergic receptor agonist, is effective orally in the treatment ofhlperprolactinemia, to treat breast engorgement, to inhibit lactation in the postpartumperiod, and to treat infertility associated with excessive prolactin secretion.

B. Posterior pituitaryhormones

1. Oxytocin is synthesized in the paraventricular nuclei of the hypothalamus and is storedin the posterior pituitary.

a. Indications for use. Oxftocin stimulates uterine contractions and is used intra-venously to induce or maintain labor at term. It is also used by intramuscular admin-istration to control postpartum bleeding. It is available as a nasal spray to cause milksecretion by contracting smooth muscle in the myoepithelial cells of the mammarygland. Dinoprostone, a prostaglandin Ez (PGEz), is also used to induce labor.

b. Uterine relaxants used to inhibit premature labor include ritodrine and terbutaline,both p2-adrenoceptor agonists.

2. Antidiuretic hormone (ADH) is synthesized in the supraoptic and paraventricular nucleiof the hypothalamus and is stored in the posterior pituitary.

a. Physiologic effects

(1) ADH increases water permeability and, thus, reabsorption of water in the col-lecting ducts of the kidney. This antidiuretic effect is produced by the action atV2 receptors,leading to an increase in cAMP.

(2) At high doses, ADH also causes smooth muscle contraction by stimulation of V1receptors.

282

Pharmacology

b. Indications for use. The main use of ADH is in treatment of central diabetesinsipidus. DDAVP (also called desmopressin), an analog of vasopressin with no V1effects, is used clinically to treat diabetes insipidus. DDAVP is of no use in the treat-Inent of nephrogenic diabetes insipidus because of dysfunctional ADH receptors.

C. Anterior pituitary hormones

1. Growth hormone (somatotropin) is secreted by anterior pituitary cells (somatotrophs).

a. Regulation of secretion is by GH-RH and somatostatin.

b. Physiologic effects

(1) Growth hormone has metabolic and anabolic effects that are mediated bysomatomedins, peptides produced in the liver. It acts on specific cell membranereceptors to stimulate the release of the somatomedins.

( 2 ) Growt*:iilin ffi:. ffi ::,t', T#i:?i.:i-:*::::

( " anticatab olic " ) It

(3) Its anti-insulin action promotes hyperglycemia; hence, it is diabetogenic.

c. Pharmacokinetics. Growth hormone is given subcutaneously or intramuscularly andhas a half-life of 20-30 minutes. A peak increase in somatomedins occurs in24 hours.

d. Indications for use. It is used for replacement therapy in children with deficienry ofgrowth hormone and for anabolic effects in burn victims.

e. Side effects and toxicity. Adverse reactions include gigantism in children, acromegalyin adults, and diabetes-like symptoms.

f. Bromocriptine, a dopaminergic receptor agonist, has been used as an adjunct tooctreotide to lower plasma levels of growth hormone in acromegaly. Adverse reactionsinclude nausea and vomiting, arrhythmias, hypotension, and paranoia/psychosis.

2. Prolactin

a. Regulation of secretion. The secretion of prolactin is inhibited by dopamine; TRHstimulates secretion. Drugs that increase prolactin secretion include antipsychotics(e.g., chlorpromazine, haloperidol) and catecholamine depletors (e.g., guanethedine).

b. Physiologic effects. Prolactin promotes milk production in the postpartum breast.High levels of prolactin inhibit the release of gonadotropin, thus inhibiting ovulation.

c. Bromocriptine suppresses prolactin secretion by stimulating dopaminergic recep-tors. It is used to treat women with hyperprolactinemia-induced amenorrhea or galac-torrhea. It is also used to treat pituitary adenomas that secrete prolactin.

3. Gonadotropic hormones. Secretion of estrogens, progesterone, and testosterone areunder control of the pituitary gonadotropins, FSH and LH, which are regulated by GnRHfrom the hypothalamus. GnRH, FSH, and LH are also under negative feedback control ofthe gonadal hormones.

a- Follicle-stimulatinghormone (FSH) is a glycoprotein hormone produced and secret-ed by gonadotropic cells of the anterior pituitary. Secretion is regulated by the con-centrations of reproductive hormones. It acts via the second messenger cAMP.

(1) In women, FSH causes maturation of the ovarian follicle; plasma levels increaseduring the follicular phase of the menstrual cycle, decrease slowly, and thenincrease at midcycle; the lowest levels occur during the luteal phase. Togetherwith LH, it causes final maturation of the corpus luteum.

Clinical Correlate

DDAVP is also useful intreating or preventingbleeding complications. ltpromotes the release of vonWillebrand factor byendothelial cells.

In a Nubhell

Bromocriptine, adopaminergic receptoragonisl has been used to:

. Lower serum CH levels

. Lower serum PRL levels

. Inhibit lactation

Adverse reactions includenausea, vomiting, arrhythmias,hypotension, and paranoia.

In a Nubhell

In females, FSH causesgranulosa cells to synthesizeestrogen and causes folliclesto mature. ln males, FSHcauses spermatogenesis.

(2) In men, FSH promotes spermatogenesis.

28t

Endocrine System

In a Nutshell

. In females, the LH surgetriggers ovulation and LHstimulates the corpusluteum to produceprogesterone.

. In males, LH stimulatestestosterone synthesis byLeydig cells.

Note

hCC is secreted by theplacenta, and its presence isdiagnostic of pregnanoT.

Flashback to Pathology

ACIH can distinguish primaryfrom secondary adrenalinsufficiency. Failure to respondto exogenous AC|H indicatesthat the adrenals themselveshave failed (primary).

b. Luteinizing hormone (LH) is a glycoprotein hormone similar in structure to FSH. It issecreted by gonadotrophic cells of the anterior pituitary. It acts through cAMP; LH actionon the ovary may also be associated with increased inositol 1,4,5-triphosphate (IP3).

(1) In women, LH levels peak at midrycle to induce ovulation and the initial for-mation of the corpus luteum. This pulse is induced by the positive feedback ofestradiol.

(2) In men, LH activates interstitial cells to secrete testosterone.

c. Human chorionic gonadotropin (hCG) is a glycoprotein hormone secreted bysyncytiotrophoblasts of the fetal placenta. It promotes growth of the corpus luteumand prevents menstruation. It is used as a pregnancytest, detectable by immunoassayin urine or blood before the first missed menstrual period.

d. Specific agents related to the gonadotropins. Menotropins are a mixture of partiallydegraded FSH and LH given to infertile women to induce maturation of the follicle. It isusually followed by HCG to induce ovulation. Adverse reactions are due to overstimula-tion of the ovaries, producing multiple pregnancies, enlargement of the ovaries, and ovar-ian rysts. In infertile men, menotropins are given after HCG therapy to induce sper-matogenesis.

4. Thyroid-stimulating hormone (TSH) is a peptide that binds to cell membrane receptorson the thyroid gland to increase iodide uptake and the synthesis and secretion of thyroidhormones. Its secretion is enhanced by TRH and is reduced by negative feedback ofthyroxine (Ta) and triiodothyronine (T3).

a. Physiologic effects. Activation of the TSH receptor produces an increase in cAMRdiacylglycerol, IP3, and intracellular calcium.

b. Indications for use. TSH is available for diagnosis of thyroid function and to increasethe uptake of iodine 131 (13lI) in certain cases of thyroid carcinoma.

5. Adrenocorticotropic hormone (ACTH, corticotropin) is synthesized and secreted by theanterior pituitary. Its secretion is stimulated by CRH and is reduced by negative feedbackcontrol of corticosteroids.

a. Physiologic effects. ACTH stimulates the human adrenal cortex to secrete cortisoland, to a lesser extent, aldosterone and androgens. ACTH binds to cell membranereceptors to stimulate adenylate cyclase, leading to an increase in activity of cholesterolesterase, which catalyzes the rate-limiting step in steroid hormone synthesis. It alsoincreases the cytochrome P-450 enryme system responsible for the production ofpregnenolone. ACTH acts as a growth factor to the adrenal cortex.

b. Indications for use. Uses of ACTH include the diagnosis of primary adrenal insuffi-ciency, therapy of secondary adrenal insufficiency, and nonendocrine illnesses, such asmultiple sclerosis. Cosyntropin, an active synthetic analog, is less antigenic and is pre-ferred for the diagnosis of adrenal function.

THYROID AND ANTITHYROID DRUGSThe thyroid gland secretes three hormones: calcitonin, which is important in calcium home-ostasis; and triiodothyronine (Tr) and thyroxine (Ta), which are important in growth andgeneral metabolic function.

284

Pharmacology

A. Thyroid drugs. Tn and T, are iodine-containing hormones that are analogs of tyrosine.

1. Regulation of thyroid function. Thyroid function is regulated by TSH, which increasesboth the synthesis and secretion of these hormones. TSH secretion is regulated by nega-tive feedback of the thyroid hormones; it is positively influenced by TRH from thehlpothalamus.

2. Thyroid hormone synthesis

a. Iodide is necessary for thyroid hormone synthesis. Iodide is obtained from the diet(e.g., seafood) and is absorbed from the gastrointestinal tract. It is taken up by the thy-roid gland by an active cotransport process involving potassium.

b. Once in the gl*d, iodide is oxidized via peroxidase to an active iodine intermediate,which iodinates tyrosine residues of thyroglobulin (a glycoprotein). An aerobic conden-sation of iodinated tyrosine molecules results in production of T, and Tn. Subsequently,proteolysis of thyroglobutin causes release of thyroid hormones into the blood.

3. Kinetic properties. Over 99o/o of T, and T, are bound to plasma proteins, most to thy-roid-binding globulin. The hormones are deiodinated and conjugated in the liver to formsulfates and glucuronides. They are excreted in the bile and urine. Tn has a half-life of 6-7days; T, has a half-life of I-2 days. Some of the circulating Tn is deiodinated to T' themore potent and rapidly acting form.

4. Mechanism of action. Most of the effects of thyroid hormones stem from activation ofnuclear nonhistone protein receptors attached to DNA. Binding of hormone to thereceptor leads to increased transcription of messenger RNA (mRNA), thus increasing thesynthesis of specific proteins. T, is ten times more potent for binding to the nuclearreceptor. The hormone may also bind to receptors on cell membranes to increase aminoacid and glucose uptake and to receptors on the inner mitochondrial membrane to reg-ulate energy metabolism.

5. Physiologic effects. Thyroid hormones produce effects in most major systems, includingnormal growth and development, increased basal metabolic rate, and activation of oxy-gen consumption. The hormones have a thermogenic effect (increased heat production),they cause increased plasma glucose and free fatty acids, and cause a reduction in plasmacholesterol and triglycerides. Increased cardiovascular activity, increased heart rate, andmaturation of the CNS are also effected by thyroid hormones.

6. Specific agents used in the treatment of hypothyroidism. Thyromimetic agents, fromanimal or synthetic sources, are indicated as replacement therapy for the treatment ofhypothyroidism and to suppress TSH secretion. The levo isomers are more potent inincreasing basal metabolic rate. They are all available orally; levothyroxine is also avail-able by injection. Once absorbed, their pharmacokinetic and dynamic properties areidentical to endogenous thyroid hormones. Adverse reactions include hyperthyroidism(or symptoms of hyperthyroidism), cardiovascular toxicity (tachyarrhythmias, angina,and infarction are possible), CNS stimulation, and insomnia.

a. Levothyroxine sodium is the synthetic levo isomer of T4. It is available for oral orintravenous administration. It is the preferred drug for treatment of hypothyroidismas a result of better standardization and stability and long duration. The long half-lifeof Tn greatly facilitates maintenance of a steady physiologic replacement of thyroidhormone.

b. Liothyronine sodium is synthetic r-triiodothyronine. It is more difficult to monitorthan Tn, is more expensive, and has a shorter duration of action.

c. Liotrix is a combination of levothyroxine and liothyronine (at a ratio of 4:1). It has noadvantage over levothyroxine.


Refer back to Figure lll-3-7to review thyroid hormonebiosynthesis.


. T, is much morepotent than To.

. T, has a shorterhalf-life than To.

. T, is bound less toTBC than To.

285

Endocrine System

Note

Both methimazole and PTUinhibit incorporation of iodineinto thyroid hormoneprecursors. However, onlyPTU inhibits the peripheralconversion of To + Tr.

Clinical Conelate

PTU is preferred tomethimazole in pregnancybecause it is more extensivelyprotein-bound (80 versus 8o/ofor methimazole) and lesslikely to cross the placenta.

Note

Radioactive iodine is veryeffective in treatment ofhyperthyroidism because theiodine in selectively taken upby the gland's follicular cells.

B. Antithyroid drugs inhibit the formation of thyroid hormones and are used in the treatmentof hyperthyroidism.

1. Iodine. Although small amounts of iodine (75-100 pglday) are required for hormonesynthesis, high concentrations ( 50+ mg/day) produce autoinhibition.

a. Pharmacologic properties. Iodine blocks the uptake of iodide by the thyroid, inhibitingsynthesis and release of thyroid hormones. It also diminishes vascularity of the gl*d.

b. Indications for use.Iodine is used only preoperatively to shrink the gland in prepara-tion for surgical removal of the thyroid gland, and in the treatment of thyroid storm.It is given as Lugol solution (iodine and potassium iodide). Effects are visible within24 hours. It is no longer used in long-term therapy.

c. Side effects and toxicity. Adverse reactions include hypersensitivity and dose-relatedeffects, such as "head cold" symptoms, gastric irritation, and parotitis. Long-term usecan lead to sudden disinhibition of hormone synthesis, producing acute hyper-thyroidism.

2. Thioamides: propylthiouracil (PTU) and methimaz,ole

a. Mechanism of action. These drugs inhibit the peroxidase enzymes catalyzing theoxidation of iodide and the coupling of iodinated tyrosyl groups, thus reducing thesynthesis of thyroid hormones. PTU also inhibits the peripheral deiodination of Ta toT3. There is a delay in onset of clinical effectiveness until preformed hormones havebeen metabolized.

b. Indications for use. These drugs are used for control of hyperthyroidism untilsurgery, in the suppression of thyroid hormone synthesis until the effect of radio-active iodide begins, and in the long-term therapy of mild-to-moderate hyper-thyroidism. The drugs are given orally.

c. Side effects and toxicit''. Most common adverse reactions include mild maculopapu-lar rash, joint pain, headache, nausea, and loss of hair. Although extremely rare, themost serious side effect is agranulocytosis. The drugs cross the placenta and enterbreast milk, which can lead to hypothyroidism in the fetus and nursing infant.

3. Radioactive iodine (t3t1,

a. Pharmacologic properties. Given orally or intravenously, l3l1 ir rapidly taken up bythe thyroid gland, where it is incorporated into thyroglobulin. With proper doses,131I leads to partial or total destruction of the gland by emission of beta particles.Damage to surrounding tissue is minimal.

b. Indications for use. 131I is used in the treatment of hyperthyroidism.

c. Side effects and toxicity. The major adverse reaction due to overdosage is a delayedincidence of hypothyroidism. 1311 r6on1d be avoided during pregnancy.

4. Propranolol and other p-adrenergic receptor blockers are used as adjuncts in the treatmentof hyperthyroidism. They reduce the symptoms of the disease (e.g., tachycardia, anxiety)until the antithyroid drugs can take effect. Propranol also inhibits the peripheral conversionof Ta to T3 via 5'deiodinase.

286

Pharmacology

DRUGS A1TERING CALCIUM HOMEOSTASISA. Calcium


a. Calcium concentration in blood is maintained within narrow limits. Calcium exists inthree forms: 50o/o ionized, 40o/o bound to protein (especially to albumin), and 10o/ocomplexed to anions. Approximately l0-20o/o of. daily intake is absorbed from theproximal intestine, with an equal amount excreted by the kidney. Calcium levels areregulated by calcitonin, PTH, and vitamin D (Table III-5-1).

Thble III-5-1. Effect of calcitonin, parathyroid hormone (PTH), and vitamin Don calcium homeostasis.

Intestinal RenalAbsorption Excretionof Calcium of Calcium Bone

Effect onPlasmaCalcium

Calcitonin J Postprandial t

PTH t Indirect due to Jincrease in 1,25-(oH)2D3

Vitamin D t I (minor) t Mineralization tt Resorption

b. Calcium is vital for many cellular functions, including:

( 1) Development of bone and teeth

(2) Control of enzyme activity

(3) Blood coagulation

(4) Excitability of nerve and muscle, including cardiac muscle

(5) Excitation-contraction coupling

(6) Tiansmembrane signaling/neurotransmitter release

(7) Cardiovascular function

2. Specific agents

a. Calcium chloride contains 25o/o calcium. It is given slowly. High concentrations cancause syncope with vasodilatation and hypotension. Because of the salt, it is not thedrug of choice in renal insufficienry.

b. Calcium gluconate, containing 9o/o calcium, is available for oral or intravenousadministration. It is used for severe tetany. It is also usefrrl for treating severe hyper-kalemia.

c. Calcium carbonate, calcium lactate, and tricalcium phosphate are all used in thetreatment of hypocalcemia and in the prevention and treatment of osteoporosis.

t Mineralization JJ Resorption

l Resorption 1

287

Endocrine System

ln a Nutshell

Calcitonin. Lowers serum calcium

. lnhibits bone resorption byosteoclasts

. Blocks Ca2* and phosphaterelease from bone

B. Phosphate

1. Physiologic effects. Phosphate helps maintain acid-base equilibrium, buffers and allowsfor renal H+ excretion, helps regulate calcium metabolism, and is an active intermediateof energy metabolism. Approximately 670/o of an oral dose is absorbed from the intestine.Excretion is via the kidney.

2. Indications for use. Various preparations of sodium phosphate are available for a cathar-tic action and in the treatment of hypercalcemia and hypophosphatemia.

3. Side effects and toxicity. The major adverse reaction of intravenous infusion for the treat-ment of hypercalcemia is metastatic calcification of soft tissues.

C. Parathyroid hormone (PTH) is synthesized by the parathyroid gland as a preprohormone.

1. Regulation of secretion. Secretion is regulated by Ca2+ concentration in the blood; lowfree Ca2+ stimulates an increase in PTH secretion.

2. Mechanism of action involves the binding to cell membrane receptors, leading toincreased cAMP. PTH increases Ca2+ concentration bv:

a. Increasing calcium resorption from bone

b. Enhancing renal tubular reabsorption of calcium

c. Indirectly increasing gastrointestinal absorption of calcium by enhancing the produc-tion of the active form of vitamin D 1,25(OH),D?


a. PTH is a peptide and, thus, must be given parenterally.

b. Human PTH is not used clinically because administration of vitamin D and calciumto raise calcium concentration is safer. A synthetic human hormone is used diagnos-tically to distinguish between hypoparathyroidism and pseudohypoparathyroidism.Patients with pseudohypoparathyroidism do not respond to the synthetic hormone.

D. Calcitonin is secreted by the parafollicular (C cells) of the thyroid gland. High blood calciumlevels reduce the secretion of calcitonin.

1. Physiologic effects. In general, calcitonin has opposite effects of PTH: it decreases theconcentration of serum calcium, inhibits bone resorption, and increases renal calciumexcretion. Although it has no major effect on the gastrointestinal tract, it may inhibit post-prandial calcium absorption.

2. Indications for use include hypercalcemia, hyperparathyroidism, vitamin D toxicity,Paget disease (to reduce bone turnover), bone tumors, and osteoporosis. Human andsalmon preparations are available.

3. Side effects andtoxicity. Adverse reactions include hypersensitivity reaction and hypocal-cemia.

E. Vitamin D

1. Synthesis. Vitamh D, (cholecalciferol) is produced in skin from 7-dehydrocholesteroland requires the presence of ultraviolet light. In the liver, vitamin D, is hydroxylated to25-hydroxy-D, (calcifediol), which is converted in the kidney to 1,25(OH)rD, (calcitriol),the most active form of the vitamin. PTH increases the activity of the hydroxylase enzymeresponsible for the final step.

2. Mechanism of action. Calcitriol acts by binding to nuclear receptors to alter gene expres-sion and initiate protein synthesis.

288

Pharmacology

3. Physiologic effects. Vitamin D stimulates intestinal absorption of calcium and phos-

phate, increases bone resorption and mineralization, and increases renal reabsorption of

calcium and phosphate. The net effect is to increase plasma calcium and phosphate.

4. Indications for use include hypocalcemia due to rickets, hypoparathyroidism, and osteo-

malacia.

5. Side effects and toxicity. The major adverse reaction is hypercalcemia.

6. Specific agents. Preparations available orally include: calcitriol, calcifediol, cholecalcif-

erol, dihydrotachysterol (vitamin D2 analog), and ergocalciferol (vitamin Dz). The

choice of agent depends on the cause of the disorder.

F. Other agents

1. Glucocorticoids reduce calcium absorption from the gastrointestinal tract and increase

renal calcium excretion. They are used in the treatment of hypercalcemia.

2. Diphosphonates (etidronate disodium, pamidronate disodium) are analogs of

pyrophosphate used in the treatment of hypercalcemia of malignancy, Paget disease,

osteoporosis, and hyperparathyroidism. They bind to hydroxyapatite crystals, reducing

their formation, growth, and dissolution, thereby reducing bone turnover.

3. Plicamycin (mithramycin) is a cytotoxic antibiotic that inhibits osteoclast function and

bone resorption by inhibiting DNA-directed RNA synthesis, thereby reducing plasma

calcium. It is used to treat Paget disease and hypercalcemia secondary to malignancy.

4. Fluoride stimulates bone formation when administered with calcium. It is accumulated

by bones and teeth and stabilizes the hydroxyapatite complex. Fluoride is substituted for

the hydroxyl group. It is used in the treatment of osteoporosis. Adverse reactions due to

the ability of fluoride to bind calcium include nausea, vomiting, arthralgias, and arthritis.

Extreme overdose can cause cardiovascular collapse or respiratory failure by inducing

hypocalcemia.

5. Estrogens inhibit bone resorption and are used in the treatment of postmenopausal

osteoporosis. The pharmacology of estrogen is described in the Reproductive

Pharmacology chapter of this book.

CORTICOSTEROIDS AND THEIR ANTAGON ISTSThe term corticosteroids designates steroid hormones normally secreted by the adrenal cortex;

these include glucocorticoids (cortisol), mineralocorticoids (aldosterone), and androgens( dihydroepiandrosterone, DHEA).

A. Glucocorticoids are natural and synthetic steroids that alter glucose metabolism.

1. Regulation of secretion. Cortisol is the principal naturally occurring hormone in

humans, which is synthesized in the zona fasciculata. Plasma concentrations are highest

between 6-8 e.v. Synthesis and release are stimulated by ACTH, via a negative feedback

mechanism.

2. Mechanism of action. Glucocorticoids enter target cells by simple diffrrsion and bind to

cytosolic receptors. The steroid-receptor complex is translocated into the nucleus, where

it regulates the synthesis of specific proteins.


a. Glucocorticoids influence carbohydrate and fat metabolism to ensure adequate deliv-

ery of glucose to the brain: they increase gluconeogenesis, decrease peripheral use of

glucose, and increase free fatty acids (increased lipolysis).

ln a Nutshell

Diphosphonates inhibit boneturnover (major store ofcalcium), decreasing serumcalcium levels.

Note

Fluoride substitution forhydroxyl groups inhydroxyapatite makes thisbone and tooth mineralresistant to degradation.

Clinical Correlate

Estrogen replacement is thefavored preventive therapy forosteoporosis. Calciumsupplements often given incombination with vitamin Dfurther reduce the fracture riskdue to bone loss.

Flashback to Histology

Adrenal cortexoutside

I zonu glomerulosa

| -+ aldosterone (salt)

II Zona fasciculata -+

I glu.ocorticoids (sugar)II Zona reticularis

V --+ androgens (sex)

inside

289

Endocrine System

ln a Nutshell

Clucocorticoid effects include:

. Anti-inflammatory actions

. t Serum glucose (enhancegluconeogenesis)

. Protein catabolism

. lmmune suppression

Note

Cortisone and cortisol havesome mineralocorticoidactivity, but much less thanaldosterone. Prednisone isactivated by the liver toprednisolone. Beclomethasoneis a long-acting, potentglucocorticoid.

b. They decrease absorption of calcium from the intestine and increase renal excretion ofcalcium.

c. Glucocorticoids produce redistribution of fat from the extremities to the trunk andface (buffalo neck).

d. Glucocorticoids favor protein breakdown and help mobilize amino acids to the liverfor gluconeogenesis.

e. Glucocorticoids have anti-inflamnatory and immunosuppressant activity. Theyincrease circulating levels of neutrophils by interfering with adhesion, and they decreaseeosinophils,lymphocytes, and monocytes. They decrease local edema, fibrin deposition,capillary dilatation, leukocyte migration, and phagocytic activity. Glucocorticoidsindirectly inhibit phospholipase Ar-mediated arachidonic acid release by increasingthe synthesis of lipocortins. The end result is decreased production of prostaglandins,thromboxanes, and leukotrienes.

f. Glucocorticoids may also alter mood, sleep patterns, and EEG activity.

4. Specific agents. Preparations are available for oral, topical, and injectable routes ofadministration. A comparison of clinically useful corticosteroids is presented in TabletII-s-2.

?able lll- 5 -2. Commonly used corticosteroids.

Corticosteroids Biologic Half-Life

GlucocorticoidsShort-acting

Hydrocortisone (cortisol)Cortisone

Intermediate-actingPrednisonePrednisoloneMethylprednisoloneTriamcinolone

Long-actingDexamethasone

MineralocorticoidFludrocortisone

Available as aerosolfor treatment ofbronchial asthma

BeclomethasoneFlunisolide

5. Indications for use. In general, drugs with mixed glucocorticoid and mineralocorticoidactivity (e.g., cortisol) are used in replacement therapy. Intermediate-acting drugs withminimal mineralocorticoid effect (e.g., prednisone, prednisolone) are used as anti-inflammatory and immunosuppressant agents when long-term therapy is needed. Dosesare gradually reduced when the patient is to be taken off the drug. Long-acting, potentsteroids (e.g., dexamethasone) are used mostly for acute, severe conditions. Therapeuticuses of corticosteroids include:

a. Replacement therapy for adrenal insufficiency

8-12 hours

18-36 hours

36-54 hours

290

Pharmacology

b. Treatment for:

(1) Allergic disorders such as anaphylactic reactions and status asthmaticus

(2) Collagen vascular disorders and other autoimmune conditions, including sys-

temic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis,

dermatomyositis, polyarteritis nodosa, polymyalgia rheumatica, myasthenia

gravis, multiple sclerosis, and temporal arteritis

(3) Hematologic disorders, including immunologically mediated aplastic anemia,

thrombocytopenic purpura, acute lymphoblastic leukemia, chronic lymphocytic

leukemia, Hodgkin disease, and multiple myeloma

(4) Cerebral edema

(5) Dermatologic disease

(6) Gastrointestinal disorders, such as inflammatory bowel disease

(7) Hypercalcemia

(8) Renal disease, including nephrotic syndrome, membranous nephropathy, and

focal sclerosis

(9) Respiratory disorders, such as sarcoidosis, chronic obstructive pulmonary disease(COPD), hypersensitivity reactions, pneumonitis, and idiopathic pulmonary

fibrosis

c. Diagnosis of Cushing disease (dexamethasone suppression test)

d. Cancer chemotherapy

6. Side effects and toxicity. Adverse reactions depend upon the route of administration(topical versus systemic), dose, and duration of therapy.

a. Metabolic disorders, such as hyperglycemia, glycosuria, negative nitrogen balance,

fat redistribution, and mineralocorticoid effects (sodium and water retention,

hypokalemia, metabolic alkalosis)

b. Hypertension (from sodium and water retention and increased plasma renin)

c. Endocrine disorders, such as suppression of hypothalamic-pituitary-adrenal axis (lead-

ing to adrenal insufficiency), atrophy of adrenal cortex (from which it may take a year to

fully recover), growth retardation in children, and secondary amenorrhea

d. Dermatologic disorders, such as hirsutism, skin thickening, poor wound healing, acne,

and purpura

e. Ocular disorders, such as cataracts (from hyperglycemia) and glaucoma (from salt and

water retention)

f. Gastrointestinal disorders, such as peptic ulceration, pancreatitis, and perforation of

colonic diverticula

g. Musculoskeletal disorders, such as myopathy, osteoporosis, and aseptic necrosis(osteonecrosis)

h. CNS reactions, including psychiatric symptoms (elation, mania, psychosis) and pseu-

dotumor cerebri (benign intracranial hypertension)

i. Increased susceptibility to infection

ln a Nubhell

Side Effects of Cofticosteroids. Hyperglycemia

. Hypertension

. Easy bruising

. Cataracts

. Osteoporosis

. Myopathy

. Dysphoria/psychosis

. Cushingoid habitus

291

Endocrine System

In a Nutshell

Adverse effects of chronic useof syste m i c gl ucocorticoidsstem from:. Suppression and atrophy of

pituitary corticotrophs andadrenal fasciculata andreticularis zones

. Symptoms associated withexcess glucocorticoidsystemic effects

These adverse effects can beminimized by: /) Usingtopical applications, notsystemic, whenever possible;2) lf systemic use is required:. Use a short (<2 weeks)

high-dose course ratherthan a longer low-dosec0urse

. Cive the highest amount ofglucocorticoids in the n.rr,r.

. Cive the glucocorticoids onalternate days, if possible

. Groduolly increase anddecrease the daily dosesduring the course, allowingthe adrenal axis time tocompensate

Clinical Correlate

. Exogerrous injected insulindoes not contain the C-peptide. Endogenousinsulin contains cosecretedC-peptide.

. C-peptide measurementsare used to determine ifhypoglycemia is due tosurreptitious insulinadministration (no elevationof C-peptide) orendogenous insul in(elevation of C-peptide).

292

B. Corticosteroid antagonists

1. Ketoconazole, an antifungal agent, inhibits steroid synthesis by the adrenal cortex andtestes. It is available for treatment of Cushing disease and prostate cancer.

2. Spironolactone is an aldosterone receptor antagonist used in the treatment of hyperal-dosteronism. Its uses as a diuretic are discussed in the Renal Pharmacology chapter ofOrgan Systems Book 1 (Volume III).

C. Mineralocorticoids promote sodium reabsorption and potassium excretion in the distal tubules.

1. Aldosterone is the most important natural mineralocorticoid, synthesized in the zonaglomerulosa of the adrenal cortex. Production and release are controlled by the renin-angiotensin system and plasma potassium; its secretion is also transiently increased byACTH. Aldosterone is not available for therapeutic use.

2. Fludrocortisone, a synthetic steroid analog, has strong mineralocorticoid and relativelymild glucocorticoid effect. It is available for oral or parenteral administration and is usedin conjunction with cortisol in the treatment of adrenal insufficiency.

PANCREATIC HORMONES AND ORAI HYPOGLYCEMIC AGENTSA. Insulin is a protein hormone, manufactured in the beta cells of the pancreas. It contains two

polypeptide chains linked by disulfide bonds.

1. Regulation of secretion

a. Insulin is synthesized as a prohormone in a single polypeptide chain. Proinsulin iscleaved to insulin. C peptide, a blproduct of cleavage, has no known physiologic func-tion. Insulin is secreted at a low basal rate of 5-15 pU/ml plasma and a high stimulatedrate of 60-90 FU/ml.

b. Synthesis and secretion are stimulated by food products (particularly glucose), gastroin-testinal hormones'(e.g., CCK, gastrointestinal glucagon), and neurotransmitter analogs(e.9., pz-adrenergic agonists and muscarinic agonists). Secretion is inhibited by o2-adrenergic agonists.

c. Glucose is taken up by pancreatic cells and metabolized, increasing production of ATP,which leads to blockade of potassium efflux. This causes depolarization, calciuminflux, and release of insulin.

2. Mechanism of action

a. Insulin acts by binding to specific receptors on the cell membrane. The receptor is aheterotetrameric membrane protein, containing two alpha and two beta subunits,linked by disulfide bonds. Insulin binds to the alpha subunits. The beta subunits spanthe membrane and contain tyrosine kinase activity. The binding of insulin causesautophosphorylation and begins a cascade activating protein kinases and phos-phatases. Some target enzymes are activated, while others are inhibited.

b. Insulin also promotes the translocation of glucose transporter proteins (e.g., GLUT 4in skeletal muscle) from intracellular pools to the plasma membrane.

c. The insulin receptor complex is then internalized.


a. Anabolic effects on liver include increased synthesis of proteins and lipids, decreasedketogenesis, increased glycogen synthesis, decreased gluconeogenesis, and decreasedglycogenolysis, decreased fat oxidation.

Pharmacology

b. Anabolic effects on adipose tissue include increased glucose and potassium uPtake, Noteincreased uptake of ftee fatty acids, incr€ased storag€ of triglycerides, and decreasedlipolysis. Insulin signals a'fed state":

c. Effects on skeletal muscle include increased uptake of glucose, potassium, and amino . Increases glucose useacids' . Enhances Drotein svnthesis

d. Insulin deffciency leads to hyperglycemia, glycosuria, tissue wasting, hyperlipemia,polpria, pruritus, vur.ut* .o-plii"tlons, pe'ripheral neuroputttn

"ttal in ."u"r" .ur"r,

' lncreases glycogen

ketoacidosis. Shortened life exPectancy is due to rnyocardial infarction, stroke, and synness

renal and vascular disease. . Enhances K* uotake

4. Specific agents. There are several insulin preparations available from bovine, porcine, and into cellshuman (recombinant DNA) souc€s. lnsulin is prepared either with protamine in phos- . lnrrpa<F< rir <rnraspphate buffer or various zinc concentralions in acetate buffer to provide differenl timecourses of action (see Table III-5-3).


a. Insulin preparations are used in the control of insulin-dePendent, or type 1, diabetesmellitus (IDDM) and noninsulin-dependent, or q'pe 2, diabetes mellitus (NIDDM).

b. Intravenous insulin is used in the tr€atment of diabetic ketoacidosis or hyperosmolarhyperglyc€mic nonketotic coma.

Table III-5-3, Insulin preparations

Preparation* Onset Time to Peak Duration

Regular crystalline 0.25-1 hour L-3 hours 5-7 hourszinc insulin

Lispro 0.25-0.5 hour 1-2 hours 3-4 hours

NPH insulin and 1-2 hours 8-10 hours 18-24 hoursknte insulin zincsuspensron

Extended insulin 2-4 hours 8-16 hours 24-36 hourszinc suspension( ultralente)

*All preparations are given subcutaneous administration. Regular and Lispro iruulin can alsobe given by intravenous administration (in emergencies) and used in an insulin pump.

6. Sid€ effects and toxicity Cliniol Correlate

a. Hypoglycenia with s)'mptoms ranging from hunger, sweatinS, and tachycardia to B-blocken blunttheconfusion, coma, and conrrlsions can occur. symPtoms of hYPoglYcemia,

b. Hypers€nsitivity with local reactions (more common with animal sources) may occur; particularly the tachycardia,anaphylaxis is rare. and are therefore to be used

c. Lipodystrophy may occur at the site ofinjection. cautlously in diabetics'

B. Oral hypoglycemic agents (tolbutamide, clrlorpropamide' glyburide, gliPizide)

1. Pharmacokin€tics. The sulfonylureas are all effective following oral administration. Theyvary in the rate and extent of metabolism ard time course of action: tolbutamide has theshortest duration of action, while chlorpropamide has the longest duration of action.

29t

Endocrine System

ln a Nutshell

Sulfonylureas enhanceinsulin secretion only in

Vpe 2 diabetes. 4.

C.

2. Pharmacologic properties. All oral hypoglycemic agents are sulfonylurea analogs, whichlower blood glucose by stimulating the pancreatic beta cells to secrete insulin. They bindto receptor sites near the potassium channel to reduce potassium efflux, thus causingdepolarization, which increases calcium influx, leading to insulin secretion. On chronicadministration, sulfonylureas also reduce serum glucagon and potentiate the effect of insulinon target tissues.

3. Indications for use. The sulfonylureas are used in the treatment of type 2 NIDDM.Because sulfonylureas enhance existing pancreatic ability to produce and secrete insulin,they are not usefi.rl in the treatment of type I IDDM.

Side effects and toxicity

a. Hypoglycemia is more likely with long-acting drugs (chlorpropamide) and high-potenry drugs (glyburide and glipizide).

b. Adverse reactions include skin rashes, gastrointestinal upset, and hypothyroidism.

c. A disulfiram-like reaction with ethanol (especially chlorpropamide) may occur.

Antihyperglycemic agents are another group of drugs used in the therapy of NIDDM. Asopposed to the more traditional oral hypoglycemic agents (sulfonylureas), these drugs donot enhance insulin release, rather they increase glucose utilization through biochemicalmechanisms. These drugs include metformin (a biguanide) and acarbose.

a. Acarbose inhibits o-glucosidase of the intestine brush border, preventing absorptionof glucose, thereby decreasing postprandial glucose and insulin requirement. Sideeffects are primarily gastrointestinal discomfort.

b. Thiazolidinediones: pioglitaz.one and rosiglitazone. These drugs bind to nuclearperoxisome proliferator-activating receptors (PPARS) involved in transcription ofinsulin-responsive genes. Overall, they increase the sensitivity of tissues to insulin.Side effects include weight gain and edema.

c. Metformin, euglycemic drug with poorly characterized mechanism of action. Mayincrease insulin sensitivity and decrease hepatic gluconeogenesis. Lactic acidosis canbe a side effect, but the agent does not cause hypoglycemia.

d. Repaglinide is a new generation of sulfonylurea-like drugs which stimulates insulinrelease from B cells of the pancreas.

D. Glucagon is a polypeptide hormone secreted by the alpha cells of the pancreas. It is aphysiologic antagonist to insulin, resulting in glycogenolysis, gluconeogenesis,lipolysis, andformation of ketone bodies. It stimulates the secretion of growth hormone, insulin, andpancreatic somatostatin. It acts by increasing activity of adenylate ryclase. Clinical usesinclude the treatment of severe hypoglycemia in diabetics and the decrease of intestinalmotility for x-ray studies.

294

sEcTloN lv

Reproductlve System

Reproductive Embryology

The genital system-consisting of gonads, ducts and their derivatives, and external genitalia-isderived from all three germ layers. Following an indifferent stage, the components of this systemdevelop into either the male or female phenotype. The sex of the embryo is genetically determinedby the presence or absence of the Y chromosome in the fertilizing sperm. However, embryonicgonads do not appear as male or female until the seventh week of development.

FORMATION OF GONADSPrimordial germ cells arise in the yolk sac early in development. When this part of the yolk sacis incorporated into the hindgut, the germ cells migrate by amoeboid movement along the dor-sal hindgut mesentery. By the sixth week, they lie beneath the coelomic epithelium medial to themesonephros. The germ cells induce proliferation of the overlying epithelium, and the result-ing sex cord cells penetrate the mesenchyme, forming the genital ridge.

DEVETOPMENT IN THE MAIEA. Gonads

1. Under the influence of the Y chromosome, the primitive sex cords give rise to the testiscords, which separate from the coelomic epithelium by proliferation of mesenchyme.

a. This mesenchyme condenses to form the fibrous connective tissue capsule of thetestis, the tunica albuginea.

b. The testis cords are composed of primitive germ cells, which give rise to spermatogo-nia, and sex cord cells, which differentiate into Sertoli cells.

2. During the fourth month, the testis cords become U-shaped and form the precursors ofthe seminiferous tubules, which remain as solid cords until puberty. The ends of the sem-iniferous tubules form the straight tubules, which join near the hilum of the testes toform the labyrinthine rete testis. The rete testis becomes canalized and joins remnants ofthe mesonephric tubules, which form the efferent ductules.

3. Mesenchyme between the seminiferous tubules gives rise to the testosterone-producinginterstitial cells of Leydig.

4. The gubernaculum testis consists of remnants of the urogenital mesentery and fibers thatrun from this mesentery to the scrotal swelling.

a. The processusvaginalis is a coelomic efiension into the scrotal swelling that carries withit extensions of the body wall to form the inguinal canal during the descent of the testes.

297

Reproductive System


The hormonal control ofsexual differentiation isdiscussed in the ReproductivePhysiology chapter ofthis book.

b. During the second month of development, rapid body growth results in movement ofthe testes below their level of origin in the dorsal body wall.

c. In the seventh month, the testes begin to descend behind the processus vaginalis andarrive in the scrotal sacs at the time of birth. The processus vaginalis forms the cover-ings of the spermatic cords and testes.

B. Ducts. The efferent ductules empty into the Wolffian (mesonephric) ducts, which, exceptfor their most cranial portion, persist in the male.

l. The cephalic portion of each of these ducts becomes the extensively coiled epididymis.

2. The caudal end forms the thick-coated ductus deferens, which continues in the prostateand opens into the prostatic urethra as the ejaculatory duct.

3. The terminal portions of the ductus deferens evaginate to form the seminal vesicles.

4. The prostatic urethra gives rise to the prostate gland.

C. External genitalia

1. Mesenchyme cells of the primitive streak migrate around the cloacal membrane duringthe third week of development and form the cloacal folds. These folds unite the cranialand cloacal membranes to form the genital tubercle. By the sixth week, the genital foldsappear on each side of the cloacal membrane.

2. Another pair of elevations, the genital swellings, soon become visible on each side of thegenital folds.

3. Development of the male external genitalia is under the influence of androgens secretedby the fetal testis. At the seventh week, the genital tubercle elongates to form the phallus,which develops an extended end, called the glans. This elongation pulls the genital foldsforward to form the lateral walls of the urethral groove.

4. By the end of the third month, the genital folds fuse over the urethral plate to form thepenile urethra, which opens at the end of the penis as the urethral meatus. The two geni-tal swellings move caudally and form the two halves of the scrotum.

DEVETOPMENT IN THE FEMATEA. Gonads

1. In the female gonad, primitive sex cords are broken up into clusters of primitive germ cellsby proliferating mesenchyme, which forms the ovarian medulla. Surface epithelium pro-liferates to form the cortical cords, which penetrate the mesenchyme by the seventh week.In the fourth month, these cords split into cell clusters that surround one or more of theprimitive germ cells.

2. The germ cells differentiate into oogonia, which undergo mitotic divisions in the ovariancortex to form primary oocytes. The primary oocytes are surrounded by a single layer ofepithelial cells, which differentiate into follicular cells. The primary oocyte and sur-rounding follicular cells comprise a primordial follicle.

B. Ducts

l. Miillerian (paramesonephric) ducts appear as invaginations of coelomic epithelium intothe underlying mesenchyme of the posterior abdominal wall of the embryo during thesixth week. Each paramesonephric duct is divided into three anatomic regions:

298

Embryology

a. A cranial vertical part, which forms the upper portion of the oviduct and opens into thecoelom cavity

b. A middle horizontal part, which forms the lower portion of the oviduct

c. A caudal vertical part, which fuses with the corresponding portion on the opposite sideto form the uterine canal and differentiates into the uterus and part of the vagina

2. Oviduct (fallopian tube). In the fourth and fifth months, the oviduct elongates andbecomes coiled. Fimbriae develop at its cranial end, and differentiation of muscle andmucous membranes gives rise to the infundibulum, ampulla, and isthmus portions ofthe oviduct.

3. Uterus. The fused paramesonephric ducts give rise to the body and cervix of the uterus.The myometrium forms from the surrounding mesenchyme, and the perimetrium isderived from the peritoneal covering.

4. Vagina. The upper one-third of the vagina is derived from the uterine canal. The lowertwo-thirds of the vagina originates from two outgrowths of the posterior urogenital sinuswall, called the sinovaginal bulbs. Cells of the sinovaginal bulbs proliferate to form thevagrnal plate, which extends around the caudal end of the uterine canal. The vaginal platecanalizes in the fifth month. The lumen of the vagina remains separated from that of theurogenital sinus by a thin tissue plate, the hymen, which is derived from the vaginal plateand the urogenital sinus.

5. Ligaments

a. As the paramesonephric ducts descend through the pelvis, they pull a transversefold of coelomic epithelium and mesenchyme toward the midline. This fold, whichextends from the lateral side of the uterine canal to the wall of the pelvis, is known asthe broad ligament.

b. The caudal end of the ovary is connected to the genital swelling by a strip of mes-enchyme, known as the gubernaculum. The part of the gubernaculum that connectsthe ovary and uterus becomes the round ligament of the ovary. The part that extendsfrom the uterus through the inguinal canal into the labia majora becomes the roundligament of the uterus.

c. The ovary is suspended from the posterior surface of the broad ligament by the meso-varium, or suspensory ligament of the ovary.

C. External genitalia. The genital tubercle elongates slightly to form the clitoris, and the geni-

tal folds remain unfused and differentiate into the labia minora. Labia majora are formedfrom the genital swellings.

299

Reproductive System

Table IV-l-f . Derivatives of embryonic genital structures.

Embryonic Structure Male Female

Indifferent gonad Testis Ovary

Cortex N/A Ovarian follicles

Medulla Seminiferous tubules MedullaRete testis Rete ovarii

Urogenital mesentery Mesorchium Mesovarium

Gubernaculum Gubernaculum testis Ovarian ligamentRound ligamentof uterus

Mesonephric tubules Ductuli efferentes EpoophoronParadidymis ParoophoronAberrant ductules Duct of epoophoronDuctus epididymis Duct of GartnerDuctus deferens lJreter, pelvis, calyces,Ureter, pelvis, calyces, and and collecting tubulescollecting tubules

Mesonephric duct Epididymis N/ADuctus deferens andseminal vesicle

Paramesonephric Appendix of testis Hydatid (of Morgagni)duct Prostatic utricle Oviduct (fallopian tube)

UterusVagina (upper)

Urogenital sinus Urinary bladder (except trigone) Urinary bladder(except trigone)

Urethra (except penile portion) UrethraProstate gland Urethral glandsBulbourethral glands Greater vestibular glands

Vagina (lower)

Genital tubercle Glans penis Clitoris

Urogenital folds Ventral (under) aspect of Labia minorapenis-penile urethra(medium raphe)

Labioscrotal Scrotum Labia maioraswellings

500

Embryology

CONGEN ITAI ABNORMATITI ESA. Gonadal agenesis. Germ cells either do not form or do not migrate, and in their absence, the

gonads do not develop. The duct systems and external genitalia differentiate along femalelines until birth.

B. Truehermaphroditism is the presence of one ovary, one testis, and external genitalia of bothsexes; it rarely occurs.

C. Pseudohermaphroditism is the presence of gonads and the karyotype of one sex, but sec-ondary sex characteristics of the other.

1. Male pseudohermaphrodites are XY but have a female phenotype. They may or may nothave testes. An example of male pseudohermaphroditism is testicular feminizationsyndrome, where the individual has female external genitalia but an XY phenotype.

2. Female pseudohermaphrodites are XX but have a male phenotype. They may or may nothave ovaries. An example is the adrenogenital syndrome with masculinization of theexternal genitalia but an XX genotype.

D. Cryptorchidism is characterized by undescended testis, unilaterally or bilaterally. Thiscondition is due to abnormalities in androgen production and gubernaculum shortening.Mature spermatozoa are not produced in the undescended testis because of the higher bodytemPerature.

E. Congenital inguinal hernia is an incomplete closure of the inguinal canal, which allowsintestinal loops to enter the scrotal sac. Obliteration of the passageway may be irregular,allowing the formation of hydroceles (watery rysts) along its course.

F. Hypospadias is characterized by an abnormal opening of the penile urethra on the inferior

side of the penis, due to failure of the urethral folds to close. A similar defect in femalesoccurs: the urethra opens into the vagina.

G. Epispadias is an abnormal opening of the penile urethra on the superior side of the penis.It is due to faulty positioning of the genital tubercle.

H. Duplication of the uterine canal. Lack of fusion of the paramesonephric ducts and sino-vaginal bulbs results in a double uterus or vagina, respectively.

I. Atresia of the uterine canal. Complete or partial atresia of the paramesonephric ducts andsinovaginal bulbs results in atresia of the uterus or vagina, respectively.

l. Ovarian hypoplasia is found in patients with Ttrrner syndrome (XO).Primordial germ cellsmigrate toward the undifferentiated gonad but primary follicles fail to develop. Germ cellseventually degenerate. The gonad produces no hormones after birth, and sex characteristicsremain infantile.

501

Male Reproductive Histology

The male reproductive system consists of the primary reproductive organs, the testes, and thesecondary organs, including a complex series of excurrent genital ducts, the accessory glands, andthe penis. The testes are paired organs that function both as exocrine glands to producespermatozoa in a process called spermatogenesis, and as endocrine glands to produce male sexhormones, the primary one being testosterone. This chapter will review the different tissue typesfound in the testes, as well as those found in the accessory ducts and glands.

TESTESThe testes are composed of many serniniferous tubules, which contain a germinal epitheliumwhere spermatogenesis occurs. The tubules are held together by an extensive connective t€stic-ular stromg which contain the androgen-secreting kydig cells.

A. Testicular stroma consists of the following components.

1. Each testis is covered by a dense fibrous capsule called the tunica albuginea.

2. Projecting inward on the posterior border of the testis, the tunica albuginea thickens toform the rnediastinum t€stis.

3. From the mediastinum, t}lin connective tissue septa divide the testis into lobules.

a. The pfititions betw€en the lobules are incomplete.

b. Each lobule contains one or more highly convoluted seminiferous tubules, which col-lectively represent the exocrin€ compartment of the testis.

4. Beneath the tunica albuginea is a loos€r conn€ctive tissue layer with many blood vesselscalled the tunica vasculosa.

a. This layer is continuous with a highly vascular layer of delicate int€rstitial connectiv€ t:U-!!S!*"[tissue located between the serniniferous tubules'

seminiferous tubures =b. The interstitial conn€ctive tissue contains the steroidogenic Ieydig cells, which collec- comDlex stratified eoithelium

tively represent the €ndocrine compartm€nt of the testis.

B. Seminiferous tubules, the site of spermatog€n€sis, are lined by a complex stratified germi- ,/ \nal epithelium composed of two cell types: supporting Sertoli cells and spermatogenic cells. Sertoli Spermatogenic

1. Sertoli cells are irregular columnar cells tlat extend ftom the basal lamina to the lumen cells cellsand proyide structural organization to the tubr:le. The large euchromatic nuclei of Sertolicells are highly folded and contain prominent nucleoli.

505

Reproductive System

Note

The blood-testis barrier isfunctionally (but notstructurally) similar to theblood-brain barrier.

Note

The development of germcells is dependent on pituitaryfollicle-stimulating hormone(FSH) and on testiculartestosterone.

Note

In terms of DNA content,primary spermatocyteshave four times as muchas spermatids.

a. Sertoli cells synthesize testicular androgen-bindingprotein, which helps to maintain thehigh androgen levels within the seminiferous tubules necessary for spermatogenesis.

b. Multiple tight junctions between adjacent Sertoli cells form the structural basis for theblood-testis barrier, which divides the seminiferous tubules into a basal compart-ment and an adlumenal compartment.

( 1) The basal compartment contains the spermatogonia.

(2) The adluminal compartment provides germ cells with an ideal environment fortheir development. It isolates the germ cells from the rest of the body, includingthe immune system, which could potentially recognize them as foreign cells.

c. Sertoli cells are also responsible for phagocytosis of residual cytoplasm discarded dur-ing the maturation of spermatids.

2. Spermatogenic cells are the germ cells located between the Sertoli cells; they consist ofspermatogonia, primary and secondary spermatocytes, spermatids, and spermatozoa.

a. In the sexually immature testes, only spermatogonia (i.e., primitive germ cells) andSertoli cells are present in the seminiferous cords.

b. At the onset of maturity, spermatogenic cells are present in all stages of differentiationand are more or less layered.

c. The spermatogonia, by repeated mitosis, give rise to primary spermatocytes.

d. Primary and secondary spermatocftes

(1) Primary spermatocftes are adjacent to and are larger than the spermatogonia.

(2) Each primary spermatocyte produces two secondary spermatocytes.

(3) Each secondary spermatocyte almost immediately divides to form two spermatids.

e. Spermatids are adjacent to the lumen of the seminiferous tubules and are recogniz-able by their small size. These cells undergo no further division, but become trans-formed into mature spermatozoa through the process of spermiogenesis.

C. Spermatogenesis is divided into three components: spermatocytogenesis, meiosis, andspermiogenesis.

1. Spermatocytogenesis begins with the spermatogonia containing 46 chromosomes, or 23pairs. After several mitotic divisions, the cells differentiate without division into primaryspermatocytes.

2. Meiosis is a unique type of nuclear division that occurs only in germ cells. It is a reduc-tion process that reduces the diploid condition of spermatocytes to the haploid conditionof sperm.

a. First meiotic (reduction) division occurs when the paired chromosomes become sep-arated. Primary spermatocytes divide to form secondary spermatocytes.

(1) This division is different from ordinary mitotic divisions in that it does not con-sist of separation of sister chromatids after DNA replication but rather involvesthe separation of previously paired, homologous chromosomes.

(2) Meiosis allows for transposition of genetic information; prior to the division(during prophase of meiosis I), crossing over occurs between the chromatids ofthe tetrad.

(3) After crossing over, each germ cell has a different genetic composition than theoriginal spermatogonia.

504

Histology: Male

b. Second meiotic division is a division of the secondary spermatocytes that results infour spermatids, each containing the haploid number of chromosomes.

3. Spermiogenesis is a di:fferentiation or maturation process in which spermatids do not dividebut mature to form spermatozoa.

a. The spermatids are enveloped by cytoplasmic processes of the Sertoli cells from whichthey receive nourishment.

b. Spermatid vacuoles containing small proacrosomal granules fuse to form a largevacuole, which contains the large acrosomal granule. As the acrosomal vesicle increasesits zone of contact with the nucleus, it forms a cap over the nucleus known as theacrosomal cap.

c. Concurrently, the centrioles move to the caudal pole of the nucleus to function as thebasal body for the formation of the flagellum of the sperm.

d. This process is followed by a posterior redistribution of cytoplasm and by a movementof mitochondria toward the proximal portion of the developing tail of the sperm.

e. The posterior cytoplasm is extruded and digested by the Sertoli cell.

Spermatozoa

1. There are approximately 60,000 spermatozoa per cubic millimeter of seminal fluid, or20M00 million in a single ejaculation.

2. The mature spermatozoa consists of a head and a tail.

a. The head of the spermatozoon is pear-shaped, and chromatin is enclosed within thenuclear envelope.

b. The tail piece of the spermatozoon consists primarily of microtubules for the flagel-lum and mitochondria for the energy of motion.

Interstitial cells of kydig are located between the seminiferous tubules in the interstitial con-nective tissue. They are epithelioid connective tissue elements that synthesize and secrete testos-terone.

1. The Leydig cells arise from fibroblast-like mesenchymal cells. They have all of the charac-teristics of steroid secretory cells: abundant smooth endoplasmic reticulum (SER), mito-chondria with tubular cristae, and numerous lipid droplets containing cholesterol esters.

2. They occur in groups and are large and polygonal in shape. They contain large, eccentricnuclei. Their eosinophilic cytoplasm is vacuolated as a result of the large amount of lipidpresent for the production of testosterone.

3. The activity of the interstitial cells depends upon the production of luteinizing hormone(LH) by the anterior pituitary gland.

4. Testosterone is responsible for development and maintenance of sex accessory organs andfor the appearance of secondary sexual characteristics in males.

In a Nutshell

Spermatogonium(primitive sperm cell) (2n)

II mrtosts

t1" spermatocytes (2n)

D.

E.

/ \ ." ' , ,2" spermatocyte 2" spermatocyte

(n) (n)r \ / \

I \ t"iotit tul

\snermaid

\ spermatid

\spermatid spermatid

(n) (n)

where n is defined as the number ofchromosomes, and chromosomescan contain either one or twochromatids

ln a Nutshell

Spermiogenesis is thedifferentiation of roundspermatids into elongatedspermatozoa:. Formation of acrosome. Condensation and

elongation of nucleus. Development of flagellum. Loss of rytoplasm


Cholesterol + pregnenolone-+ progesterone -) l7a-0Hprogesterone +androstenedione +testosterone

505

Reproductive System

EXCURRENT GENITAL DUCTSThe system of excurrent ducts provides a conduit for the external transmission of sperm andglandular secretions during ejaculation. Some ducts also serve as sites for the maturation andstorage of sperm.

A. Terminal portions of the seminiferous tubules converge toward the mediastinum of thetestes.

1. As the tubules approach the mediastinum of the testes, the germ cells disappear from theepithelium,leaving a short segment lined onlyby Sertoli cells. This terminates in a valve-like structure that prevents reflux back into the seminiferous tubules. The continuousproduction of testicular fluid by Sertoli cells helps to move the gametes out of the semi-niferous tubules.

2. These one-way valves open into the tubuli recti, which are short, straight channels linedwith a simple cuboidal epithelium that connect the seminiferous tubules with the retetestis.

B. Rete testis is composed of anastomosing labyrinthine channels within the mediastinum.

1. It is lined with a simple epithelium. Some of the epithelial cells may possess a singleflagellum.

2. The passageways of the rete testis converge toward the efferent ductules.

C. Efferent ductules are lined with an epithelium that is pseudostratified.

1. Cilia are present on many of the epithelial cells and may aid in the transport of sperm bybeating in the direction of the epididymis.

2. The efferent ductules open into the ductus epididymis at the head of the epididymis.

D. Ductus epididymidis is a single, elongated, tortuous duct that may be 6 meters or more inlength.

1. The epithelium of this duct is pseudostratified; surface cells contain long microvillicalled stereocilia.

2. As the sperm slowly move through the epididymis, they undergo maturation and devel-op increased motility and fertilizing capacity.

E. Ductus deferens (vas deferens) is connected with the ductus epididymidis proximally andthe urethra distally.

1. The proximal portion of the ductus deferens is somewhat coiled, but it straightens out asit passes into the abdominal cavity to terminate in the prostatic urethra.

2. Before reaching this point, however, the ductus deferens forms a spindle-shaped dilation,the ampulla. The ampulla gradually narrows to form the ejaculatory duct, which pene-trates the prostate gland and empties into the urethra.

3. The ductus deferens consists of three layers.

a. The mucosa consists of pseudostratified epithelium, like that of the ductus epi-didymidis, and an underlying lamina propria rich in elastic fibers.

b. The muscularis is the thickest coat.It consists of three smooth muscle layers arrangedlongitudinally in the inner and outer layers and circularly in the intermediate layer.

c. The adventitia is a fibroelastic tissue with numerous blood vesels, nerves, and scat-tered bundles of smooth muscle.

506

Histology: Male

F. Urethra is the final common pathway of the reproductive and urinary systems in the male.

1. The urethra extends from the bladder to the end of the penis and consists of a prostaticportion and a penile portion.

2. The epithelium varies from transitional in the prostatic portion to stratified or pseudos-tratified in the proximal penis to stratified squamous in the distal penis.

G. Sperm storage occurs in the efferent ductules, epididymis, and proximal ductus deferens.

1. Sperm passes rapidly through the straight tubules and rete testis into the storage ductsand are thus rarely seen in the straight tubules and rete testis.

2. The maturation and survival of the sperm in these ducts is aided by a secretion from theepithelium, which, in turn, is dependent upon testosterone production.

3. Following epididymal maturation, sperm is stored primarily in the tail of the epididymisand in the ductus deferens.

ACCESSORY GTANDSAccessory glands provide the fluid secretions that mix with the sperm to form semen. They serveas substrates for the metabolism of sperm and lubricate the excurrent ducts during ejaculation.

A. Seminal vesicles are elongated, convoluted sacs that lie near the ampullae of each ductusdeferens and empty into the junction of the ampulla and the ejaculatory duct. They possessa well-developed muscularis, consisting of inner circular and outer longitudinal smoothmuscle fibers.

1. The mucosa is folded, and the epithelium is pseudostratified.

2. They secrete a slightly alkaline, viscous fluid into the semen that is rich in fructose andserves as an energy source for the sperm.

3. While spermatozoa are occasionally seen in the seminal vesicles, they are not a storageorgan for sperm per se.

B. Prostate gland is an aggregation of approximate$ 3f50 small, branched tubuloalveolar glands.

1. The epithelium of the glands is pseudostratified with cuboidal or columnar surface cells.

2. The ducts leading from these glands to the urethra are lined by a cuboidal epithelium,which changes at the distal end to the transitional epithelium of the urethra.

3. Concretions occur normally in most prostate glands. These are spherical bodies, roughly250 mm in diameter, which are composed of protein and carbohydrate. Normally, theyincrease in number with age.

4. Normal prostatic secretion is rich in citric acid, lipids, zinc, acid phosphatase activiryand PSA (prostate specific antigen)-a serine protein.

C. Bulbourethral (Cowper) glands are two small glands located close to the base of the penileurethra. They are surrounded by strands of smooth and skeletal muscle.

1. The glands are of the tubuloalveolar type. They are lined by a simple epithelium, whichranges from columnar to cuboidal.

2. Most of the cells are mucus secreting. The gland secretes a viscous alkaline fluid into theurethra for lubrication prior to ejaculation.

In a Nutshell

Urethral Epithelium. Prostatic = transitional

. Proximal penis = stratifiedor pseudostratified

. Distal poflis = stratifiedsquam0us

Clinical Correlate

Benign pro$atic hypertrophy(BPH) is hyperplasia of themucosal glands that can leadto clinically significantob$ruction of the urethra.

,07

Reproductive System

PENISThis organ is made up of three rylindrical bodies of erectile tissue: two dorsal corpora caver-nosa and a single ventral corpus spongiosum. The corpus spongiosum surrounds the urethraand terminates distally as the glans penis.

A. Corpora cavernosa consist of a system of irregular vascular channels, or cavernous spaces,separated by trabeculae.

1. The trabeculae consist of a dense fibrous connective tissue that contains bundles ofsmooth muscle fibers.

a. Their surfaces are covered with the endothelium that lines the venous spaces.

b. In the flaccid penis, the spaces contain little blood and thus appear as collapsed clefts.

2. Each of the dorsal cavernous bodies is surrounded by a thick, resistant fibrous capsulecalled the tunica albuginea. The inner surface of the tunica albuginea has a plexus ofsmall veins that drain the cavernous spaces.

B. Corpus spongiosum exhibits a similar arrangement of erectile tissue.

l. Its fibrous tunic is thinner than that of corpora cavernosa.

2. This body does not attain the same rigidity as the corpora cavernosa during erection.

C. The trabeculae of erectile tissue contain branches of the deep artery of the penis, which endin small arteries that open directly into the cavernous spaces.

508

Female Reproductive Histology

The female reproductive system consists of the ovaries, fallopian tubes (oviducts, uterine tubes),uterus and cervix, vagina, external genitalia, and mammary glands. The ovaries are paired organsthat function both as exocrine glands to produce the female gametes (oogenesis) and as endocrineglands to produce the female sex hormones. This system also provides a suitable environment forfertilization, embryonic, and fetal development, and delivery of the conceptus at parturition. Themammary glands are important compound tubuloalveolar glands that produce the exocrinesecretions used by the neonate.

OVARIESA. Structural overview. The stroma and parenchyma of each ovary is organized into two zones

that blend into one another.

1. The cortex is a broad outer layer that is covered by a visceral peritoneum called thegerminal epithelium. The tunica albuginea is a white fibrous connective tissue layerlocated beneath the germinal epithelium. The cortex contains ovarian follicles andcellular connective tissue.

2. The medulla, or zona vasculosa, is the central deeper layer that consists primarily of aloose elastic connective framework and contains many large blood vessels and nerves.

B. Ovarian follicles and follicular development

1. Overview. Ovarian follicles are located in the cortical stroma and are composed ofoocytes surrounded by follicular (granulosa) cells.

a. Approximately 400,000 follicles are present in the newborn ovaries. Only a smallpercentage of the oocftes (approximately 450) reach maturity in the adult (i.e., 13

rycles per year x 35 reproductive years). The remaining follicles eventually degen-erate through a process called atresia. Atresia may occur at any stage of folliculardevelopment.

b. Follicular development in preparation for ovulation involves maturational changes inthe oocytes and granulosa cells.

2. Primordial follicles consist of an oocyte surrounded by a single layer of flattened follicularcells.

a. The primordial follicles are inactive reserve follicles that contain primary oocytes,that is, oocytes arrested in prophase of their first meiotic division.

b. As maturation continues, the primordial follicle becomes a primary follicle.

r09

Reproductive System

3 . Primaryfollicles are relatively small and spherical with a central oocyte and one or morelayers of cuboidal-like follicular cells.

a. The central oocyte has a deeply staining nucleus and a rather indistinct nucleolus.

b. During the growth of the primary follicle, there is a proliferation of follicular cells, anincrease in the size of the oocfte, and formation of a connective tissue capsule aroundthe follicle by the follicular cells.

c. Soon thereafter, small spaces begin to appear in the follicular mass, which fuse to formthe follicular cavity, or antrum. Once the antrum develops, the follicle is termed asecondary follicle.

Secondary (vesicular) follicles continue to enlarge, become more ovoid, and are dis-placed into the deeper regions of the ovary.

a. As a result of the continued mitosis of the follicular cells and the increase in the size ofthe antral cavity, the oocfte is pushed to one side of the follicle.

b. The oocyte becomes surrounded by a hill of follicular cells known as the cumulusoophorus, and the cells adjacent to the oocyte are referred to as the corona radiata.

c. At the same time, the connective tissue surrounding the follicle develops into a follic-ular sheath, or theca, with internal and external layers.

(l ) Although the entire sheath derives from connective tissue, the theca interna hasepithelioid characteristics and a prominent vascular bed. The theca externa ismore fibrous and less vascular.

(2) The theca interna is separated from the follicular cells by a follicular basementmembrane. Theca cells produce androgens, which are converted into estradiol bygranulosa cells.

Zona pellucida. As the oocyte grows, its nucleus becomes large, vesicular, and euchro-matic with a large, deeply staining nucleolus. Yolk accumulates in the cytoplasm, and athick membrane, known as the zolna pellucida, forms around the outer surface of theoocyte directly beneath the corona radiata. The zona pellucida is rich in polysaccharidesand thus stains PAS-positive.

6. Graafian follicle is the mature follicle that extends through the entire cortex and bulgesout at the ovarian surface.

a. Antral fluid continues to accumulate and appears between the cells of the cumulusoophorus. This weakens the attachment of the oocfte and the corona radiata to thefollicular wall and facilitates ovulation.

b. The amount of antral fluid continues to increase rapidly, causing an increase in pres-sure on the wall of the follicle and on the thin layer of ovarian tissue at the surface ofthe ovary.

c. The follicle eventually ruptures and the ovum, along with its corona radiata, passes outof the ovary in a process known as ovulation.

(1) The ovum briefly enters the peritoneal cavity and passes into the fimbriated fun-nel of the fallopian tube.

(2) The ovum must be fertilized within 24 hours or it degenerates.

(3) Fertilization usually occurs in the upper third of the fallopian tube. The fertilizedovum begins to undergo cleavage almost immediately as it moves through thefallopian tube to the uterus, where it arrives approximately 3 days after ovulation.

4.

5 .


Ovulation is controlled by thecyclic release of LH and FSH.The midcycle surge of LHtriggers ovulation.

5r0

Histology: Female

(a) Implantation in the endometrium of the uterus occurs approximately 6 daysafter ovulation.

7. Follicular changes after ovulation result in the formation of the glandular corpusluteum.

a. The cells of the follicle and the theca interna cells enlarge and become epithelioid. Thetheca lutein cells secrete estrogen.

b. The cytoplasm of the granulosa lutein cells contain yellow pigment and lipid droplets.These cells secrete progesterone.

c. If the ovum is not fertilized, the corpus luteum reaches its maximal development approx-imately 7 days after ovulation and then begins to degenerate.

d. If the ovum is fertilized, the corpus luteum increases in size for approximately 3months. The corpus luteum persists until the third trimester before degenerating, andis maintained by hCG secreted by the placental trophoblast of the developing embryo.After day 40 of pregnanry, the placenta produces the progesterone necessary to maintainpregnancy.

8. Changes after fertilization. The first meiotic division is normally completed within theovary just prior to ovulation. Therefore, it is a secondary oocyte that is ovulated. Spermpenetration during fertilization activates the secondary oocyte to complete the second mei-otic division. The final result is a single, mature ovum, albeit with a male pronucleus. Mostof the cytoplasm of the primary oocyte ends up in the ovum. The other two cells resultingfrom meiosis, which contain very little cytoplasm, are discarded as polar bodies.

FAIIOPIAN TUBESThe fallopian tubes (uterine tubes, oviducts) are muscular tubes approximately 12 cm long thatopen to the peritoneal cavity at their ovarian ends and into the uterine cavity at the oppositeends. The function of the fallopian tube is to receive the oocyte, provide an appropriate envi-ronment for its fertilization, and transport the zygote to the uterus for implantation.

A. Fallopian tube wall is richly vascularized and consists of a mucosa, a muscularis, and aserosa.

1. Mucosa consists of a simple columnar epithelium and a lamina propria of loose connec-tive tissue. TWo types of cells occur in the epithelium.

a. Ciliated cells beat toward the uterus.

b. Secretory cells produce components of the tubal fluid, which provides nutrients forthe zygote and participates in the activation of sperm.

2. Muscularis is alayer of smooth muscle that is irregularly arranged as inner circular andouter longitudinal fibers.

3. Serosa consists of a layer of connective tissue covered with visceral peritoneum.

B. Regions of the fallopian tube

1. Infundibulum is the funnel-shaped end that is open to the peritoneal cavity.

a. Ridges of its mucosa extend from the open end like a fringe of branched processescalled fimbriae. Fimbriae are covered with ciliated cells that beat toward the mouth ofthe tube.

In a Nutshell

l" oocyte (2n)

/ \ (meiosisr)

2o oocyte lst polar bodyt \| \ (meiosis ll)Y\

Oocyte (n) 2nd polar body

IV

Ovum (n)

In a Nutshell

Oogenesis vs. Spermatogenesis

. One . Fourfunctional functionalovum and spermatozoatwo polar are producedbodies areproduced

. All primary . Primaryoocytes are spermatorytespresent at birth are produced

throughoutlife afterpuberty

5t l

Reproductive SySem

b. Before ovulation, estrogens induce engorgement of blood vessels in the fimbriae,which expands the fallopian tube toward the surface of the ovary. Estrogens similarlyinduce growth and activity of the cilia as well as enhancement of the peristaltic con-tractions of the fallopian tube.

2. Ampulla is the thin-walled longest region of the oviduct. Fertilization usually occurs inthe ampulla. This is also the most frequent location of ectopic pregnancy.

3. Isthmus is a narrow, thick-walled segment nearest to the uterine wall.

4. Uterine (interstitial) segment is the portion of the tube that traverses the uterine wall.

UTERUSThe uterus is a pear-shaped, 6.5-cm-long organ composed of an upper fundus, a dilated body,and a lower cylindrical portion called the cervix. The cervix bulges into the vaginal lumen at theexternal os.

A. Uterine wall is relatively thick and is formed by three coats: an inner mucosa called theendometrium, a thick (12-15 mm) muscular layer called the myometrium, and an outerserosal layer called the perimetrium.

1. Endometrium is lined by a simple columnar epithelium composed of ciliated and non-ciliated cells.

a. The lamina propria contains numerous fibroblasts. Many tubular glands, consistingmainly of columnar secretory cells, extend into the endometrium.

b. Different layers of the endometrium are distinguishable.

(1) The basalis, the deeper layer, is relatively thin and is not discharged during men-struation. Its glands change very little during the menstrual rycle.

(2) The functionalis, the superficial layer, undergoes the cyclic ovulatory changes ofthe menstrual cycle and is lost at menstruation.

2. Myometrium is composed mostly of smooth muscle, connective tissue, and prominentblood vessels. During pregnancy, the myometrium undergoes tremendous growth in sizedue to cell division and growth.

a. Four layers of the myometrium are distinguished: the innermost and outermost layersare mainly longitudinal, while the middle layers contain circular and longitudinalfibers.

b. The innermost middle layer, called the stratum vasculare, contains many blood ves-sels and mostly longitudinal fibers.

3. Perimetrium is a serous membrane that forms the peritoneal layer of the broad ligamentand covers the body of the uterus and part of the cervix.

B. Cyclic endometrial changes occur monthly in preparation for ovulation and fertilizationof the ovum. In preparation for pregnancy, the endometrium undergoes hlpertrophy of itsglandular, vascular, and interstitial components. If the ovurn becomes fertilized and theembryo implants, this hypertrophy continues. If the egg is not fertilized, the endometriumbreaks down and the tissue, as well as some blood, is discharged as menstrual fluid. The firstday of the menstrual rycle is, by convention, the first day of the menstrual flow. There are fourstages through which the endometrium passes during the menstrual rycle. The averagemenstrual cvcle lasts 28 davs.

tl2

Histology: Female

1. Menstrual stage occupies the first 3-5 days of the cycle and is characterizedby menstru-al flow.

2. Proliferative (estrogenic) stage begins during the later stages of menstrual flow and con-tinues through the 13th or 14th day of a typical 28-day cycle. This stage is characterizedby the regrowth of endometrium from what remains after menstruation.

a. The epithelial cells of the glandular structures remaining after menstruation migrateand proliferate to cover the new mucosal surface.

b. Spiral arteries also grow into the regenerating endometrium.

c. Significant edema develops by the end of the proliferative stage and continues todevelop during the secretory phase.

d. During proliferation, the endometrium increases in thickness six-fold.

3. Secretoryphase continues the hlpertrophyof the endometrium.

a. Mitosis has ceased by this point. The tissue expands by cellular hlpertrophy and by anincrease in vascularity and edema. At the same time, the spiral arteries continue togrow toward the mucosal surface.

b. At the beginning of the secretory stage, glycogen, mucigen, and various lipids accu-mulate rapidly in the glandular cells of the functionalis.

c. During the second half of the secretory phase, the secretions move from the basalregion of the glandular cells to the apical region.

d. Once the glycogen, mucin, and lipid secretions appear in the lumina of these glands,the secretory stage has ended.

4. Premenstrual phase consists mostly of changes in the spiral arteries that lead to thebreakdown of the functionalis.

a. Constriction of the spiral arteries leads to anoxia and ischemia. The glands degener-ate along with their endometrial surface, and blood and tissue debris appear in theuterine lumen.

b. Menstrual blood is fibrinolytic and, therefore, does not clot.

C. Uterine changes in relation to the ovary. Cyclic changes of the uterus are closely associatedwith cyclic changes of the ovary.

1. The onset of menstruation corresponds to the involution of the corpus luteum.

2. The proliferative phase of the uterus corresponds to the preovulatory period of follicularmaturation.

3. Ovulation normally occurs at the end of the proliferative phase.

a. Ovulation occurs 14 days before menstruation begins.

b. It may occur anytime between the 8th and the 20th day of the cycle, but most com-monly, occurs on the llth, 12th, or 13th day.

4. The secretory phase is associated with the luteal phase of the ovary.

5. Estrogen is necessary for the proliferative phase, and progesterone is necessary for thesecretory phase.

a. The appearance of estrogen precedes that of progesterone and is responsible for theappearance of progesterone later on in the menstrual cycle.

In a NuBhell

Four stages of endometrialchanges during the menstrualcycle:

(l) Menstrual (days I to 3-5). Menstrualflow. Coincides with involution

of corpus luteum

(2) Proliferative (end of men-$rual flow till day 13 or 14). Regrowth of endometium. Coincides with develop-

ment of ovarian folliclesand estrogen production

. Ovulation occurs at endof this phase

(5) Secretory (l5th to 2sth day). Occurs after ovulation. Depends on proges-

terone from corpusluteum, which stimulatesgland cells to secreteglycoprotein

(4) Premenstrual. Breakdown of functional

layer of endometrium

t r !

Reproductive System

D.

b. If the ovum has not been fertilized, the degeneration of the corpus luteum 12 daysafter ovulation leads to a rapid drop in progesterone and estrogen levels. The func -

tionalis degenerates, and menstrual flow commences because the endometrium is no

longer being maintained under the direction of these hormones.

Uterine changes in relation to fertilization

1. If the ovum is fertilized, the developing embryo implants in the endometrium on approxi-mately the sixth day after ovulation.

2. Once the developing embryo implants, its chorionic membrane proliferates into a tro-phoblast, which eventually completely covers the embryo.

a. Irregular spaces then appear in the trophoblast, which are eventually filled with mater-nal arterial blood from the spiral arteries that supply the developing embryo.

b. The trophoblast layer changes throughout pregnanry.

3. The original, inner cellular layer of the trophoblast gives rise to an outer, syncytial layeron approximately the 1lth day of pregnancy.

a. These two layers persist through the first half of pregnancy, after which time the innercytotrophoblast layer slowly begins to decrease in size, becoming inconspicuous andleaving only the outer syncytiotrophoblast layer.

b. Underneath the two layers of trophoblast, the embryonic mesenchyme develops.

4. Villi with a core of mesenchyme grow from the trophoblastic surface and become chori-onic villi. In the connective tissue core, branches of the fetal blood vessels appear.Eventually, these villi attach to the chorion and form the chorionic plate.

5. There are two tnres of chorionic villi: anchoring and floating.

a. Anchoring villi anchor the decidua of the endometrium to the chorionic plate.

b. Floating villi are branches of the anchoring villi. They traverse the spaces between thechorionic plate and the decidua in which maternal blood circulates.

6. At the same time that the embryo develops chorionic villi and the chorionic plate, theendometrium forms the decidua basalis, which consists of differentiated stromal cellscalled decidual cells.

Placenta. The placenta develops in the uterus during pregnancy, and has both fetal andmaternal components. The function of the placenta is to allorv for exchange of nutrientsand waste products between the maternal and fetal circulations. While the maternal and fetalcirculations are completely separate, they pass very close to each other, allowing for exchangeof materials.

1. The fetal component consists of the chorionic plate and villi. It lies adjacent to the spacesnear the endometrial decidua through which the maternal blood circulates.

2. The maternal component of the placenta is the decidua basalis.

3. The maternal blood vessels from the decidua pass into the intervillous spaces of the placenta,where floating villi are present.

a. Maternal blood is separated from fetal blood by several layers of tissue (i.e., cftotro-phoblast, syncytiotrophoblast, a basement membrane, little or no fetal mesenchymeand fetal capillary endothelium).

b. The proximity of the floating villi to the maternal blood allows for the exchange ofnutrients (from maternal) and wastes (from fetal) between the two circulations.

Flashback toGeneral Principles

Fertilization is reviewed indetail in the Embryologysection of the CeneralPrinciples Book 2 (Volume ll).

ln a Nutshell

Placenta consists of:

. Fetal portion (chorionicplate and vill i)

. Maternal portion (deciduabasalis)

E.

5 t4

Histology: Female

c. The placenta is selective; not all substances can be transmitted to the fetus fromthe mother.

F. The cervix contains a thick muscular wall, which is a continuation of the corpus of the uterus.

1. The mucosa, which does not undergo cyclic changes, contains deep transverse folds.

2. The surface and glandular epithelia are composed of simple columnar mucus-secretingcells, whose product fills the lumen of the cervix.

3. Ovarian hormones, especially estrogens, influence cervical stromal growth. The Papsmear, developed by Papanicolaou, screens for any cervical abnormalities.

VAGINAThe vagina is a flexible tubular organ that extends from the vestibule of the external genitaliato the cervix. There are no glands in the vagina, and the mucus lubricating it originates fromthe glands of the cervix and the vestibular glands. The fibromuscular wall consists of a mucosa,muscularis, and adventitia.

A. Mucosa consists of several transverse folds, or rugae.

1. It is composed of a stratified squamous epithelium, a basement membrane, and an under-lying lamina propria.

2. Vaginal epithelium is rich in glycogen, which increases throughout the menstrual rycle asestrogen levels increase.

a. During the estrogenic (i.e., follicular, preovulatory) phase of the menstrual rycle, vagi-nal fluid has a lower pH than during the rest of the cycle as a result of the formationof lactic acid by bacteria from the carbohydrates in the vaginal epithelium.

b. The drop in estrogen and therefore in glycogen causes an increase in vaginal pH andthus an increase in the likelihood of infection.

c. Lymphocytes and polymorphonuclear leukocytes are commonly found beneath theepithelium, especially during menstruation, when they also appear as free cells in thelumen of the vagina.

B. Muscularis of the vagina consists mostly of longitudinal bundles of smooth muscle, with aninner circular layer.

C. Adventitia is composed of dense connective tissue and attaches the vagina to the surround-ing structures.

EXTERNAT GENITATIAThe external genitalia (or vulva) of the female includes the clitoris,labia minora,labia majora,and vestibular glands.

A. Clitoris is an erectile structure homologous to the dorsal portion of the penis.

1. It is composed of two corpora cavernosa, containing erectile tissue enclosed in a fibrousmembrane.

2. The clitoris is lined by stratified squamous epithelium.

Clinical Correlate

The cervical $roma is ofteninfiltrated with inflammatorycells, which appear inresponse to microorganisms.

In a NuBhell

VaginalWall

Inside -+ Outside

Mucosa -+ Muscularis -+ Adventitia

J J V

Stratified Smooth Densesquamous muscle connectiveepithelium tissue

5t5

Reproductive System

B. Labia minora are two small folds of skin containing a spongy connective tissue core.

1. The epithelium is keratinized, stratified squamous, and contains cells with melanin.

2. Sebaceous and sweat glands are numerous on both sides of the folds.

C. Labia majora are two prominent folds of skin containing a large quantity of adipose tissueand a thin layer of smooth muscle.

1. The inner aspect is similar in composition to the labia minora. and the outer aspect iscovered with skin and coarse, curly hair.

2. Sebaceous and sweat glands are numerous on both sides of the folds.

D. Vestibular glands (of Bartholin) are similar in structure to the bulbourethral glands in themale. The secretions of the vestibular glands help to lubricate the vagina, which lacks glandsof its own.

1. These mucous glands are two small round bodies situated on each side of the vestibulum(i.e., the cleft between the labia minora).

2. Minor vestibular glands that secrete mucus are also present.

MAMMARY GTANDSThe mammary glands are modified sweat glands that respond to hormonal changes. Theysecrete various components of milk by merocrine and apocrine mechanisms.

A. Mammary gland structure consists of secretory alveoli and a compound duct system thatopens onto the surface of the skin at the mammary papilla, or nipple.

1. Each mammary gland consists of approximately 15--20lobes.

a. Each lobe is an independent compound gland, drained by a separate lactiferous ductthat opens at the nipple. Dilations of the lactiferous ducts, before they open onto thesurface of the nipple, are called lactiferous sinuses.

b. The lobes are enclosed in a layer of dense connective tissue and are surrounded bv adi-pose tissue.

c. Each lobe is subdivided into lobules, and within the lobules, ducts and alveoli are sup-ported by loose reticular connective tissue.

2. The lactiferous duct is lined by stratified squamous epithelium and branches into termi-nal ducts entering each lobule as an intralobular duct.

a. The epithelium lining the smaller ducts is simple cuboidal and becomes stratifiedsquamous near the opening to the cutaneous surface.

b. Myoepithelial cells are at the base of the smaller ducts.

3. The secretory alveoli begin to develop at puberty, when the immature mammary glandcomes under the influence of estrogen and progesterone.

a. True secretory alveoli are not present until pregnancy.

(1) Early secretions that are rich in protein and poor in lipids are known ascolostrum. Colostrum is available to the newborn in the first few days. It con-tains many antibodies that help protect the newborn.

(2) Protein and related components are secreted by a merocrine mechanism, where-as lipid components are secreted by an apocrine mechanism.

5t6

Histology: Female

b. Myoepithelial cells with extensive contractile filaments in their cytoplasm occupy thespace between the secretory cells and their basement membranes.

B. Nonlactatingmammaryslurd The glandular tissue of a mature, nonpregnant woman is scanty.

1. The glands are grouped together as lobules and appear narrow as a result of the lack ofmammary secretions, which, if present, would distend the lumina of the glands and ducts.

2. The mammary glands lack a capsule, but an extensive interlobar connective tissue con-tains abundant adipose tissue.

C. Mammary gland during pregnancy. The inactive glands form buds that expand to formalveoli.

1. The alveoli are lined by a simple cuboidal epithelium with a thin basement membrane.

2. During gestation, there is continuous production of both estrogen and progesterone,which results in the full development of the mammary glands.

a. The production of milk components is called lactation. It requires prolactin, apolypeptide synthesized and released by the adenohypophysis.

(1) Milk is a proteinaceous fluid (consisting of casein,lactose, and salts) in which themilk lipids are suspended.

(2) Milk is also rich in calcium, an element necessary for the growing infant.

b. If the mammary gland is primed by estrogen, progesterone, corticosteroids, andinsulin, then prolactin stimulates milk secretion.

3. Oxytocin, produced by the hypothalamus and stored and secreted by the posterior pitu-itary, causes the contraction of the myoepithelial cells. These cells surround the alveoliand subsequently cause the ejection of milk. The stimulus of suckling on the nipple areasends neural impulses to the hypothalamus, initiating oxytocin secretion, and, in turn, milksecretion, or let-down.

D. Mammary gland after menopause. The mammary glands atrophy, with the lobules andducts becoming obliterated. The connective tissue becomes increasingly dense, occupyingthe space where the lobules and ducts were formerly present.

Note

At the end of pregnancy,lymphorytes and plasma cellsincrease in number in theintralobular connective tissueof the mammary glands. Thisleads to secretion of lgA,which confers passiveimmunity on the newborn.

In a Nubhell

. Prolactin + milk production(anterior phuitary)

. Oxytocin + milk secretion(etiown) (po$erior pituitary)

t l 7

Reproductive Anatomy

This brief chapter reviews the gross anatomy of the external and internal organs of both the maleand female reproductive systems. The arterial supply, venous and lymphatic drainage, andinnervation of reproductive organs are also discussed.

PERINEUMThe perineum is the diamond-shaped area between the thighs; it supports the external geni-talia. The perineum is divisible into two triangles (Figure IV-4-1).

Bulbospongiosus Crus of clitorismuscle

lschiocavernosus Vestibular bulb

Bartholin glandmuscle

Superficialtransverseperineal muscle

lschial tuberosity

External analsphincter muscle

Levator ani muscle

Anococcygeal ligament

Coccyx

Figure lV-4-1.The perinium in the female.

A. Urogenital triangle

1. Superficial pouch contains the cavernous bodies (corpora cavernosa and corporaspongiosa) and their associated muscles (ischiocavernosus and bulbospongiosus) in bothmen and women.In women, the superficial pouch also contains the vestibular (Bartholin)glands.

Clitoris

5t9

Reproductive System

Clinical Correlate

An abscess of the ischiorectalfossa may spread from oneside to the other through thecommunicating anteriorrecesses. These infectionsgenerally respond poorly toantibiotic therapy.

2. Deep pouch consists of the urogenital diaphragm, which is a sheet of muscle, and thesuperior and inferior perineal fasciae. The muscular portion includes the sphincter ure-thrae in men and the sphincter urethrae plus the sphincter vaginae in women. In men, thedeep pouch also contains the bulbourethral (Cowper) glands.

B. Anal triangle

1. External anal sphincter

2. Ischiorectal fossa is a bilateral wedge-shaped space bound by the pelvic diaphragm medi-ally and the obturator internus laterally. This space is filled by the ischiorectal fat pad. Theanterior recesses of the ischiorectal fossae extend forward superior to the urogenitaldiaphragm and are continuous across the midline.

MATE REPRODUCTIVE VISCERA

Retrovesical Urinary bladderpouch

SeminalDuctus deferens

Prostate glandMedian lobe (M)Anterior lobe (A)Posterior lobe (P)

Ejaculatory n.;

duct

Urethra

l ' It i

Urogenitaldiaphragm

Bulbourethralgland

Figure lV-4-2. Male pelvis.

A. Testis. The male gonad originates from the posterior wall of the abdomen, not in the pelvis.The testes descend through the inguinal canal to the scrotum.

l. Tunica vaginalis is a double-layered derivative of the peritoneum. Its visceral surfacecovers the testis.

2. Scrotum is a cutaneous sac derived from the anterior abdominal wall. It houses the testesand provides an environment a few degrees below body temperature, which is suitable forsperm development.

3. Spermatic cord consists of ductus deferens, nerves, blood vessels, and fascial layersexternal to the tunica vaginalis.

;- Penis

,20

Anatomy

4. Blood supply. The major arterial supply is from the testicular artery, which is a branch

of abdominal aorta. Venous drainage is from the pampiniform plexus, which coalesces to

form the testicular vein.

5. Lymphatics. The scrotum drains to the superficial inguinal nodes, and the testis drains to

the para-aortic nodes.

6. Innervation. The genital branch of the genitofemoral nerve supplies motor fibers to the

cremaster muscle. The ilioinguinal nerve supplies the skin of the scrotum and the medi-

al thigh with sensory fibers.

B. Epididymis is a paired tubular structure that conveys sperm from the efferent ductules of

the testis to the vas deferens (ductus deferens). Sperm must spend time within these struc-

tures to become viable.

C. Vas deferens is a paired muscular duct that carries sperm to the prostatic urethra via the

ejaculatory duct.

D. Seminal vesicle is a paired gland located posterior to the urinary bladder that produces a

viscous, alkaline component of semen. The ducts of the seminal vesicles join with the vas

deferens to form the ejaculatory ducts.

E. Prostate gland is a single structure that lies inferior to the bladder and transmits the pro-

static urethra. Prostatic secretions enter the urethra through minute ducts.

l. Blood supply. Arterial blood to the prostate comes from branches of the internal iliac

artery. Venous drainage is from the prostatic venous plexus, which drains to the internal

iliac veins and communicates with the vertebral venous plexus.

2. Lymphatics. The lymph of the prostate drains mostly to internal iliac nodes.

F. Penis

1. Structure

a. Root of the penis is located in the superficial pouch. It contains the bulb and the crura

of the penis.

b. Body of the penis

(1) Corpus spongiosum is located ventrally; it transmits the penile (spongy) ure-

thra. Its terminal portion is the glans.

(2) Corpora cavernosa are paired, dorsally located bodies of erectile tissue.

2. Arterial supply. The penis is supplied by branches of the internal pudendal artery, which

is a branch of the internal iliac artery.

3. Venous drainage. The deep dorsal vein, which drains the sinusoidal spaces of the cav-

ernous bodies, joins the prostatic venous plexus. The superficial dorsal vein drains super-

ficial layers and joins the superficial external pudendal vein.

a. Lymphatics. Most of the penis drains to the superficial inguinal nodes.

5. Innervation. The muscles of the superficial pouch are supplied by motor branches of the

pudendal nerve,which is derived from sacral spinal nerves 2,3,and 4. Erection of the

penis is under parasympathetic control (pelvic splanchnic nerves), and ejaculation

involves both sympathetic and parasympathetic stimulation.

Clinical Correlate

Testicular torsion is caused bythe twisting of the testis alongthe axis of the spermatic cord.It usually occurs spontaneously,and can often be resolved bymanipulating and untwistingthe cord.

Clinical Correlate

Prostatic cancer may spread tothe vertebral column and CNSvia the valveless venousi nterconnections of theprostatic venous plexus withthe vertebral venous plexus.

tzl

Reproductive System

FEMATE REPRODUCTIVE VISCERA

Oviduct

Uterus

f ne.tout*in.I pouch (pouchI of Dougtas)

Posteriorfornix

Cervix

Vagina

"'o''" -- -,,.. -- " -,_ri;r,r..,

Ureter

Suspensoryligament

Roundligament

Vesicouterinepouch

Urinarybladder

Urethra

Clitoris

Urogenitaldiaphragm

Figure lV-4-3. Female pelvis.

A. Vulva

1. Structure

Clinical Correlate

An episiotomy is an incisionmade during childbirth tofacilitate delivery of the infant'shead. lt is performed either inthe median plane ormediolaterally throu gh theperineal body to avoid tearingof the external anal sphincter.

2.

a. Labia majora are the skin swellings that lie lateral to the labia minora and vestibule.They are homologous to the scrotum in men.

b. Labia minora are the thin, mucosal folds that flank the vestibule.

c. Vestibule is the central area that contains openings for the urethra, vagina, and ductsof the vestibular (Bartholin) glands.

d. Clitoris is a mass of erectile tissue located anterior to the vestibule. Its structure issimilar to that of the penis.

e. Perineal body is located posterior to the vestibule and is a mass of fibrous tissue thatseparates the vagina from the anal area.

Blood supply. The arteries of the superficial perineal area in women are mostly branchesof the internal pudendal artery. The labia majora are supplied by the external pudendalarteries. Venous drainage of the area is via branches of the internal pudendal vein, whichdrains to the internal iliac vein, and the external pudendal veins, which drain to the greatsaphenous vein.

Lymphatics. Skin and fascia of the vulva drain to superficial inguinal nodes, and theclitoris drains to the internal iliac nodes.

Innervation. Motor branches of the pudendal nerve supply the muscles of the superficialpouch, and the cutaneous areas receive sensory supply from the ilioinguinal and pudendalnerves. The clitoris,like the penis, is supplied by autonomic and sensory fibers.

3 .

4.

t22

Anatomy

B. Ovary. The female gonad,like the testis, descends from the posterior wall of the abdomen but

remains in the pelvis and does not enter the inguinal canal. A portion of the gubernaculum,

the ligament that extends from the gonad through the inguinal canal in both sexes, remains as

the round ligament of the uterus in women.

1. Ovarian ligament is the proximal remnant of the gubernaculum, which attaches the

ovary to the uterus.

2. Suspensory ligament of the ovary attaches the ovary to the lateral pelvic wall and con-

veys the ovarian vessels.

3. Cuboidal epithelium is a specialized surface epithelium that is continuous with peri-

toneal mesothelium. This epithelium allows the egg to rupture into the peritoneal cavity

following ovulation.

4. Blood supply. Arterial blood reaches the ovary from the ovarian artery, a branch of the

abdominal aorta. Venous drainage is through the ovarian veins.

5. Lymphatics. Lymph vessels follow the course of the ovarian artery and vein. They drain

to the lumbar para-aortic nodes.

C. Fallopian tubes (uterine tubes, oviducts)

1. Paired structures that receive the ovum following ovulation.

2. Ferttlization normally occurs in the ampulla (outer one-third) of the tube.

D. Uterus is a muscular, hollow organ.

1. Fundus is the dome-shaped, upper portion of the uterus.

2. Body is the major part of the uterus.

3. Cervix is the narrow inferior neck of the uterus that protrudes into the vagina.

4. Supports of uterus. The levator ani muscle and the round and broad ligaments offer

variable support to the uterus. Additional support comes from the transverse cervical(cardinal) ligaments (of Mackenrodt) and the sacrouterine ligaments.

5. Blood supply. Arterial supply to the uterus is derived primarily from the uterine branch of

the internal iliac artery. Venous drainage is mostly through the corresponding uterine vein.

6. Lymphatics. The lymphatic drainage is multiple through the para-aortic nodes, the exter-

nal and internal iliac nodes, and the superficial inguinal nodes (from the round ligament

in the inguinal canal).

E. Vagina is a muscular tube extending from the uterine cervix to the vaginal opening of the

perineum. Fornices (anterior and posterior) are the vaginal recesses around the cervix.

1. Arterial supply. The vaginal artery is a branch of the internal iliac artery. There is also a

vaginal branch of the uterine artery.

2. Venous drainage. Vaginal veins drain to the internal iliac vein.

3. Lymphatics. Lymph from the vagina drains to the external and internal iliac nodes as well

as to the superficial inguinal nodes.

4. Innervation. The vagina is supplied by nerves derived from the pelvic splanchnic nerves

and the hypogastric plexus, and in its lowermost portion by somatic fibers from the

pudendal nerve.

Clinical Correlate

Tubal ectopic pregnanciesusually occur in the ampulla ofthe fallopian tube. The tubewill rupture at approximately12 weeks of gestation, causingsevere, acute, lowerabdominal pain. lf leftuntreated, there is a danger ofbleeding to death.

Clinical Correlate

The ureter passes directlyinferior to the uterine artery,lateral to the body of theuterus near its junction withthe cervix ("water flows underthe bridge"). During ahysterectomy, therefore, theureter (instead of the uterineartery) may be inadvertentlyligated.

Clinical Correlate

The rectouterine pouch(of Douglas) is the mostinferior part of theperitoneal cavity in women.Culdocentesis to obtain asample of peritoneal fluid is aperformed via the posteriorfornix of the vagina.

t2!

Reproductive System

Clinical Correlate

Breast cancer develops mostfrequently in the upper outer(superolateral) quadrant, wherethere is a preponderance ofglandular tissue.

F. Breast

l. The breast (mammary gland) is a subcutaneous glandular organ of the superficial pec-toral region. It is a modified sweat gland, specialized in women for the production andsecretion of milk. A variable amount of fat surrounds the glandular tissue and duct sys-tem and is responsible for the shape and size of the female breast.

a. The nipple contains the openings of the lactiferous ducts. It is located approximatelyat the level of the fourth intercostal space in nulliparous women and in men. It con-tains circular, smooth muscle fibers that contract during emission (let-down) of milkfrom the ducts.

b. The areola is a variable area surrounding the nipple. It contains sebaceous glands.

c. There are 15-20lactiferous ducts, each of which drains a glandular lobule of breasttissue. The ducts radiate outward from the nipple. The terminal portion of each duct,the lactiferous sinus, is dilated.

d. Cooper ligaments are suspensory ligaments, which attach the mammary gland to theskin and run from the skin to the deep fascia.

2. Arterial supply. Most of the blood supply to the breast is derived from branches of theinternal thoracic (internal mammary) artery. However, the lateral thoracic and thora-coacromial branches of the axillary arlery and the intercostal arteries also contribute tothe blood supply.

3. Venous drainage. Venous blood from the breast drains primarily to tributaries of the axil-lary vein.

4. Lymphatic drainage. Most of the lymph of the breast drains to axillary nodes (pectoralgroup). Lymphatics from the deep surface drain to the apical group of axillary nodes.From the medial surface, lymph drains to the parasternal nodes, which accompany theinternal thoracic vessels. It may pass to the parasternal nodes of the opposite side.

5. Innervation. Sensory fibers from the breast contribute to intercostal nerves2-.6. Thesenerves also carry sympathetic fibers, which supply the smooth muscle of the areolae.

t24

Reproductive Physiology

Reproductive physiology is governed primarily by a delicate balance of hormones secreted into theblood. These hormones put into motion a sequence of events that eventually lead to the desired

response by the target tissues. This chapter will discuss the interplay among the differentreproductive hormones as well as the role they play in gametogenesis, reproduction, pregnancy, and

the puerperium. lt also reviews the hormonal control of sexual differentiation as well as thehormonal role in reproductive development from puberty to old age.

REVIEW OF STEROID HORMONESA. C2l steroids-pregnenes (pmgestins, corticoids). These steroid hormones are either

involved with pregnancy (progestational, progestins) or rnade by the adrenal cortex (corti-

coids). The major progestin, progesteron€, is made in the greatest quantities in the ovary.

B Cl9 steroids-androgens. Androgens are male sex steroids that are synthesized in both men

and women. They are produced in the testes, ovaries, and t}te adrenal corter< and have bio-

Iogical activity in botl males and females.

C. CIE steroids---cstrogens. Estrogens are female sex steroids and are synthesized in the Fhshba* to End'Gdneovaries and testes. Estrogens have biological activity in both males and females.

The Leydig cells cannot

MA1E REpRODUCIION svnthesizeslucocorticoidsormineralocorticoids

A. Androgen s€cretion because theY do not

1. Production of the predominant androgen, testosterone, is via a s),nthetic pathway that haglFhydroxylase or

includes pregnenolone, 17-hydrory-prelnenolone, dehydroepiandrosterone (or$n)' ana I I Flrydroxylase'

androstenedione as intermediates. This synthesis occurs in both the Leydig cells ofthe testisand the adrenal gland.

2. Dihydrotestosterone (DHT) is a metabolic product of testosterone' Conversion toDHT is catalyzed by So-reductase. This conversion is a necessary step for androgenaction in many tissues.

3. There are biologically imPortant small oscillations of Gstosterone. Oscillations follow anequal number of pulses of GnRH secretion by the hlpothalarnus and LH from the pituitary'

4. There is a natural decline in androgen secretion with aging in bot}l males and fema.les.

,25

Reproductive System

Progesterone 1 sB-hYdrory-21 B-hydroryla"" / \ lsteroid dehy-

I \ 17,20-lYase fdrogenasell-Deorycorticosterone l7-Hydrcxyprogesterone -* Androstenedione

I| 11 p-hydrorylaseY

CorticosteroneAngiotensin ll --->l atdosterone

stimulates {

sVnthasethis reaction

Aldosterone

Zona Glomerulosa

| 21 p-hydrorylase| (most common

Y deficiency)11-Deorycortisol

I

| 11 p-hydrorylase

VCortisol

Zona Fasciculata

17,20 -lyasel7-hydroxy- > Dehydro-pregnenolone epiandrosterone

(DHEA)

V

Testosterone

V

Estradiol

GholesterolACTH stimulates---* | chotesterol desmolase

this reaction V 17 u-hydroryrasePregnenolone

' - -

3p-hydrorysteroid Idehydrogenase Y Zona

Reticularis

Note

No, it's not your imagination:This is the same chart youreviewed in the EndocrinePhysiology chapter.

IesfesandOvaries

Figure lV-5-1. Pathways in steroidogenic cells.

B. Transport of androgens in blood. Testosterone circulates bound to sex hormone-biodiogglobulin (SHBG). SHBG binds testosterone, DHT, and estradiol. At least 90olo of testosteroneis bound. Androgens suppress liver production of SHBG. Therefore, compared to females,males have lower levels of SHBG and higher levels of free androgens.

C. Metabolism of androgens. The half-life of testosterone is approximately 90 minutes.Testosterone is activated in specific target tissues to DHT, which is more potent in sometissues.

D. Mechanism of action of androgens.In prostate, hair follicles, and external genitalia, testos-terone is activated to DHT in order for action in that tissue to occur. The active moleculethen binds directly to the nuclear androgen receptor and activates mRNA transcription.

E. Physiologic effects of androgens

1. Fetal. The physiologic effects of androgens on the fetus are so profound that an entiresection on sexual differentiation is included later in this chapter.

2. Spermatogenesis

a. The sertoli cells participate in the initiation of spermatogenesis when FSH binds toreceptors on the sertoli cell. Testosterone from the Leydig cells entering the seminifer-ous tubules is also necessiuy for spermatogenesis. This intratesticular action of testos-terone on spermatogenesis is an example of paracrine effect.

b. The spermatogenic tubules are surrounded by a lymphatic sinus that bathes thetubules in high concentrations of testosterone.

c. Testosterone also acts on the Sertoli cells and stimulates the production of androgen-binding protein (ABP).ABP carries androgens in the spermatogenic tubules towardthe epididymis. While some ABP enters the circulation, it is not the major plasmaandrogen-binding protein. As noted earlier, SHBG is the major carrier of androgensin the plasma.

d. The Sertoli cell also secretes inhibin. Inhibin inhibits FSH secretion by the pituitarygland (see following section on control).

526

Physiology

3. Internal ducts and organs

a. Epididymis. High levels of testosterone are essential for epididymal function. These

levels are derived from transport from the testis inside the duct system. Circulating

levels of testosterone are inadequate for epididymal support.

b. Vas deferens. Circulating levels of testosterone support function of the vas deferens.

Testosterone is essential for optimal function of both the muscular components of the

vas as well as its epithelial lining.

c. Seminal vesicles. Testosterone is essential for the production of seminal vesicle fluid,

a major component of seminal fluid.

d. Prostate. The prostate must convert testosterone to DHT before activiry can occur. In

a condition where the enryme 5c-reductase (the enzyme that converts testosterone to

DHT) is greatly reduced or absent, the prostate gland never develops. DHT causes

growth and secretion in the prostate gland. Growth becomes a problem in older men

who develop benign prostatic hypertrophy (BPH). As the prostate gland enlarges, it

can occlude the urethra and cause a characteristic constellation of symptoms, includ-

ing urinary frequenry, urgency, and nocturia.

4. External genitalia

a. Scrotum. During and after puberty, DHT is responsible for the thinning and develop-

ment of folds (rugation) of the scrotum. This greatly increases the surface area of the

scrotum and allows for heat transfer to keep the testes cool. The lower temperature is

essential for normal sperm production, as well as optimal testosterone production.

DHT is also responsible for scrotum pigmentation.

b. Penis. DHT is essential for enlargement of the penis at puberty.

5. Pubic and axillary hair. DHT is essential for development of pubic and axillary hair in

both males and females. DHT also increases beard growth (this is counteracted by estro-

gens in females) and is responsible for the temporal pattern of balding seen in males (also

counteracted by estrogens in females). If 5u-reductase is absent, males have very scant

facial, pubic, and axillary hair and temporal balding patterns do not appear.

6. Larynx. At puberty, androgens increase the size of the larynx in both males and females,

deepening the voice.

7. Sebaceous glands. Sebaceous gland activity increases in response to androgens. During

the pubertal transition phase, this activity leads to acne (mi1d to severe forms).

8. Behavior

a. Androgens are responsible for maintenance of the libido in males and probably

females. Cultural and psychological aspects also greatly influence sexual behavior.

b. Androgens are also thought to be responsible for aggressiveness. Although there is

much anecdotal evidence to support this hypothesis, definitive proof is still forth-

coming.

9. Anabolic actions of androgens

a. Effect on muscle. Testosterone is the most potent anabolic steroid. Synthetic anabolic

steroids (the legal and illegal varieties) are all essentially modifications of the basic C19

androgen. Testosterone increases protein synthesis in muscles and increases the overall

muscle mass. There is very little 5cr-reductase in muscle, and testosterone (not DHT)

appears to be the predominant effector of androgen activity.


BPH can be treated withdrugs that block theconversion of testosteroneto DHT (e.g., finasteride).

527

Reproductive System

b. Growth spurt. At puberty, both males and females have an acceleration of lineargrowth. Testosterone is presumably the major factor in males, and probably synergizeswith estrogen in females. The mechanism may be direct (there are androgen receptorsin the end plates of long bones) or indirect by stimulating growth hormone secretion,which then stimulates IGF-1 production.

c. Epiphyseal maturation. Androgens have paradoxical effects on bone. They cause theacceleration of long bone growth, but they also stimulate the closing of the epiphy-seal plates (end plates). Thus, androgens limit growth. This is regulated by the totalamount of androgens that the long bones are exposed to. Thus, adding exogenousandrogens (such as taking anabolic steroids) would result in premature closure of thelong bones and a decreased adult height.

F. Control of testosterone secretion (Figure IV-5-2)

CNS

HypothllamusI

GnRH I+Pituitary gonadotrophs

(.)/ \t.l FSH

/ \Leydig cells Seminiferous tubules

ti/ / \t*r, !J )n,o,n-/

Figure lV-5-2. Control of testosterone secretion.

l. GnRH from the hypothalamus is secreted in rycles of l2-24bursts per 24hours. It stim-ulates the pituitary gland to synthesize and release LH and FSH.

2. LH stimulates the Leydig cell to synthesize and secrete testosterone.

3. FSH stimulates the Sertoli cell to synthesize and release ABP and inhibin.

4. Testosterone stimulates the seminiferous tubules and synergizes with FSH to initiate andmaintain spermatogenesis. Testosterone also feeds back at both the hypothalamus andpituitary gland to slow production of GnRH and block synthesis and secretion of LH.

5. Inhibin feeds back to the pituitary gland to block synthesis and secretion of FSH. However,the importance of inhibin in male reproduction is still not completely understood.

6. Input from higher centers in the central nervous system (CNS) can either stimulate orinhibit hypophyseal secretion of GnRH.

G. Regulation of penile erection

1. Erection is mediated by the parasympathetic nervous system and ejaculation is mediatedby the sympathetic nervous system.

a. The autonomic neurons that stimulate erection have been termed nonadrenergic,noncholinergic (NANC) autonomic neurons and they release nitric oxide (NO).

528

Physiology

b. The NO is released at a myoneural junction on the vascular smooth muscle cells of thecorpus cavernosum. The NO binds to the iron in the heme molecule of guanylate

ryclase and activates the ryclase to form cGMP. This, in turn, results in a decrease inintracellular calcium and subsequent smooth muscle relaxation and vasodilatation inthe corpus cavernosa, resulting in erection.

2. The initial stimulation for erection is usually through the central nervous system.Androgen action in the central nervous system is essential for normal libido and erectionto occur. Androgens are also necessary to maintain normal amounts of nitric oxidesynthase, the enzyme that synthesizes NO. Thus, androgens are essentid both in the CNSand in the penis for normal erection to occur.

H. Sperm transport

1. Tiansport from testis to epididymis. Sperm are shed from seminiferous epitheliumalong with fluid that is constantly secreted into the lumen. The fluid is moved with thesperm in suspension. The sperm are not motile or fertile at this stage. Contractile ele-ments in the tubules and lamina propria along with the tunica albuginea propel the fluidforward. Additionally, fluid absorption in the ductule efferentes causes a decreased pres-sure downstream and thus a hydrostatic pressure differential that drives the fluid for-ward. There is a high concentration of testosterone in this fluid.

2. Transport within the epididymis

a. Because of fluid absorption (up to 90o/o) in the efferent ductules, the sperm are con-centrated upon entry into the head of the epididymis.

b. Sperm can stay in the epididymis and survive up to 40 days. Sperm are transported tothe body of the epididymis by peristalsis and move to the tail of the epididymis bycontinued peristalsis. In the tail, a protein is formed called forward motility factor.The interaction of this factor plus testosterone on the sperm allow the sperm tobecome motile. They are still, however, not fertile (not able to fertilize an ovum).

3. Transport from epididymis through the urethra

a. The muscle-to-lumen ratio of the vas deferens is greater than in any other tube in thebody. Major muscular contractions in the vas deferens drive the sperm through therest of the male reproductive tract. It is possible that the muscular contractions arefacilitated by oxytocin and prostaglandins.

b. At the same time that the vas deferens is contracting during ejaculation, fluid (from

the prostate gland and the seminal vesicles) is emitted.

( 1) Prostatic fluid is alkaline and helps neutralize the acid pH of the vagina.

(2) Most of the seminal fluid is from the seminal vesicles. Fluid from the seminalvesicles contains fructose and prostaglandins. The fructose provides an oxidativesubstrate for sperm, while the prostaglandins may be involved in induction ofcontractions in the uterus to help propel the sperm forward.

c. When the seminal vesicles expel their fluid, the rush of fluid past the opening of theterminal portion of the vas deferens draws sperm out of the vas deferens.

I. Testosterone insensitivity syndrome (testicular feminization). This genetic anomalywhich results in a male genotype with a female phenotype is due to inactive or improperlyformed testosterone receptors on cells. As a result, individuals are incapable of respondingto any testosterone stimulation. Such people are in many respects "perfect" females,lackingany testosterone-induced characteristics.

Clinical Correlate

Sildenafil citrate is the firstFDA-approved oral medicationfor the treatment of erectiledysfunction. Sildenafil inhibitsthe phosphodiesterase in thecorpus cavernosum thatconverts cCMP to CMP. Theincreased cCMP potentiatesthe vasodilatation responsiblefor erection.

t29

Reproductive System

In a Nutshell

Estrogen formation issynthesized via a two-cellprocess. Androgens(androstenedione, primarily)are produced in the thecainterna cell and converted toestrogens in the granulosa cell.

a. Due to the presence of the Y chromosome they lack a uterus and ovaries and harborinternal testes.

b. The condition is usually detected at the age of puberty with a chief complaint ofamenorrhea.

c. Because such individuals are physically appearing and psychologically female, treat-ment usually involves surgery to:

(1) Remove the ineffective testes (which at internal abdominal temperatures arelikely to become malignant)

(2) Enlarge and extend the blind vagina to accommodate sexual intercourse

d. Although relatively uncommon, the syndrome is a source of confusion for the under-standing of testosterone action.

(1) These women undergo a growth spurt at the age of puberty and are usually tallerthan the average woman and are frequently thought to be quite beautifrrl. They areoften found working as fashion models. Their long-bone growth cannot be accel-erated by testosterone, nor can their epiphyseal plates be prematurely closed.

(2) They have libido despite no effective testosterone action and they describe theurge to have children which, of course, can be satisfied only by adoption.

(3) Since neither the hypothalamus nor pituitary can respond to testosterone, there

;T:#:*:i:f :"1*;:,Hli;*il:ii#fi':i::J#:"x#:1Jl?i:1T:promotion of protein synthesis and the production of hormone-bindingglobulins (TBG, CBG, SHBG) and all the generalized actions of estrogens notinvolving the primary sex organs.

FEMATE REPRODUCTIONA. Synthesis of ovarian hormones

1. Pathway in theca interna-androgen synthesis. Cells in the theca interna have recep-tors for LH. LH binding to its receptor on the cell membrane stimulates the conversionof cholesterol to pregnenolone. Pregnenolone is converted in a series of steps toandrostenedione, an androgen. Androgens are secreted from thecal cells and are carriedto the granulosa cells as well as to the blood.

2. Pathway in granulosa cells-<strogen synthesis. The granulosa cell contains receptorsfor FSH. FSH binding to its cell membrane receptor has two functions. First, it stimulatesaromatase to convert androstenedione to estrone, which is then converted to estradiol.Second, FSH stimulates the production of new LH receptors on the granulosa cells.

3. Pathway in corpus luteum-estrogen and progesterone synthesis. Corpus luteum cellsare derived from both theca interna cells and granulosa cells.

a. Theca interna cells have very little aromatase enzyme and thus do not make estrogens.As the cell luteinizes, aromatase enzymes develop and thus, LH stimulates the cellsto produce estrogens. Progesterone, which is already in the pathway for the productionof androgens, is also secreted.

b. As noted, granulosa cells already possess the enrymes necessary for conversion ofandrogens to estrogens. FSH induces LH receptors in this cell and as it luteinizes, itdevelops the enzymes necessary to convert cholesterol to androstenedione.Progesterone, from the cholesterol to androstenedione pathway, is also secreted.

550

Physiology

c. Thus, both types of luteal cells (those derived from theca interna cells and those derivedfrom granulosa cells) have the ability to make androgens, estrogens, and progestins.

B. Hormone transport

l. Estradiol binds to SHBG, the same binding protein that carries testosterone in the blood.

2. Progesterone binds to corticosteroid-binding globulin (CBG). Although it is a sex hor-mone, progesterone is structurally closer to the glucocorticoids than to the androgens orestrogens (it is a 21-carbon steroid rather than 19- or 18-carbon steroid). Thus, it bindsto the glucocorticoid-binding protein rather than the sex hormone-binding protein.

C. Hormone metabolism and mechanism of action

1. Estrogens and progesterone are metabolized by sulfonation in the liver and kidney. Thesulfates make these compounds water soluble and they can then be excreted in bile orurine.

2. Progesterone is also metabolized to dihydroprogesterone. This is catalyzed by the sameenzyme that converts testosterone to dihydrotestosterone ( 5o-reductase).

3. These steroids exert their mechanism of action by binding to a cytoplasmic receptor. Thehormone-receptor complex migrates to the nucleus and promotes transcription. Therecent discoveries of the estrogen cr and B receptors has given new insight into estrogenaction and allowed the development of new estrogenic drugs that have specific estrogenactions while being devoid of other estrogen actions.

D. Physiologic effects

1. Estrogen effects on sex characteristics

a. Estrogens are the primary hormones responsible for breast growth.

b. Estrogen is necessary for ovulation.

c. Estrogen stimulates contraction of the fallopian tubes. It acts by increasing oxytocinreceptors in the fallopian tubes. Estrogens also increase the size of the epithelial cellslining the tubes and increases the rate of beating of the cilia in those cells.

d. Estrogens have many effects on the uterus.

(1) Promote endometrial growth (both hypertrophy and hyperplasia) of endometrialcells

(2) Increase both the length and number of the endometrial glands

(3) Increase blood flow to the uterus

(4) Increase the length of the coiled arteries

(5) Increase the amounts of actin and myosin in the myometrium

(6) Increase the spontaneous muscular activity of the uterus, probably by increasingoxytocin receptors

(7) Increase the concentration of estrogen and progesterone receptors

e. Estrogens make the cervical mucus thin and watery.

f. Estrogens thicken the mucosal lining of the vagina. During sexual excitation, estrogenstimulates vaginal epithelial cells to produce a transudate secretion (called vaginalsweating).

g. Estrogens (possibly in combination with androgens) cause an increase in labial andclitoral growth.

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Reproductive System

E.

h. Estrogens may play an indirect role in the libido of females (as in the male, libido isprobably increased primarily due to androgens).

2. Generalized actions of estrogens

a. Estrogens, like androgens, are anabolic. They promote growth and, in combinationwith androgens, are probably responsible for the growth spurt at puberty and epiphy-seal closure.

b. Estrogens promote protein synthesis. One class of proteins that are of specific impor-tance is the hormone-binding globulins (TBG, CBG, SHBG). Estrogens stimulate theliver to increase production of these binding globulins. Estrogens also increase high-density lipoproteins (HDL) and decrease low-density lipoproteins (LDL).

c. Estrogens promote salt and water retention. This is most readily observed in theuterus.

d. Estrogens are responsible for fat deposition. This is seen most prominently in thebreasts, hips, and skin.

e. Estrogens are responsible for inhibiting bone resorption. This is one of the primaryreasons postmenopausal women are given estrogen replacement therapy.

3. Progesterone effects. Progesterone prepares the uterus for pregnancy.

a. It causes further proliferation of the endometrium after estrogen has had an initialstimulation.

b. It counteracts the action of estrogen in sensitizing the uterus for muscular contrac-tion. Progesterone probably accomplishes this by blocking the action of oxytocin, notby blocking the synthesis of oxytocin receptors.

c. Progesterone and dihydroprogesterone increase basal body temperature.

4. Androgen effects. Androgens are secreted by the ovary in very significant amounts,though clearly not to the same levels as in males. The role of androgens in the female isunderstood to a much greater extent than the role of estrogens in males.

a. Androgens are responsible for pubic and axillaryhair growth in females as well as males.

b. While estrogens inhibit bone resorption, evidence is rapidly accumulating that andro-gens stimulate deposition of new bone.

c. Androgens are also responsible for the basal levels of libido in both male and female.

Menstrual cycle (Figure IV-5-3). Although almost all schematic representations of the men-strual cycle have a starting and ending point, it must be remembered that this is a cycle withno fixed beginning or end. We have arbitrarily chosen to begin with the start of menstrua-tion. The cycle represented is 28 days long. This is the average human female cycle, not thenormal cycle. TWo standard deviations from the mean gives an approximate range of normal

rycle length from 2l*35 days.

1. Follicular phase

a. Declining progesterone levels from the previous menstrual cycle release its negativeeffect on the pituitary gland and hypothalamus. As progesterone falls, the cyclicity ofGnRH increases, i.e., there are more spikes per 24 hours. This stimulates FSH secretion.

b. FSH stimulates the follicle to grow and produce more estrogen. Estrogen has a pos-itive effect on the GnRH cyclicity and increases the number of spikes per 24 hours.Increasing estrogen levels then feedback negatively to suppress FSH. LH levels areessentially constant during this phase.

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Physiology

60

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Figure lV-5-3. Monthly cycles of FSH, LH, estrogen, and progesterone.

Midcycle. As estrogen increases rapidly at the end of the follicular phase, this creates thepositive feedback of estrogen on the hypothalamus and pituitary gland and increasesthe number of GnRH spikes per 24 hours, causing a surge of both FSH and LH. It is prob-ably the rate of estrogen rise, not the actual levels, that induces this positive feedback. Thesurge of LH, in combination with the high estrogen levels, induces ovulation.

Luteal phase

a. After ovulation, the cells from the Graafian follicle collapse into the antrum and formluteal cells. Progesterone is secreted in greatly increased quantities as compared to thefollicular phase.

b. Note that as progesterone increases, it is not being driven by any parallel increases in LH.The increase in progesterone is due to neovascularization of the corpus luteum, essen-tially providing a greater surface area for transport of progesterone into the blood.

c. Although LH does not rise, its presence at low levels is essential for normal luteal cellfunction.

d. Progesterone slows the cyclicity of GnRH. Although estrogen is also increased, theeffect of progesterone is greater and the GnRH surges are much less frequent.

e. LH and FSH levels are essentially constant.

f. The corpus luteum then undergoes luteolysis and progesterone and estrogen levelsdecrease. The exact triggering mechanism for luteolysis is not known. When levels ofprogesterone and estrogen are decreased to low enough levels, the lining of the uterusis no longer hormonally supported and the cells undergo apoptosis.

g. With the cells dying, the lining of the uterus sheds and the menstrual period begins.The suppressive effect of progesterone on the hypothalamus is removed and the num-ber of GnRH spikes per 24 hours increases. We are now back at the beginning of thefollicular phase and the cycle repeats.

4. Basal body temperature (BBT). Note that the basal body temperature rises after ovula-tion during the luteal phase of the cycle. This change is probably due to the action ofdihydroprogesterone on the temperature regulation centers in the hypothalamus.

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Reproductive System

5. Inhibin. The ovary, like the testis, secretes inhibin. Inhibin inhibits FSH secretion.However, regulation of FSH in the female is more complex than in the male because estro-gens also inhibit FSH secretion. Inhibin appears to play only a minor role in the female.

6. Regulation of uterine activity and ovum transport during the menstrual cycle

a. Follicular phase. During the follicular phase there is an increased estrogen/proges-terone ratio. This ratio is used to predict the effects on uterine activity. When the estro-gen/progesterone ratio is increased, the oxFtocin receptors increase and uterine andfallopian tube motility is increased. Under oxftocin stimulation, the fimbriae of theoviduct start to sweep over the ovary in order to "capture" any egg that is ovulated.

b. Midcycle. The estrogen/progesterone ratio remains high and at midcycle, the fimbri-ae achieve maximum sweeping frequenry over the ovary. As the egg is released, it ispicked up by the fimbriae and begins its travel down the oviduct. The oviduct itself ismoving in segmental waves and the rate at which the cilia lining the fallopian tube beattoward the uterus increases. As the ovum (which is surrounded by the corona radiatacells) moves towards the uterus, it travels through the ampullary portion of the fal-lopian tube. At the junction between the ampulla and isthmus of the fallopian tube(ampullary-isthmic junction), the contractions become so frequent that the junctionessentially goes into tetany and constricts, thereby blocking passage of the ovum. Theovum remains at this point of the fallopian tube to await fertilization. Most fertiliza-tion occurs at the ampullary-isthmic junction or in the ampulla.

c. Luteal phase. During the luteal phase of the cycle, the estrogen/progesterone ratio isdecreased, and the contractions of the fallopian tube and uterus decrease. This alsorelaxes the ampullary-isthmic junction, allowing the possibly ferttlized ovum (now amorula) to be released and travel toward the uterus. Remember that during the follic-ular phase, estradiol increased the numbers of progesterone receptors so that now,during the luteal phase when progesterone levels are increased, progesterone activityis potentiated and the action of oxytocin is inhibited (via a postreceptor mechanism).Now that the uterus is calm, the blastocyst can implant in the endometrium.

F. Sperm transport in the female reproductive tract

1. Sperm activity in the vagina

a. When sperm are deposited in the vagina, they are not able to fertilize the ovum. Theymust undergo capacitation. Seminal fluid contains decapacitation factors that keepthe sperm from gaining the ability to fertilize. If sperm stay in the female reproductivetract for several hours, they acquire the capacity to fertilize an ovum. However, iffreshly ejaculated sperm are washed in culture medium, they quickly gain the abilityto fertilize. Thus, there are factors normally in semen that keep the sperm decapaci-tated. Once sperm are capacitated, they have a shorter life span (2 days maximum). Inthe decapacitated state, they live longer (possibly one week).

b. The prostatic and seminal vesicular secretions are alkaline and help neutralize the acidmedia of the vagina. The vaginal environment is neutralized.to a pH of 7.0-7. ,whichis optimal for sperm motility.

2. Major impediments to sperm transport

a. Cervical mucus. During most of the menstrual cycle, the cervical mucus is thick andnot easily penetrated by sperm. The sperm move via flagellar motion but have difficul-ty traversing the cervical mucus plug. During midcycle, the cervical mucus becomesthin and watery due to the action of estrogen (an increased estrogen/progesteroneratio). The mucin strands, which are normally coiled and tangled with one another,straighten out and actually form channels of mucin strands that are approximately the

t!4

Physiology

width of a sperm head. The sperm are then able to quickly swim up the channel andenter the uterine lumen.

b. Uterus

(1) Travel of sperm through the uterus is not well understood. This process cannotbe flagellar because the sperm move through the uterus and oviduct much tooquickly to be attributed to flagellar motion alone. Some form of active uterinetransport must be present.

(2) Overall, the pH of the uterus is not good for sperm motility. The contractionsinduced at midcycle (estrogen/progesterone ratio is high so contractions aremost frequent) are opposite in direction to the direction the sperm are traveling.

c. Uterotubal junction. The uterotubal junction is highly folded and estrogen stimula-tion causes swelling of the tissue so that much of the lumen is occluded.

G. Regulation of uterine activity during pregnancy and labor

1. Pregnancy. If pregnancy occurs, the corpus luteum continues to grow and secrete pro-gesterone. Therefore, the estradiol/progesterone ratio is low. Progesterone levels contin-ue to rise throughout pregnancy, thus keeping the ratio low. Since the ratio is low, theuterus remains calm.

2. Labor. The mechanism for the actual initiation of labor is still unknown. It appears thatit is probably caused by the fetal hypothalamic-pituitary-adrenal axis. The most com-monly accepted theory is that just before term, the estrogen/progesterone ratio changes.However, the mechanism of this change also has at least two explanations.

a. The first is that maternal progesterone levels fall in response to elevated fetal cortisollevels. Elevated fetal cortisol does have specific known effects, such as lung maturation.If progesterone falls while estrogen remains constant, then the estrogen/progesteroneratio increases and the uterus can now respond to oxytocin.

b. The other possible explanation is that estrogen increases in relationship to proges-terone. This can also be accomplished by activating the fetal adrenal gland to producemore DHEA. The DHEA is then easily converted to estradiol by the placenta and thematernal circulating estrogen/progesterone ratio increases. Remember that estradiolalso increases oxftocin receptors so that the uterus, at the end of pregnancy, hasapproximately 100 times the concentration of oxytocin receptors as compared to thenon-pregnant state. Thus, without changing the oxytocin concentration, the actionof oxftocin is still amplified because of the increased concentration of the receptors.

3. Delivery. As the uterus begins to contract at the beginning of labor, the head of the fetusis pushed down against the cervix. This causes some cervical stretch. As the cervix stretch-es, neural stretch receptors transmit information to the hypothalamus for new synthesisand secretion of oxftocin. Circulating oxftocin rises, causing a greater contraction of theuterus and further expulsion of the fetus. The upward spiral (positive feedback) of thisneuroendocrine reflex continues until the fetus is expelled. Contractions will continue fora short time after the fetus is delivered and are helpfirl in shutting down blood vessels inthe uterus and expelling the placenta. Once the placenta is expelled, positive feedbackceases and oxytocin levels fall.

H. Placental hormones and the endocrinology of pregnancy

1. Polypeptidehormones

a. Human chorionic gonadotropin (hCG)

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Reproductive System

Clinical Correlate

ln addition to pregnancy, hCClevels are also elevated inwomen with choriocarcinomaand hydatidiform moles.

2.

(l) hCG is similar in structure to LH, FSH, and TSH in that it has both alpha andbeta chains. The alpha chain is the same as that of LH, FSH and TSH. The betachain is different and confers the specificity of hCG and makes it biologically dif-ferent from the other hormones.

(2) hCG binds specifically to LH receptors and is a potent LH agonist. hCG stays onthe LH receptor for a longer time than LH does and this accounts for itsincreased potenry.

(3) hCG is synthesized in the syncytiotrophoblast and secreted into both the fetaland maternal circulations. hCG is manufactured in very high amounts andsecreted into the urine of pregnant women. Measurement of hCG in the urine isthe basis of the home pregnanry tests. Circulating hCG (specifically, the betachain) is usually measured by the physician to confirm pregnancy.

(4) During the first trimester, HCG is responsible for stimulating the corpusluteum to produce estradiol and progesterone.

b. Human placental lactogen (hPL; human chorionic somatomammotropin [hCS]).hPL is similar in structure and function to prolactin and growth hormone (GH). hPLis secreted by the syncytiotrophoblast into both the fetal and maternal circulations. Itdoes not function like prolactin in the pregnant woman (i.e., for milk production)because the breast is not prepared for the production of milk. Milk production willcome after pregnancy, when hPL is no longer present. hPL is more like GH and bindsto the GH receptor as well as to the prolactin receptor.

Steroid hormones

a. Progesterone

(1) Progesterone is initially manufactured by the corpus luteum (stimulated byhCG). The corpus luteum of pregnanry does not undergo luteolysis like thecorpus luteum during the menstrual cycle. At 8 weeks of gestation, the corpusluteum of pregnancy starts to decline in function and by 10-12 weeks of gesta-tion the placenta takes over the production of progesterone.

(2) Progesterone is formed in the placenta via the normal steroid pathway. The pla-centa does not contain any l7a-hydroxylase, so it cannot hydroxylate and can-not cleave the side chain between carbons 17 and 20. Thus, progesterone is theend product of this steroid biosynthetic pathway.

b. Estrogens

(1) Estrone and estradiol. Even though the placenta does not contain 17cr-hydroxy-lase, it is able to form androgens and estrogens from DHEA-sulfate provided bythe maternal and fetal adrenal gland. DHEA-sulfate is desulfated to DHEA.

(2) Estriol. Estriol production, like estrogen and androgen production, depends onfunctional fetal and maternal adrenal glands and a functional placenta. The onedifference is that estriol production also depends on a functional fetal liver.

Function of hormones during pregnancy

a. hCG. The primary role of hCG is to keep the corpus luteum functioning and pro-ducingprogesterone. hCG declines to much lower levels after the deterioration of thecorpus luteum of pregnancy.

b. hPL. hPL primarily functions like GH. It is glucose sparing and makes glucose avail-able from the mother for the fetus. Like prolactin, hPL increases estrogen receptors inthe breast.

3 .

tt6

Physiology

c. Progesterone. The primary function of progesterone is to calm the uterus.Progesterone blocks oxytocin receptor activation by u postreceptor mechanism.Progesterone also acts as an immunosuppressant and blocks cellular-mediated immu-nity at a very local level. Specifically, the very high levels of progesterone in the pla-centa keep the fetus from being rejected. The circulating levels of progesterone are nothigh enough (although they are higher than at any other time in life) to be immuno-suppressive.

d. Estrogens. All three estrogens rise throughout pregnancy.

(1) Estrone and estradiol help keep the endometrium functional during preg-nancy so that the placenta and fetus are well maintained. Estrogens also stimu-late breast tissue during pregnancy and increase the blood flow to the uterus.Estrogens that pass to the fetus are inactivated by a fetal protein called alpha-fetoprotein. This protein binds estrogens so tightly that very little, if any, freeestrogen is available. However, it does not bind androgens at all.

(2) Estriol is a very weak estrogen; it binds very weakly to the estrogen receptor.However, estriol is very good at increasing uterine blood flow and thus may keepthe uterus well supplied with blood without hyperestrogenization in otheraspects.

I. Preparation for lactation prior to birth

1. Function of estrogens. Estrogens increase several parameters that will be essential formilk formation after pregnancy.

a. During pregnancy, estrogens are continually rising and sensitize the pituitary tosecrete more prolactin.

b. The rising estrogen levels also increase the total number of estrogen receptors in thebreast.

c. Estrogen also increases the number of progesterone receptors in the breast.

d. Estrogens stimulate ductal elongation in the breast.

e. High estrogen levels inhibit milk formation.

2. Function of progesterone. Progesterone combined with estrogen causes alveolar growth.High levels of progesterone may also be inhibitory to milk formation.

3. Function of prolactin and hPL

a. Prolactin (which increases during pregnancy due to increasing estradiol levels) andhPL increase estrogen receptors in the epithelium of mammary glands.

b. Although the breast is being prepared for lactation, no milk is produced (due to veryhigh levels of estrogen and possibly progesterone). Toward the end of pregnanry andthe beginning of the period right after pregnancy (the puerperium), the alveoli are fullof colostnun, a thin, watery fluid that is rich in antibodies. During the first few daysafter delivery, colostrum is the fluid that the newborn uses for nourishment.

L Hormonal regulation of milk production and secretion

1. Estrogens and progesterone. After birth, estrogen and progesterone levels decline.However, it takes several days before the levels are low enough to allow lactation to begin.Estrogen and progesterone levels do not go to zero; some estrogen and progesterone isrequired for lactation.

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Reproductive System

2. Permissive hormones. In addition to the necessity of low levels of estrogen and proges-terone, other "permissive" hormones are also necessary at low levels for lactation to occur.These hormones are insulin, thyroxine (or triiodothyronine), and cortisol.

3. Prolactin. In the presence of the hormones mentioned above, prolactin stimulates milkproduction. The feedback system that regulates the secretion of prolactin is a neural feed-back, not hormonal. Prolactin synthesis and secretion is under tonic inhibition bydopamine (prolactin-inhibiting hormone). The primary neural feedback for prolactinsecretion is nipple stimulation. Nipple stimulation suppresses dopamine release andthus removes the inhibition of prolactin secretion.

4. Oxytocin

a. Oxytocin causes contractions of the myoepithelium, resulting in milk let-down.Oxytocin does not stimulate milk production like prolactin does. This is another neu-roendocrine loop. The suckling stimulus sends a neuronal impulse to the hypothala-mus that releases oxytocin into the bloodstream from the posterior pituitary.

b. Other stimuli will also result in oxftocin secretion. Psychologic stimulation will cause arelease of oxytocin. The two primary psychologic situations that induce oxFtocin releaseare the mother hearing the ba\ crylng and mental sexual stimulation. fu was pointedout for the situation for labor, stretching of the cervix induces oxytocin stimulation.Additionally, stimulation of the external genitalia results in oxytocin stimulation.

K. Return of hormonal cyclicity after birth. The return of hormonal cyclicity after birth isdependent on the recovery of the profound suppression of LH and FSH present during preg-nancy and lactation. During pregnancy, the high levels of estrogen and progesterone havekept the hypothalamic-pituitary axis suppressed. At the end of pregnansy, levels of estrogenand progesterone fall to low levels but prolactin continues to remain high if nursing occurs.High levels of prolactin will also suppress LH and FSH. Thus, the longer nursing continues,the longer the suppression of LH and FSH.

HORMONAT CONTROT OF SEXUAT DIFFERENTIATIONA. Genetic sex. Genetic sex is determined at the instant of fertrlization. If the embryo is XX, it

will develop into a female; if the embryo is XY, it will develop into a male.

1. A true hermaphrodite is an individual that is both XX and XY and possesses all of thesexual structures of both females and males. This is extremely rare in nature.

2. Nomenclature for describing abnormalities of sexual differentiation always compare backto the genetic sex of the individual.

a. A phenotypic female that is genetically XY is called a male pseudohermaphrodite.

b. A phenotypic male that is genotypically XX is called a female pseudohermaphrodite.

B. Gonadal sex. The primitive gonads arise bilaterally from a region near the developingadrenal glands. The primitive gonad consists of a cortex and a medulla.

1. In an XX genotype female, the cortex grows and the medulla atrophies. Thus, the cortexbecomes the adult ovary.

2. In an XY genotype male, the medulla expands and the cortex atrophies, with the medullaforming the precursor of the adult testis. The medulla secretes a substance called "testisdetermining factor," which is coded for on the Y chromosome. This factor causes regres-sion of the cortex and induction of the medulla.

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Physiology

C. Development of internal duct systems

1. Wolffian ducts (mesonephric ducts). The Wolffian ducts will develop into the adultmale internal duct system consisting of the epididymis, vas deferens, and seminal vesi-cles. The prostate gland and the urethra develop from the urogenital sinus. The ducts arepresent in both males and females until approximately 8 weeks of age.

a. At this point in the female, the Wolffian duct begins to degenerate, starting at thegonad and progressing toward the urogenital sinus. The ovary during this period isquiescent and is not producing steroids.

b. In the male, testosterons slaSilizes theWolffian duct. Testosterone will stabilize all ofthe structures of theWolffian duct as the hormone drains toward the urogenital sinus.However, as it reaches the prostate gland, it must be converted to DHT in order toinduce prostatic outgrowth of the urogenital sinus. The prostatic and penile urethraare also DHT dependent.

2. Miiilerian ducts. The Mtillerian ducts develop lateral to the Wolffian ducts. They are alsopresent in both sexes until acted upon by a protein from the Sertoli cells of the fetal testiscalled anti-Miillerian hormone (AMH).

a. In males, AMH causes the active degeneration of the Miillerian ducts.

b. In females, there is no AMH and the Mtillerian ducts continue to proliferate andbecome the adult female internal duct structures. This includes the fallopian tubes(oviducts), the uterus, and the upper two-thirds of the vagina. The lower one-third ofthe vagina is of ectodermal origin and is produced by the infolding of ectoderm.

D. Development of external genitalia. The external genitalia begin in an indifferent stage thatis identical in both sexes. Development into the male structures is entirely DHT depen-dent. If no hormones are present (as is the case when an ovary has developed) the femalestructures develop.

E. Neural differentiation. Male hormones appear to induce a male sexual brain, while theabsence of male hormones leads to the development of a female sexual brain.

REPRODUCTIVE DEVETOPMENT: PUBERTY AND AGINGA. Prepubertal reproductive development

1. Birth to 6 months of age. In males, there is a postnatal testosterone surge that may haveimportance in future sexual behavior. There is no concomitant estrogen or androgensurge in the female.

2. Early state of the hypothalamic-pituitary-gonadal axis. In the early prepubertal axis,gonadal steroids do not feed back to the hypothalamus and pituitary gland. LH and FSHserum levels (reflecting diminished secretion by the pituitary gland) are low. Additionally,GnRH secretion is also minimal and noncvclic.

B. Puberty

1. Underlying mechanisms regulating maturation of the hypothalamic-pituitary-gonadal axis

a. Sleep-associated hormone secretion.In the early prepubertal child, GnRH secretionis fairly constant. The very first sign that a child is entering puberty is sporadic spikesof GnRH that occur during sleep. This results in concomitant spikes in LH (FSHchanges very little at this time).

ln a Nutshell

Early in development, bothmale and female fetuses haveboth sets of internal ductsystems, the Wolffian ductsand the MUllerian ducts. Thetestis produces two majorhormones, testosterone andAMH. The testosteronestabilizes the Wolffian ducts,thereby stabilizing the malereproductive tract. AM Hinduces degeneration of theMullerian ducts and thereforegets rid of the potential femalestructures in the male. ln thedeveloping female, theabsence of testosterone resultsin a failure to stabilize theWolffian ducts and the maleduct system disappears. Sincethe ovary is not making AMH,the Mullerian duct systemremains and proliferates intothe internal femalereproductive tract.

In a Nutshell

lf androgens are present andthe 5a-reductase enzyme isactive in the external genitaliaprimordia, then the fetus willdevelop male external genitalia.The absence of hormonesallows for development offemale external genitalia.

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Reproductive System

Note

You don't need to know theTanner Stages for the Step Iexam;you will need to knowthem for Step 2.

Clinical Correlate

Although the ovary hasstopped ovulating, there areprobably some ova left (notmany, but some) in themenopausal ovary. This facthas been used clinicallv toartificially primepostmenopausal females withhormones that induceovulation, thereby enablingthem to conceive at this stagein their life cycle.

Clinical Correlate

Hot flashes are the primaryreason that women initiallyseek medical intervention withhormones after menopause.

b. Decreasing negative-feedback sensitivity. As puberty progresses, the feedback systembecomes less sensitive. The very low levels of gonadal steroids become capable of sup-pressing GnRH and LH secretion. The hypothalamus seems to be the primary organthat initiates puberty in that it now starts to become less sensitive to the feedback ofthe gonadal steroids. The nocturnal spikes of GnRH become more frequent, occurringthroughout the 24-hour day. LH, following the pattern of GnRH, stimulates the gonadin an oscillatory pattern.

c. Development of positive feedback in girls. One of the last phenomena of puberty isthe development of positive feedback of estrogen on GnRH in females. The mecha-nism is not yet completely understood.

d. Adrenal gland. Another development that occurs at puberty is the process called theadrenarche. The adrenal gland starts producing greater amounts of androgens duringearly phases of puberry usually prior to the increase in serum gonadotrophin levels.This adrenal androgen secretion is probably responsible for the initial growth ofpubic and axillary hair in both males and females. Adrenarche is not associated withany changes in CRH or ACTH; it appears to be completely associated with sponta-neous changes in the adrenal gland itself.

2. Physical changes of puberty (Tirnner stages). The physical changes that occur in breastdevelopment and pubic hair growth in females and in external genitalia and pubic hairgrowth in males were classified many years ago by Dr. Thnner, a pediatrician. Dr. Tannerclassified different grades of sexual development into five stages. Puberty is still classifiedaccording to the five Thnner stages.

C. Aging.In both men and women, there is a diminution in gonadal function with age.

l. Females

a. In women, reproductive aging is very dramatic in that there is a specific, clearly notice-able change, the cessation of menstruation. The process is somewhat gradual, withlengthened cycles preceding the actual cessation. This phenomenon is termedmenopause and usually occurs between 45 and 55 years of age. Accompanying thecessation of menstruation is a cessation of ovulation. Menopause in humans is thoughtto be a gonadally mediated event, as opposed to puberry which is hypothalamicallymediated. However, although the ovary probably initiates menopause, the resultingchanges in the hormones that bathe the hypothalamus probably permanently reset thehypothalamus as well.

b. When the ovary stops ovulating, follicles are no longer formed and estrogen produc-tion greatly diminishes. Since ovulation does not occur, a corpus luteum does notform and progesterone production is greatly diminished. Basal levels of LH and FSHrise, with FSH levels rising much more than LH levels.

c. A striking feature of menopause in many women is the occurrence of hot flashes.Tieatment with estrogen suppresses these flashes.

d. Beneficial effects of estrogen treatment

(1) Estrogen helps prevent bone resorption and osteoporosis. Calcium supple-mentation from early ages (right after puberty) is also recommended to com-bat osteoporosis.

e. Estrogen treatment after menopause may increase the risk of breast cancer.

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Physiology

2. Males

a. Although males experience reproductive aging, there is no dramatic demarcation ofloss of fertility as there is in the female. What is many times referred to as the "malemenopause" usually refers to a psychologic event where the male is trying to "regainhis youth."

b. As men age, there is a gradual decrease in androgens. After the age of 60, a rise in plas-ma LH levels can be detected and is much more pronounced between 65 and 70 yearsof age. Spermatogenesis continues throughout life. FSH may rise slightly as menreach 65 to 70 years of age, but it is much less marked than the rise in LH.

c. One of the main changes that accompanies male reproductive aging is an enlargementof the prostate gland, termed benign prostatic hyperplasia (BPH). Because the prostategland is almost completely dependent on DHT rather than testosterone, BPH andprostate cancer treatment is currently being directed at inhibiting the conversion oftestosterone to DHT.

Clinical Correlate

One of the problems thatwomen occasionally complainof after menopause isexcessive growth of hair. Athicker mustache or some chinhairs may be apparent. Thereason that some hirsutismis noticed after menopauseis that the androgenic activityis unopposed by estrogens.

Bfidge to Pathology

BPH is discussed in greaterdetail in the ReproductivePathology chapter inthis book.

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Male Reproductive Pathology

The most common clinical findings in male reproductive pathology are solid tumors of the testes,prostate, and penis. Prostate carcinoma, in fact, is the most common cause of cancer in men. Sincethe majority of the tumors are well differentiated and respond to chemotherapy, radiation therapy,or surgery, it is important to be able to identify the tumors early on in the course of the disease,through the use of screening tests, tumor markers, and clinical signs and symptoms. This chapterwill focus on these diseases, as well as on other disorders that commonly affect the malereproductive system.

TESTESA. Cryptorchidism

1. Clinical features. Cryptorchidism is the failure of normal descent of intra-abdominaltestes into the scrotum. It affects approximately lo/o of the adult male population, moreoften on the right side than the left, and may be unilateral or bilateral. Bilateral cryp-torchidism can cause infertility by elevating temperature of the testes to a level that inter-feres with spermatogenesis. Maldescended testes are also susceptible to trauma, and havea greatly increased incidence of testicular cancer.

2. Pathogenesis. Cryptorchidism may be a mechanical, hormonal, or idiopathic congenitalanomaly.

B. Germ cell tumors. Approximately 95o/o of testicular tumors are germ cell tumors. They arethe most common malignancy in men l5-34years of age. Although the reason is unknown,cryptorchidism increases the likelihood of malignanry 14-fold.Infection, trauma, and genet-ic factors also influence incidence. Generally, germ cell tumors begin as a painless testicularenlargement, with potential for widespread dissemination, usuallyvia the lymphatics to iliacand para-aortic nodes (Table IV-6-1).

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Reproductive System

Thble IV-6-f . Testicular tumors.

Tirmor Clinical Feature Pathology

Germ cell

Seminoma

Embryonal carcinoma

Choriocarcinoma

Yolk sac tumors

Teratoma

Nongerm cell

Interstitial (Leydig)

cell tumors

Sertoli cell tumors

Lymphoma

Radiosensitive

Often metastatic

Highly malignant;

elevated hCG'|'r 'n' '-:, '

Infants and children;

elevated AFP

Mature or immature

May produce estrogens

or androgens

May produce estrogens

or androgens

Older men

Bully and homogeneous

Hemorrhagic nodules

Cyto- and

syncytiotrophoblast

Nonencapsulated

Variery of tissues

Usually unilateral

Usually unilateral

Often disseminated

1 . Seminoma

a. Clinical features. Rare in infants, incidence increases to a peak in the fourth decade.

b. Pathology

(1) Grossly, the tumors appear as a bu\, grey-white mass exhibiting a homoge-neous cut surface (Figure IV-6-1).

(2) Microscopically, seminomas are composed of sheets of uniform polyhedral cells,divided by fibrous septa of connective tissue; lymphocytes and multinucleatedgiant cells can also be present. Ten percent of all seminomas show increasedmitoses and nuclear atypia, i.e., "anaplastic seminomas" (Figure IV-6-2).

c. Course and prognosis. With treatment, the 5-year survival rate exceeds 90olo. Thetumors are highly radiosensitive, and metastases are rare.

Embryonal carcinoma

a. Clinical features. Embryonal carcinomas occur most commonly in the 20-30-year agegroup and are more aggressive than seminomas. These tumors present with testicularenlargement, and 30olo have metastatic disease at the time of diagnosis. Serum AFP isusually elevated.

b. Pathology

(1) Grossly, embryonal carcinomas form nodules with areas of hemorrhage andnecrosis, often involving the epididymis, the spermatic cord, and the tunicaalbuginea.

(2) Microscopically, embryonal tumors are comprised of pleomorphic epithelialcells, frequently exhibiting mitoses, hemorrhage, and necrosis. Cellular arrange-ments are varied in composition, including papillary, glandular, tubular, andalveolar cells.

2.

,44

Pathology: Male

Figure lV-6-1. Seminoma of the testis (gross).

Figure lV-6-2. Seminoma of the testis (microscopic).

c. Course and prognosis. The 5-year mortality rate is 650/o. Less radiosensitive thanseminomas, embryonal carcinomas often metastasize to lymph nodes, lungs, andliver. Patients may require orchiectomy and chemotherapy.

3. Choriocarcinoma

a. Clinical features. Most common in men 15-25 years of age, these highly malignanttumors may coincide with gynecomastia or testicular enlargement. Laboratory stud-ies typically show elevated serum and urine hCG levels.

b. Pathology

(1) Grossly, the picture is variable. Usually, small amounts of preserved tissueappear amidst areas of hemorrhage and necrosis.

!45

Reproductive System

Note

Yolk sac tumors may beconsidered a variant form ofembryonal carcinoma.

Note

Alpha{etoprotein is also veryelevated in liver cancer; it canbe less markedly elevated innonneoplastic liver disease.

(2) Microscopically, both cytotrophoblast and syncytiotrophoblast must be pre-sent, usually arranged around fibrous septa of connective tissue. Hemorrhage isprominent. Choriocarcinoma is often mixed with other germ cell tumors.

c. Course and prognosis are poor. These tumors tend to disseminate hematogenously,invading lungs,liver, and brain, and are treated with orchiectomy and chemotherapy.

4. Yolk sac tumors

a. Clinical features. Most common in children and infants, these testicular tumors are rarein adults. Thev can also coincide with embryonal carcinoma. SerumAFP is elevated.

b. Pathology

(1) Grossly, yolk sac tumors are nonencapsulated, homogeneous, and whitish-yel-low in appearance.

(2) Microscopically, there may be solid cords of cells or a papillary arrangement.The cytoplasm contains eosinophilic globules full of AFP and u,-antitrypsin.

c. Course and prognosis. Yolk sac tumors are very aggressive, exhibiting a 50o/o 5-yearmortality rate.

5. Teratoma

a. Clinical features. Teratomas can occur at any age, but are most common in infantsand children. This type of tumor appears as a testicular mass.

b. Pathology

(1) Gross pathology is variable, often appearing as a whitish-grey matrix in whichdiverse elements (e.g., bone, cartilage, cysts) can amalgamate.

(2) Microscopically, teratoma cells may show differentiation into any of three germlayers: endoderm, mesoderm, or ectoderm. Mature teratomas tend to be well dif-ferentiated, exhibiting a variety of tissues, such as nerve, muscle, cartilage, andglands. Immature teratomas show incomplete differentiation with primative-appearing cells.

c. Course and prognosis. Generally, teratomas exhibit benign activiry during childhoodyet behave variably in adults. Overall, the 2-year mortality is 30olo. Tieatment isorchiectomy, followed by chemotherapy and radiation.

6. Tumor markers

a. Alpha-fetoprotein is a protein synthesizedby the fetus during the first year of life thatcan be produced by some germ cell tumors.

b. Human chorionic gonadotropin is a glycoprotein synthesized by placental syncy-tiotrophoblast. The B subunit of HCG has a unique amino acid sequence, making spe-cific assay possible. It is produced mostly by choriocarcinomas.

c. Diagnosis and staging. Ttrmor markers may prove useful in diagnosis, staging, andfollow-up; elevated markers following treatment can serve as early indicators ofrelapse. Staging of germ cell tumors of the testis is as follows:

( 1) Stage I is confined to the testis.

(2) Stage II spreads to the nodes below the diaphragm.

(3) Stage III is distant metastases.

546

Pathology: Male

7. Treatment plans vary according to characterization and stage of tumor. Surgery, radia-tion, and chemotherapy may all be used.

C. Nongerm cell tumors

1. Interstitial (Leydig) cell tumors

a. Clinical features. L.ydig cell tumors can produce androgens, estrogens, or corticos-teroids. In children, they often present with masculinization or feminization and inadults with gynecomastia.

b. Pathology

(1) Grossly, interstitial tumors form large, brownish-yellow masses or small nod-ules. More than 90olo are unilateral.

(2) Microscopically, tumor cells resemble normal L.ydig cells with round nuclei,eosinophilic cytoplasm, and lipid granules. Approximately one-half of thesetumors contain cigar-shaped crystalloids of Reinke.

c. Course and prognosis. They are usually benign and only I0o/o are invasive. Surgerymay be curative.

2. Sertoli cell tumors

a. Clinical features. Sertoli cell tumors can produce small amounts of androgens orestrogens, but usually not enough to cause endocrinologic changes. They may presentwith testicular enlargement.

b. Pathology

(1) Grossly, these tumors cause enlarged testicles or may form small nodules in anormal-sized testicle.

(2) Microscopically, they are composed of uniform tall or polyhedral cells, withclear cytoplasm, growing in cords resembling spermatic tubules.

c. Course and prognosis. Over 90o/o of these tumors are benign.

3. Lymphomas are the most common testicular cancer in elderly men. The tumors are rarelyconfined to the testes.

D. Inflammatorylesions

1. Mumps

a. Clinical features. Orchitis develops in approximately 25o/o of patients over age 10,usually within a week after parotid swelling. Orchitis is less common in patientsunder 10 years old.

b. Pathology

(1) Mononuclear inflammatory infiltrates predominate in the acute phase.

(2) Atrophy is rare.

c. Course. Mumps rarely leads to sterility. However, should atrophy follow, it may pre-

dispose patients to testicular neoplasm.

2. Gonorrhea

a. Clinical features. A neglected urethral gonococcal infection may spread to theprostate, to the seminal vesicles, and to the epididymis, but rarely to the testes.

b. Pathology. There may be purulent inflammation or abscesses.

,47

Reproductive System

3. Syphilis

a. Clinical features. Acquired or congenital syphilis may involve the testes.

b. Pathology. There are two forms: gummas or a diffuse interstitial/lymphocytic plasmacell infiltrate.

c. Course. Syphilis can lead to sterility; Leydig cell involvement can cause a loss of libido.

4. Tuberculosis

a. Clinical features. TB usually spreads from the epididymis; this is almost always asso-ciated with foci of TB elsewhere.

b. Pathology. Caseating granulomata are the classic finding, as with TB disseminationelsewhere.

5. "Nonspecific" inflammation is usually caused by Chlamydia trachomatis spread from theepididymis.

E. Torsion

1. Clinical features. TWisting of the spermatic cord may compromise both arterial supplyand venous drainage. Torsion may be precipitated by sudden movement, trauma, or con-genital anomalies.

2. Pathology

a. Grossly, the testis is usually enlarged and can become soft and necrotic.

b. Microscopically, the pathology is variable, depending on the duration and severity ofthe insult. Findings range from congestion to hemorrhagic infarct.

3. Course. If not surgically corrected early, torsion may result in testicular infarction withresultant loss of function.

PROSTATEA. Benign prostatic hyperplasia (BPH)

1. Clinicalfeatures. BPH is characterizedby the formation of large nodules in the peri-urethral region (median lobe) of the prostate, which may narrow the urethral canal toproduce varying degrees of urinary obstruction. Patients often present with difficultyurinating. It is increasingly common after age 45, and the incidence increases steadilywith age (e.g.,90o/o of men after age 70).

2. Pathogenesis. The mechanism is poorly understood, but blocking androgens reduces theincidence.

3. Pathology

Note

The "H" in BPH moreaccurately representshyperplasia than hypertrophy,although you may seeeither term still used.

548

Pathology: Male

Figure lV-6-3. Fibromuscular and adenomatous hyperplasiaof the prostate (gross).

a. Grossly, the prostate is enlarged, and the nodules compress surrounding prostate tis-sue (Figure IV-6-3).

b. Microscopically, there are multiple patterns of nodular hyperplasia. Both glandularand fibromuscular stromal proliferation can occur in the same gland.

4. Course. The course can follow an asymptomatic pattern, or it could result in urinarysymptoms and urinary retention, leading to secondary bladder changes, such as smoothmuscle hypertrophy. Currently, it is thought that this disease does not predispose to pro-static carcinoma.

B. Carcinoma

1. Clinical features. Prostatic carcinoma is the most common cancer in men. Prostate cancerusually occurs after age 50, and the incidence increases steadily with age. In addition toclinically significant tumors, a high incidence of small "incidental" or "latent" carcinomasis discovered at autopsy in men over age 50. The disease may present with urinary prob-

lems or a palpable mass on rectal examination.

2. Pathogenesis is unknown. The tumor is age related, associated with race (more commonin African Americans than in Caucasians, relatively rare in Asians), and is underendocrinologic and environmental influences.

3. Pathology

a. Grossly, prostate cancer is found usually in peripheral tissue and is firm and "gritty"

as a result of fibrosis.

b. Microscopically, most are adenocarcinomas. Patterns range from a well-differentiat-ed glandular pattern with uniform epithelium, oval nuclei, pale cytoplasm, and raremitotic figures, to a poorly differentiated glandular pattern that is hard to discern,where tumor cells grow in sheets and may show mitoses and cellular atypia (Figure

IV-6-4).

Clinical Correlate

The urinary symptoms of BPHinclude frequency, nocturia,and problems initiating andstopping the urinary stream.

Note

While prostate cancer is morecommon than lung cancer,mortality from lung cancer ismore than twice the mortalityfrom prostate cancer.

,49

Reproductive System

Clinical Correlate

An elderly man witho$eobla$ic metastases visibleon x-ray should be consideredto have pro$ate carcinomauntil proven othenruise.

C.

4. Course and prognosis

a. Staging of prostatic tumors depends upon the size of the tumor, the degree of infil-tration to local tissues, and the degree of metastasis.

b. Metastases may occur via the lymphatic or hematogenous route; bone is commonlyinvolved with osteoblastic metastases, typically in the pelvis and lower vertebrae.

c. Tumor markers. PSA (prostate-specific antigen) is an enzyme produced by normal,hyperplastic, and malignant prostate glands. It is elevated in both hyperplasia and can-cer, but usually more so in the latter (particularly when extracapsular efiension hasoccurred). The usual cutofffor serum PSA is 4 nglmlbelow age 50. The normal rangerises graduallywith age. Levels between 4 and 10 ng/ml are in agray area. Elevated PSA

:".*;,1* with an enlarged prostate on digital rectal exam is highly suggestive of carci-

d. Survival is correlated with stage and grade. Unfortunately, most patients present withadvanced disease and have a lO-year survival rate of less than 30o/o.

e. Treatment involves surgery, radiation, and hormonal modalities (orchiectomy andandrogen blockade).

u u F

Figure lV-6-4. Well-differentiated adenocarcinoma of the prostate (microscopic).

Infections

1. Acute prostatitis

a. Clinical features. This condition usually results from a bacterial infection of theprostate. Pathogens are often organisms that cause urinary tract infection. ̂ Esch erichiacoli is the most common, followed by other Gram-negative rods, including Kebsiella,Proteus, Pseudomonas, Enterobacter, and Serratia.Infection may follow manipulationof the prostate or urethra (e.g., rystoscopy, catheterization).

b. Pathogenesis. Bacteria spread by direct extension from the posterior urethra or thebladder. Lymphatic or hematogenous spread can also occur.

550

Pathology: Male

c. Pathology

(1) Grossly, the gland is enlarged and boggy. Edema and congestion, multiple smallabscesses, or small areas of necrosis may all be seen.

(2) Microscopically, necrotic foci and a leukocytic infiltrate occur.

d. Course. Appropriate antibiotic therapy is usually curative.

2. Chronic prostatitis

a. Clinical features. Chronic prostatitis is a common cause of recurrent urinary tractinfections in men. There are two types: bacterial and nonbacterial. Both forms may beasymptomatic or may present with lower back pain and urinary symptoms.

b. Pathogenesis. Bacterial infection may be a sequela of acute prostatitis; nonbacterialinfections are most often caused by Ureaplasma and Chlamydia trachomatis.

c. Pathology

( 1) Grossly, there is usually an enlarged prostate.

(2) Microscopically, the inflammatory reaction in the prostate is usuallylymphocytic.

PENISA. Congenitd malformations

1. Hypospadias and epispadias

a. Clinical features. These are malformations of the urethral groove and canal. They areoften associated with crlptorchidism and other congenital anomalies.

b. Pathology. In hypospadias, the urethra opens onto the ventral surface of the penis. Inepispadias, the urethra opens onto the dorsal surface.

c. Course. Both of these malformations may cause infertility.

2. Phimosis. In this condition, the prepuce orifice is too small to be retracted normally. Itinterferes with hygiene, and can also predispose to bacterial infections. If the prepuce isretracted over the glans, it may lead to painfirl swelling with subsequent urethral constric-tion, termed paraphimosis. Circumcision is indicated.

B. Infections

1. Condyloma acuminatum

a. Clinical features. This is a benign lesion of papillomavirus origin, which may occuron any mucous membrane.

b. Pathology

( 1) Grossly, lesions usually form on the inner surface of the prepuce or on the coro-nal suface. They are red papillary lesions a few millimeters in diameter, whichmay be sessile or pedunculated.

(2) Microscopically, there is thick, hyperplastic squamous epithelium covering abranched connective tissue stroma. Maturation is orderly, but some mitoticfigures are present. "Fried egg" cells (a pyknotic nucleus in a clear cytoplasm)are visible, indicative of papillomavirus.

551

Reproductive System

Note

Chancroid is not caused bythe same etiologic agent aschancre Gyphilis). Chancroidis caused by H. ducrei,whereas chancre is causedby T. pollidum.

2. Syphilis. Syphillis is a sexually transmitted or congenital disease caused by the spirocheteTreponema pallidum. The acquired form initially presents with cutaneous manifestationsfollowed by widespread dissemination. The disease occurs in stages.

a. Primary syphilis has an average 3-week incubation during which spirochetes spreadthroughout the body. Painless chancre sores form and heal within 1-3 months.

( 1) Grossly, chancres usually occur on the glans penis in men and the vulva or cervixin women. Occasionally, they appear on other mucous membranes, such as theoral cavity. They appear as single, firm, red papules that may ulcerate.

(2) Microscopically, there is a mononuclear infiltrate with obliterative endarteritis.Plasma cells are very prominent. Special stains may show treponemes.

b. Secondary slphilis usually develops 1-2 months after the primary stage. There is alocal or generalized rash lasting 1-3 months. The rash can involve the palms and solesas well as mucous membranes. Condyloma lata can appear on the penis.

(1) Grossly, condyloma lata are flat, brown-red papules on the penis or othermucous membranes. They may form large plaques or ulcerate.

(2) Microscopically, there is an obliterative endarteritis and plasma cell infiltrate.Treponemes are present.

c. Tertiary slphilis develops in one-third of untreated patients. It may affect the centralnervous system (CNS), heart, and skin. Neurosyphilis has a varied presentation,including meningovascular, tabes dorsalis, and general paresis. CNS gummas are rare.An obliterative endarteritis can occur, involving the vasa vasorum of the aorta, whichcan lead to the formation of an aneurysm. Elastic stains show destruction of fibers. Inother tissues the characteristic lesion is the gumma.

( 1) Grossly, gummas may be single or multiple. They have rubbery, necrotic centralfocus that is variable in size. They are most common in the liver, testes, and bone.

(2) Microscopically, gummas are composed of mononuclear cells surrounding acenter of coagulative necrosis. Gummas resemble caseating granulomas butusually do not have multinucleated giant cells and do not have any stainableacid-fast organisms. Tieponemes are rare.

d. Serologic tests for slphilis

(1) VDRI tests for nonspecific antibodies evoked by spirochetal infection; theseantibodies react with cardiolipin, a lipoid substance from beef heart. The VDRLbecomes positive a few weeks after primary infection and may remain persis-tently elevated. "False positives" *uy occur in many acute illnesses, as well as inchronic mononucleosis, leprosy, hepatitis, and autoimmune disorders.

"'i*".:ffi:ilit.T::l1T'L:,1:!,.il'i.;fi",:l'# T,:fl TTl,',:?":T,'ff;?:"3. Chancroid

a. Clinical features. This is a sexually transmitted infection caused by Haemophilusducreyi. Patients have a painfrrl chancre and regional lymphadenopathy.

b. Pathology

(l) Grossly, patients present with a soft chancre, usually on the penis. It is initiallymacular, becomes papular, and then ulcerates.

(2) Microscopically, inflammation and granuloma formation occur. There are notreponemes.

,52

Pathology: Male

4. Lymphogranulorna venereurn (I,GV)

a. Clinical features. LGV is a sexually transmitted disease caused by Chlamydia tra-

chomais, lt is rarc in t}Ie United States but common in tropical areas. IGV can present

with genital or anorectal lesions or regional l1'rnphadenopatly.

b. Pathology

(1) Grosdy, I,GV causes a painless ulcer on the penis, mouth, anus, or rectum. Glinkal Corelate

(2) Microscopically, tlere is a neutrophilic exudate. Lymph nodes show hlaerplasia

and granuloma formation in small necrotic centers, which may coalesce to form HSV I usually appears abovestellate abscesses. the wai$line; HSV ll typically

c. Course. Scarring and fibrosis can follow chronic infection. Subsequent lymphatic appears below They share

obstruction can Lad to edema and elephantiasis ofthe lower extremities and external genes, and either can appear

genitalia. anYwhere

5. Genital herpes

a. Clinical features. There are two subtypes: herpes simplex (HSV I) and herPes geni-

talis (HSV II), causing an overlapping spectrum of disease.

b. Pathology

(1) Grossly, HSV I and II cause vesicles on the external genitalia and mucous mem-

branes; ulcerations can also develop.

(2) Microscopically, epithelial cells show cytopathic changes (Cowdry type A aci-

dophilic intranuclear inclusions) and slightly increased cellular and nuclear size'

Cell fusion leads to giant cells or polykaryons, which can be seen on a smear of

blister fluid or Tlanck smear'

c. Course. HSV inf€ctions tend to recur. The virus can remain latent in nerve ganglia'

Acyclovir may prevent or d€crease tie ftequenry of recurrences.

6. Granulorna inguinale

a. Clinical features. Granuloma inguinale is a chronic' sexually transmitted disease

caused by the bacterltm Calymmatobacteium donovani.It is common in India and

New Guinea but rare in the United States. It Presents witl ulcerating granulomas of

genital skin and mucous membranes.

b. Pathology

(1) Grossln there are multiple ulcerating papules on t}re skin and mucous mem-

branes. Lymph nodes are not involved.

(2) Microscopically, there are granulation and microabscesses. Macrophages

contain Donovan bodies, which are diagnostic.

c. Course. Granuloma inguinale generally remains localized.

C. Carcinoma

l. Bowen disease is carcinoma in situ and can be associated with visceral malignancy' It

usually occurs in men or women over age 35. In men, it tends to involve the shaft of the

penis and the scrotum.

a. Grossly, a thick, ulcerated plaque appears.

b. Microscopicalln there is squamous cell carcinoma in situ. Nuclei may be bizarre in

apPearance.

555

Reproductive System

Note

Squamous cell carcinomas,particularly those associatedwith papilloma viruses, show amarkedly higher incidence inHIV infection. lts configurationis often papillary. Patients canalso have perianal carcinomasor papillomas.

Papillomaviruses (types l6 andlB) are most often associatedwith squamous carcinoma.

2. Squamous cell carcinoma

a. Clinical features. Squamous cell carcinoma of the penis accounts for |o/o of cancers inmen in the United States, usually age 40-70. Circumcision decreases the incidence.Human papilloma virus infection is closely associated with the development of squa-mous carcinoma.

b. Pathology

( I ) Grossly, squamous carcinoma presents as a plaque progressing to an ulceratedpapule or fungating growth.

(2) MicroscopicallS a papillary invasive, ulcerating squamous cell carcinomaappears.

c. Course and prognosis. Squamous carcinoma is usually slow growing and nonpainfi.rl;patients often delay seeking medical attention. Metastases can go to local lymph nodes.The prognosis depends on the degree of advancement of the tumor.

,54

Female Reproductive Pathology

Each organ in the female reproductive system is susceptible to specific disease states, including

cancers, benign hyperplasia, and infection. Cynecologic malignancies account for a large majority of

cancers in women: breast cancer is the second leading cause of cancer death in women in the

United States, and cervical cancer is the sixth leading cause. Because many Synecologic disorders

present with similar symptoms of menstrual irregularities, nonmenstrual vaginal bleeding or

discharge, and pelvic pain, it is important to be able to recognize the features that differentiate one

disease state from another. This chapter will focus on these disorders and will highlight the risk

factors and clinical and pathologic features that distinguish them'

UTERUSA. Endometrium

1. Endometritis

a. Acute endometritis is relatively uncommon. It is caused by bacterial infection of the

endometrium, usually following childbirth or abortion. It may be related to retained

products of conception. The usual pathogens are group A p-hemolytic streptococci and

staphylococci, producing a nonspecific interstitial inflammation with neutrophils.

b. Chronic endometritis may occur postabortion or postpartum but is also related to the

use of intrauterine devices (IUDs), tuberculosis (TB), or pelvic inflammatory disease

(PID). There is a chronic inflammatory infiltrate with plasma cells in the interstitium.

2. Endometriosis

a. Clinical features. Endometriosis refers to ectopic endometrial tissue outside the

uterine cavity, most often in the ovaries, uterine ligaments, rectovaginal septum'

pelvic peritoneum, postlaparotomy scars, vagina, vulva, and appendix. It occurs in

women of reproductive age and is rare over age 50. It is commonly associated with

infertility. Depending on the location of ectopic tissue, it may cause dysmenorrhea,

pelvic pain, dyspareunia, pain on defecation, dysuria, and an inability to conceive.

b. Pathogenesis is a debated issue. Possibilities include metaplasia, implantation of

abnormal epithelium at the time of menses, or lymphatic or hematogenous spread of

benign endometrial cells that can nonetheless attract a blood supply and grow at a

new site.

c. Pathology

(1) Grossly, endometriosis forms blue-red or brown-yellow nodules, 1-2 cm in

diameter. They may cause fibrosis and adhesions.

Nole

Endometriosis is characterizedby cyclic bleeding from theectopic endometrial tissue,resulting in "chocolate cysts"-brown, blood{illed spaces.

555

Reproductive System

Note

In postmenopausal women,endometrial hyperplasia isoften due to exogenousestrogen administration.Occasionally, well-differentiated adenoca rci nomaarises in this setting. ltregresses when estrogentherapy is stopped.

Clinical Correlate

Risk factors for endometrialcarcinoma:

. Prolonged estrogenstimulus

. Obesity

. Diabetes

. Hypertension

556

(2) Microscopically, two of the following must be present: glands, stroma, orhemosiderin pigment. Cyclic menstrual changes may be seen.

d. Course and prognosis. Infertility may result from fibrosis and scarring of tubes andovaries.

3. Endometrial hlperplasia

a. Clinical features. Hyperplasia may occur in both perimenopausal and post-menopausal women. It may present with abnormal or excessive uterine bleeding, oftenassociated with states of elevated estrogen production (e.g., prolonged estrogen ther-apy, adrenocortical hyperfunction, certain ovarian tumors). It may be a precancerouslesion.

b. Pathology is variable.

( 1) Mild hyperplasia (cystic) consists of many glands of multiple sizes (often rystic)with scant mitoses, dilatation of glands, and the appearance of a proliferativeendometrium, including increased stromal elements, all leading to a "Swisscheese" appearance.

(2) Moderate hnrerplasia (adenomatous) produces a thick, gray mucosa. There areirregular glands, a hyperplastic epithelium, and papillary projections. There mayalso be increased stromal mitoses.

(3) Atfpical hyperplasia is grossly similar to adenomatous hyperplasia, but micro-scopic study may show crowding of glands, disorganized epithelium, cellularatypia, closely packed glands, and frequent mitoses. This may resemble well-differentiated adenocarcinoma.

c. Course andprognosis. Although cystic hyperplasia is benign, adenomatous and atyp-ical hyperplasia are considered premalignant and are associated with an increasedincidence of endometrial carcinoma.

4. Endometrial polyps

a. Clinical features. These are most common in perimenopausal or postmenopausalwomen. They usually present with uterine bleeding.

b. Pathology

( I ) Grossly, polyps may be single or multiple and are usually less than 3 cm. Theyare often sessile but may be pedunculated.

(2) Microscopically, there are two types: functional endometrium and hyperplastic(rystic or adenomatous) endometrium.

c. Course and prognosis. Malignant transformation is rare.

5. Endometrial carcinoma

a. Clinical features. This disease primarily occurs in the postmenopausal age group.It is associated with obesity, diabetes, hypertension, and infertility. It may be asympto-matic or present with abnormal uterine bleeding/discharge.

b. Pathogenesis is thought to be the result of prolonged estrogen stimulation. There isa correlation with prolonged estrogen therapy, estrogen-secreting neoplasms, andendometrial hyperplasia (which may also be a result of estrogen stimulation).

c. Pathology

(1) Grossly, tumors are either polypoid or diffirse and may become fungating andnecrotic.

Pathology: Female

(2) Microscopically, one sees primarily adenocarcinomas, showing glandular patterns

with varying degrees of differentiation. Other conlmon types include adenoacan-

*ffi J:liil:il:'l:il:#*|;}ru"'ffi ililTil:T:*.ill,adenosquamousd. Course and prognosis. There is early spread by contiguous growth through the

myometrium, into the broad ligament, and then to nearby portions of the gastroin-

testinal and urinary tract. Later, lymphatic and hematogenous spread occur. Survival

depends on the stage at diagnosis. Tieatment is usually surgery, with or without radi-

ation.

B. Myometrium

1. Leiomyoma (fibroids)

a. Clinical features. These are benign smooth muscle neoplasms representing the most

common tumor in women and occurring generally in the third and fourth decades.

Incidence is increased in African American women. There is a possible role of estro-

gens in the pathogenesis. They may present with excessive menstrual bleeding, abnor-

mal uterine bleeding, pain, infertility, or urinary symptoms.

b. Pathology

(1) Grossly, tumors are whitish-gray, discrete, myometrial masses, often multiple,

and varying in size. They are usually in the corpus of the uterus but may arise in

the cervix or lower uterine segment (Figure IV-7-1). Common descriptive terms

are:

(a) Intramural, or embedded in the myometrium

(b) Subserosa, or beneath the covering serosa

(c) Submucosal, or close to the endometrium

Note

Leiomyomas were among thefirst neoplasms to bedemonstrated to bemonoclonal by using glucose-6-phosphate dehydrogenase(C6PD) isoenzymes. Inheterozygous women, thetumors have only one isotype,while the adjacentnormal myometrium has both.

Figure lV-7-1. Leiomyoma of the uterus (gross).

t57

Reproductive System

*v , ,: *.&!r

Figure lV-7-2. Leiomyoma of the uterus (microscopic).

(2) Microscopically' tumors are composed of bundles of smooth muscle cells withincreased fibrous elements visible on a trichrome stain (FigureIY-7-2).

c. Course and prognosis. Malignant transformation is rare. They may require surgicalremoval for bleeding or infertility.

2. kiomyosarcomas

a. Clinical features. Leiomyosarcomas are arare myometrial malignancy. They may arisein a pre-existing leiomyoma, but this is so rare that it is reportable. Tlrmors may occurbefore or after menopause.

b. Pathology

(1) Grossly, there are two patterns: bulky invasive (growing into the wall) or poly-poid (growing into the lumen).

(2) Microscopically, there are variable degrees of atypia. To make the diagnosis,there must be more than 10 mitoses per high-power field (a00x), and over halfof these mitoses must have cellular atypia. The tumor must be searched exten-sively because atypia and mitotic rates are not constant throughout the tumor.The worst fields establish the diagnosis.

c. Course and prognosis. Leiomyosarcomas are highly malignant, and 5-year survival isonly 40o/o. They metastasize widely and tend to recur after removal.

FAttoptAN TUBES (UTER|NE TUBES, OVIDUCTS)A. Inflammation

1. Pelvic inflammatory disease (PID)

a. Clinical features. Inflammation begins in the vulva or accessory glands (Bartholin'sglands or Skene ducts) and may spread upward throughout the reproductive system.The most common organism is N. gonorrhoeae,but Staphylococcus, Streptococcus, coI-iforms, Clostridium perfringens, Mycoplasma, Chlamydia, and anaerobes may be seen.PID may occur spontaneously, postabortion, or postpartum. Presentations includeabdominaUpelvic pain, menstrual irregularities, dysmenorrhea, and fever.

558

Pathology: Female

b. Pathogenesis. For gonococcal PID, the initial inflammation of the accessory glands is

followed tn l-2 weeks by inflammation of the fallopian tubes. In children, vulvo-

vaginitis may develop; it is rare in adults.

c. Pathology

(l) Grossly, there is a suppurative salpingitis (lumen of tube filled with pus).

ii*:':irffl,3:."me adherent to the ovary, causing salpingo-oophoritis and

(2) Microscopically, inflammation is present in the mucosa and submucosa and

may involve the serosa.

d. Course and prognosis. Complications are severe and include sepsis, peritonitis, adhe-

sions with intestinal obstruction, and infertility from tubal scarring or tubo-ovarian

abscess. Early diagnosis and appropriate antibiotic therapy are essential.

B. Tirmors in the fallopian tubes are rare.

cERVIXA. Inflammation

1. Acute and chronic cervicitis

a. Clinical features. Various forms of cervicitis are common and are of variable clinical

significance. The most common pathogens are Streptococctts, Enterococci, Escherichia

coli, and Staphylococcus; olhers include gonococci, Trichomonas vaginalis, Candida,

and herpes (usually HSV II). Infection may follow intercourse, childbirth, and gyne-

cologic instrumentation. Predisposing influences include high estrogens, alkaline

mucus, and congenital anomalies.

b. Pathology

(1) Grossly, one observes a swollen, edematous cervix.

(2) Microscopically, there are two phases. The acute phase reveals stromal edema

and a neutrophilic infiltrate. The chronic phase reveals inflammation or cervical

glands, with a mononuclear infiltrate leading to cystic dilatations, which are due

to duct obstruction.

c. Course and prognosis. Cervicitis may be asymptomatic or present with a vaginal

discharge. It is important to distinguish it from cervical cancer, usuaily by Pap smear

or biopsy.

B. Tumors

1. Cervical polyps

a. Clinical features. Polyps are common in

sent with irregular vaginal bleeding.

b. Pathology

the fourth and fifth decades. They may pre-

(l) Grossly, polyps are usually single, arise in the endocervical canal, and maybe

sessile or pedunculated.

(2) Microscopically, they are composed of hypertrophic glands with rystic dilata-

tion and fibromyxomatous stroma; they may have chronic inflammation.

c. Course and prognosis. They may be removed by curettage.

559

Reproductive System

Clinical Correlate

Risk factors for cervicalcarcinoma:

. Early sexual activity

. Multiple sexual partners

. Lower socioeconomicgr0up

Clinical Correlate

Now that we appreciate theimportance ofpapillomaviruses as causativeagents of cervical cancer, insitu hybridization studies forspecific viral DNA may bedone on suspicious lesions.

Clinical Correlate

The recommended frequencyof Pap smears is underdiscussion. Sexually activewomen should probably havea Pap smear every year.Sexually inactive women mayonly need a smear every 3years. Women with suspiciousfindings should have repeatPap smears perhaps as oftenas every 3-6 months.Repeatedly suspicious orpositive smears should lead tocervical biopsy for definitivediagnosis.

2. Squamous cell carcinoma of the cervix

a. Clinical features. This is the sixth most common cause of cancer death in women. Itmay occur at any age from the second decade onward, but it is most common in thefourth and fifth decades.

b. Pathogenesis. There is an increased risk associated with early onset of sexual relationsand multiple sexual partners. Human papillomaviruses, particularly types 16 and 18,are clearly associated with squamous carcinoma. Other types are associated withbenign papilloma. In patients infected with HIV cervical cancer due to papillo-maviruses is increasing in incidence.

c. Pathology

( 1) Grossly, advanced, invasive cervical cancer may be fungating, ulcerating, or infil-trative.

(2) Microscopically, koilocytosis and squamous vacuolizations are seen. Cervicalcancer is viewed as the end stage of progression of atypia in cervical epithelium,or cervical intraepithelial neoplasia (CIN). Premalignant squamous epitheliumbegins to show atypical features (pleomorphism, loss of polariry frequentmitoses, and increased nuclear/cytoplasmic ratio), but maintains differentiationin the upper cell layers. Atypia is graded on a scale from I to III, based on the pro-portion of epithelium that is involved: involvement of less than one-third ofepithelium is CIN I, one-third to two-thirds is CIN II, and greater than two-thirdsis CIN III. Full-thickness involvement is carcinoma in situ (Figure IV-7-3). Atypiausually begins at the squamocolumnar junction (transition zone).

d. Course and prognosis. Cervical cancer spreads by contiguous growth to involve uri-nary structures and bowel. Lymphatic or hematogenous dissemination may occur.Mortality is declining as a result of early recognition of the precursor dysplastic cervi-cal epithelium via the Pap smear, which should be a part of every woman's yearlyphysical examination from reproductive age onward. The cure rate for carcinoma insitu may be as high as l00o/o. More advanced disease has a much lower cure rate( 10-15o/o if metastasis has occurred) and may require both surgery and irradiation.

W@*i1i "*' '*

560

Figure lV-7-3. Gervical carcinoma in situ (microscopic).

Pathology: Female

VAGINAA. Congenital anomalies

1. Gartner duct cysts

a. Clinical features. These cysts must be distinguished from tumor masses.

b. Pathology

(1) Grossly,l-2 cm submucosal rysts on the lateral vaginal walls are present.

(2) Microscopically, the cysts may have cuboidal, columnar, transitional, or a mixedepithelial lining. There is no atypia.

B. Inflammation may be due to various pathogens.

l. Trichomonas vaginalis is a flagellated protozoan.It typically causes a "strawberry red"vaginal mucosa and microscopic, suppurative inflammation.

2. Candida albicans (monilia) causes a thick, white exudate.

3. Herpes simplexvaginitis may accompany vulvar infection. It may lead to neonatal infec-tion during delivery. The organism is usually herpes simplex virus (HSV) II.

4. Gonococcus may cause vulvovaginitis in children, as well as adults.

C. Tumors

1. Squamous cell carcinoma

a. Clinical features. This tumor is quite rare, comprising less than lo/o of female genitalcancers. It may present with irregular bleeding, spotting, or discharge but is occasion-ally asymptomatic until advanced.

b. Pathology

(1) Grossly, the tumor starts as aplaque.

thickened epithelium, progressing to a large

(2) Microscopically, these are usually well-differentiated squamous carcinomas.

c. Course and prognosis. Squamous carcinoma of the vagina spreads by local extensionto the cervix, rectum, and bladder. Late lymphatic or hematogenous spread may occur.

2. Adenocarcinoma

a. Clinical features. Adenocarcinoma is very rare; of the vaginal cancers, 95o/o are squa-mous and 5o/o are adenocarcinoma. It is much more common in young women whosemothers were treated during pregnancy with diethylstilbestrol (DES). Because DES isno longer used to treat threatened abortion, this cause of adenocarcinoma has almostdisappeared.

b. Pathology

(1) Grossly, tumors usually appear in the upper one-third of the anterior vaginalwall and may arise in the cervix.

(2) Microscopically, the classic picture is a "clear cell" carcinoma, resulting from vac-uolated cells containing glycogen.

c. Course and prognosis. Tirmors grow by contiguous spread; later, they grow bylymphatic or hematogenous spread. Treatment includes surgery with or withoutradiation. DES-related tumors have an 80o/o 5-vear survival.

Clinical Correlate

DES therapy in pregnantwomen increases the incidenceof vaginal neoplasms in theirdaughters. Vaginal adenosis isa benign condition that isthought to be a precursor ofclear cell adenocarcinoma inthese women.

56r

Reproductive System

Note

BRCAI, a gene implicated inearly, premenopausal breastcancer, is also implicated insome ovarian carcinomas.

Note

Surface epithelial tumors ofthe ovary increase in incidencewith the number of ovulationsa woman experiences. Thus,pregnancy and birth controlpills are protective. Repeatedtearing and regroMh of theepithelium is apparently arisk factor.

3. Sarcoma botryoides

a. Clinical features. This is a rare vaginal rhabdomyosarcoma most common underage 5.

b. Pathology

(1) Grossly, polypoid tumors, protruding from the vagina and resembling clustersof grapes, are present.

(2) Microscopically, tumors are composed of small, crowded cells with oval nucleiand a teardrop shape, constituting malignant rhabdomyoblasts. One may have tosearch diligently for cross-striations.

c. Course and prognosis. Sarcomas spread by local invasion. Treatment is usuallysurgery with or without chemotherapy.

OVARIESA. Overview. The most common ovarian lesions are cysts and tumors. Ovarian cancer is the

fifth most common cancer in women, accounting for 60/o of all female cancers. Eighty per-cent of ovarian tumors are benign. The benign tumors tend to occur earlier (in the thirdthrough the fifth decades), whereas the malignant tumors are more common in olderwomen (in the fifth through the seventh decades). Familyhistory, earlymenarche, and nul-liparity are risk factors. There is an increased incidence in children with gonadal dysgenesis.Tumors are often asymptomatic until large; then, they may present with abdominal pain,distension, vaginal bleeding, and gastrointestinal or urinary symptoms. Ovarian tumors areclassified into four groups: surface epithelial tumors, germ cell tumors, sex cord/stromaltumors, and metastatic tumors involving the ovary.

B. Surface epithelial tumors

1. Overview. Sixry percent of ovarian tumors arise from surface epithelium. There are variablepresentations. In addition to abdominal discomfort, vaginal bleeding, andgastrointestinaVgenitourinary symptoms, patients may present with malignant ascites fromperitoneal seeding or with an acute abdomen from torsion of a large tumor or rupture of a

ryst. Unfortunately, these slow-growing tumors are often asymptomatic until the disease isfar advanced.

2. Classification is according to epithelial cell type: five groups are commonly recognized.

a. Serous neoplasms are characterized by serous, fluid-filled cysts lined with ciliatedcolumnar epithelium. They are most common in the third through sixth decades.Most are malignant.

(1) Benign serous cystadenoma is clinically benign and usually cured by oophorec-tomy. It is usually composed of unilateral, thin-walled, fluid-filled rysts, with asmooth, glistening surface. Cysts are lined with ciliated cuboidal epitheliumwithout afypia.

(2) Borderline serous tumor may present with an adnexal mass. TWenty-five per-cent are bilateral and composed of small papillary growths, protruding throughthe serosa. Microscopically, two to three layers of stratified epithelium line the

rysts, forming papillary projections with variable atypia. Psammoma bodies arepresent in approximately 25o/o of cases. Of utmost importance is the fact thatthere is no stromal invasion. Peritoneal implants are common, but patients havea 90o/o lO-year survival. Treatment is bilateral salpingo-oophorectomy, hysterec-tomy, and removal of the omentum to remove microscopic implants.

t62

Pathology: Female

(3) Serous cystadenocarcinoma is the most common malignant ovarian tumor. Itis usually bilateral. Tumors may be solid masses with hemorrhagic and necroticareas, or they may be primarily cystic. Microscopically, there are papillarygrowths with multiple layers of epithelium, frequent psammoma bodies, markedcellular atypia, and stromal invasion. These tumors spread via peritonealimplants, contiguous growth, or lymphatic or hematogenous dissemination.There is only a 20o/o 5-year survival rate because patients generally present withlocal spread and metastases. Treatment is bilateral salpingo-oophorectomy,followed by chemotherapy, radiation, or both.

b. Mucinous tumors are most common between puberty and menopause. Most are large,unilateral, and benign. They are composed of nonciliated, columnar, mucus-secretingcells.

(1) Benign mucinous cystadenomas are unilateral in 95o/o of cases. They have asmooth surface, and they form large masses that may contain multiple mucus-fiIled cysts. The epithelium is well-differentiated columnar with no atypia and amucin-filled cytoplasm. Oophorectomy is curative.

(2) Borderline mucinous cystadenocarcinomas are moderately aggressive tumorsthat form multiloculated rysts, lined by a papillary growth of layered epithelialcells with some atypia. Peritoneal implants may occur, and therapy is surgical (asit is for serous tumors of the same grade).

(3) Mucinous cystadenocarcinomas are malignant tumors that form solid masseswith hemorrhage and necrosis. They are composed of papillary arrangements ofepithelium with cellular atypia and stromal invasion. Mucinous cystadenocarci-nomas may spread via implants, contiguous growth, or lymphatic or hematoge-nous routes. Tieatment includes surgery, radiation therapy, or both.

(4) "Pseudomproma peritonei" is a term used to describe a peritoneal cavity filledwith mucinous material derived from a tumor that has ruptured or metastasized.It is associated with a small percentage of ovarian mucinous tumors and withrupture of an appendicular carcinomatous mucocoele. Multiple mucinousimplants on serosal surfaces in the peritoneal caviry which may cause interad-herance of viscerae, are present. Tumor cells form a nonciliated, columnar,mucus-producing epithelium. Prognosis is very poor. Tieatment is surgical, butrecurrences are frequent.

c. Endometrioid tumors

( 1) Clinical features. Most are malignant. They contain glandular structures resem-bling endometrium, and they maybe accompanied by endometrial carcinoma orby ovarian endometriosis.

(2) Pathology. Grosslp cysts are embedded in a solid matrix, usually unilateral.Microscopically, the structure resembles the endometrium: glandular structuresin a connective tissue stroma.

(3) Course and prognosis. Five-year survival is approximately 50o/o. Bilateralinvolvement usually indicates spread beyond the reproductive tract.

d. Clear cell adenocarcinomas are rare and are almost always malignant.

(1) Ctinical features. They may be associated with ovarian endometriosis orendometrioid carcinoma.

!65

Reproductive System

C.

(2) Pathology. Thmors may be solid or cystic. Microscopically, there are sheets oftubules of clear cells in solid tumors. In cystic tumors, atypical columnar cellsline fluid-filled cysts.

(3) Course and prognosis. There is a 50olo S-year survival. Treatment combinessurgery radiation, and chemotherapy.

e. Brenner tumors

(1) Clinical features. These are rare, comprising only 2o/o of ovarian neoplasms.They can be seen at all ages, with a peak incidence from the fifth through eighthdecades. Most are benign.

(2) Pathology. Grossly, tumors are usually unilateral and are variable in size (1-20cm). They are usually solid but may be rystic. Microscopically, solid nests oftransitional epithelium in ovarian stroma are present. The malignant type showsatypia and invasion.

(3) Course and prognosis. These tumors may have endocrine activity. Surgery isusually curative.

Germ cell tumors

l. Overview. These comprise l5-20o/o of all ovarian neoplasms; most (over 95o/o) arcbenign cystic teratomas. They occur primarily in young women and children.Presentations vary. Germ cell tumors are divided into four groups: teratomas, dysgermi-nomas, endodermal sinus (yok sac) tumors, and "other," a group that includes chorio-carcinoma, embryonal carcinoma, polyembryoma, and mixed germ cell tumors.

2. Teratomas

a. Mature (benign) teratomas are also called dermoid cysts because they are lined byskin and adnexae and are often filledwith keratin and hair. There is a high incidencein women of reproductive age. They may present with an abdominal mass, pain, andgastrointestinal or menstrual abnormalities.

(1) Grossly, they are usually unilateral, small, unilocular cysts that may have a mix-ture of hair, tooth structures, and bone (Figure IV-7-4).

&ww4

wW

til

Figure lV-7-4. Dermoid cyst of the ovary (gross).

Pathology: Female

3.

(2) Microscopically, they are usually composed of cysts, lined by stratified squa-mous epithelium and structures derived from multiple germ layers, includingendoderm, mesoderm, and ectoderm (Figure IV-7-5).

Figure lV-7-5. Dermoid cyst of the ovary (microscopic).

(3) The course is usually benign. Surgical resection leads to cure. Torsion may occur.

b. Immature (malignant) teratomas are rare, containing embryonic elements derivedfrom all three germ layers.

(1) Grossly, they form smooth, large masses that are primarily solid but may have

rystic spaces. Necrosis and hemorrhage are common. As with the benigntumors, malignant teratomas may contain hair and bone.

(2) Microscopically, they are composed of immature tissues differentiating intonerve, muscle, bone, and a variety of other tissues. The characteristic of malig-nancy is undifferentiated areas.

(3) These tumors are fast-growing and invasive with both lymphatic andhematogenous spread. Grading is based on degree of maturity of cells andpresence of neural tissue: The more immature the cells and the more neuroep-ithelium, the higher the grade and the worse the prognosis.

Dysgerminoma

a. Clinical features. This tumor is analogous to testicular seminoma. It is rare and usu-ally occurs in the second through third decades. Patients may present with abnormalmenstrual bleeding. Elevated levels of hCG should raise suspicion of a focus of chori-ocarcinoma.

b. Pathology. Dysgerminomas vary in size and are usually unilateral and solid. They arecomposed of sheets of large cells with clear cytoplasm and regular nuclei in a fibrousstroma. There are variable degrees of atypia.

c. Course and prognosis. One-third are aggressive and all are very radiosensitive. The5-vear survival is 70-90o/o.

565

Reproductive System

ln a Nutshell

Granulosa CellTumors. Usually estrogen-secreting

. Call-Exner bodies

. Associated with endometrialhyperplasia andendometrial carcinoma

4. Endodermal sinus (yok sac) tumor

a. Clinical features. These tumors are rare and usually produce o-fetoprotein (AFP)and, occasionally, c,-antitrypsin. They occur in young women and children, and pre-sent with a pelvic mass and abdominal pain.

b. Pathology

( 1) Grossly, they usually form a large, smooth tumor with areas of hemorrhage andnecrosis.

(2) Microscopically, there are papillary:rrangements of immature epithelium aroundblood vessels. Intracellular and extracellular hyaline droplets containAFP.

c. Course and prognosis. They are rapid growing and aggressive. Surgery andchemotherapy prolong survival and occasionally produce a cure.

5. Other germ cell tumors

a. Choriocarcinoma may arise as an ovarian germ cell tumor. These tumors produceelevated hCG levels in serum and are usually widely metastatic.

b. Embryonal carcinoma is an aggressive ovarian carcinoma, resembling testicularembryonal carcinoma.

c. Polyembryoma may contain "embryoid bodies." These structures show all three germlayers, just as in normal embryologic development.

d. Mixed germ cell tumor may combine elements of other germ cell tumors. It is usu-ally composed of dysgerminoma, combined with yolk sac tumor, and immatureteratoma.

D. Sex cord-stromal tumors

1. Overview. These tumors comprise only 5-10o/o of ovarian neoplasms. They occur at allages, and produce steroid hormones that may lead to endocrinologic syndromes. Thethree most important groups of these tumors are granulosa-theca cell, fibroma, andSertoli-Leydig cells.

2. Granulosa-theca cell tumors

a. Clinical features. These usually occur in postmenopausal women. They containgranulosa and theca cells in variable ratios.

b. Pathology. They are usually unilateral with a yellow hue. They may be small or large,solid or cystic. Histology is variable. Some contain only granulosa cells, which aresmall polygonal follicle cells in sheets or strands, which may be filled with acidophilicmaterial (Call-Exner bodies). Others are pure thecomas; these cells arecuboidal/spindle-shaped with lipid droplets. Many are mixed.

c. Course and prognosis. These tumors may secrete estrogens. They are associated with

rystic hyperplasia/carcinoma of the endometrium and breast cancer. Some granulosatumors make androgens with resultant virilization. Thecomas are benign. Granulosacell tumors may be malignant (5-25o/o). Surgery may be curative.

3. Fibromas

a. Clinical features. Fibromas comprise 5o/o of ovarian neoplasms. They present with painand a pelvic mass; ascites is common, and hydrothorax (usually right-sided) may occur.

b. Pathology

566

Pathology: Female

(1) Grossly, they are usually unilateral, solid, hard, grey masses, 5-10 cm in diame-ter, with an intact serosa.

(2) Microscopically, they are composed of well-differentiated fibroblasts with raremitoses. If thecal elements are present, the tumor is a "fibrothecoma."

c. Course and prognosis. The triad of ovarian tumor, hydrothorax, and ascites is called"Meig syndrome." This triad may occur with other ovarian neoplasms, but it is mostcommon with fibromas. It does not imply pleural or peritoneal metastases.

4. Sertoli-Leydig cell tumors (androblastoma, arrhenoblastoma)

a. Clinical features. These are most common in the second and third decades. They mayproduce masculinization, anovulation, and sterility.

b. Pathology. Tumors are usually unilateral, solid, and whitish-gray. Microscopy is vari-able. They may be well differentiated with easily identifiable Sertoli or Leydig cells;they may have immature tubules with large L.ydig cells; or they may appear sarcoma-tous with no Leydig cells.

c. Course and prognosis. The course is benign. Manifestations range from defeminiza-tion (breast atrophy, amenorrhea) to frank virilization (hirsutism, male hair pattern).

5. Other sex cord-stromal tumors

a. Lipid cell tumors are often virilizing and are composed of large, vacuolated cells.TWenty-five percent are malignant.

b. Stromal luteoma is composed of pure lutein cells that may produce estrogens andandrogens. (Normal corpus luteum cells produce large amounts of progesterone.)These tumors are benign.

c. Hilus cell tumors (pure L.ydig cell tumors) cause masculinization. They are usuallyunilateral. Cells contain lipochrome pigment and Reinke crystals. They follow abenign course.

d. Gonadoblastoma is rare, occurring in young patients with abnormal sexual develop-ment. It may cause amenorrhea and virilization. Cells resemble immature Sertoli andgranulosa cells.

E. Tirmors metastatic to the ovary. The most common sites of origin are other pelvic organs,upper gastrointestinal tract, and breast. Iftukenberg tumor is bilateral, metastatic, mucin-producing adenocarcinoma (usually signet-ring cells derived from the stomach).

F. Cysts

1. Follicular cysts

a. Clinical features. These are often asymptomatic cysts, originating in unruptured orresealed follicles.

b. Pathology

(1) Grossly, these cysts are usually in the cortex, multiple, filled with clear fluid, andapproximately 1 cm in size.

(2) Microscopically, granulosa lining cells may be identified in cysts with little fluid;with large amounts of fluid, pressure causes atrophy of lining cells.

c. Course and prognosis. These cysts generally remain small. Some may produceestrogens and cause endometrial hyperplasia.

ln a Nubh-gll

Meig Syndrome. Ovarian fibroma

. Hydrothorax

. Ascites

' t67

Reproductive System

2. Lutealcysts

a. Clinical features. These benign cysts are less common than follicular rysts.

b. Pathology

( 1) Grossly, cysts are usually approxim ately 2 cm and yellow.

(2) Microscopically, the rystic lining is luteal tissue, comprised of large cells filledwith smooth endoplasmic reticulum (like normal corpus luteum cells).

Thble lV-7-1. Ovarian neoplasms.

Tirmor Clinical Features Pathology

Tirmors of surface epitheliumSerous

Serous cystadenoma Usually benign Usuallv unilateralBorderline serous tumor Adnexal mass, moderately Twenty-five percent

aggressive bilateralSerous cystadenocarcinoma Most common malignant Usually bilateral

ovarian tumor

MucinousMucinous rystadenoma Benign Usuallv unilateralBorderline mucinous tumor Moderately aggressive Multiloculated rystsMucinous cystadenocarcinoma Malignant

Endometrioid carcinoma Usually malignantClear cell adenocarcinoma Rare, malignant

Hemorrhagic/necrotic

Glandular structuresSolid or rystic

Brenner tumor Rare, usually benign Usually unilateral

Germ cell tumorsTeratomas

Mature (dermoid cyst) Usually benign Usually unilateral,mixture ofhair/teeth/bone

Immature Rare, invasive Immature tissuesDysgerminoma Rare, radiosensitive Usually unilateralEndodermal sinus tumor Rare, produces cr-fetoprotein Hemorrhagic, necroticChoriocarcinoma Elevated hCG Often metastatic

Sex cord-stromal tumorsGranulosa-theca cell May elaborate estrogens Usually unilateral

or androgensFibroma Meig syndrome Usuaily unilateralSertoli-Leydig Masculinizing in some cases UnilateralGonadoblastoma Rare Immature Sertoli/

granulosa cells

3. Polycystic ovaries

a. Clinical features. Polycystic ovaries may be associated with three clinical syndromes:virilism; excessive menstrual bleeding; or the Stein-Leventhal syndrome, which ischaracterizedby secondary amenorrhea, obesity, hirsutism, infertility, and bilaterallyenlarged, polycystic ovaries. They are most common in young women in the secondand third decades.

568

Pathology: Female

b. Pathology Ina Nu! hell( 1 ) Grossly, the ovaries are enlarged, with a thick, white outer covering and multiple lolycystic Ovaries

cysts, . Occur mainly in young(2) Microscopically, cysts are lined with granulosa tleca cells. women

c. Pathogenesis involves hyperinsulinism and insulin resistance, increased ftequency of . Asociated with:GnRH pulses, and dysregulation of androgen secretion in ovaries and adrenals.

d. Course and prognosis, Wedge resection (by removing cysts and tleca cells) may - Amenorrhea

restore normal menses and fertility. - Infertility

- Obesitv

PLACENTA - HirsutrsmA Gestational trophoblastic neoplasms are derived ftom trophoblastic tissue associated with - t LH secre,tion

pregnancy.

1. Hydatidiform mole

a. Clinical features. Hydatidiform mole occurs in l/2,000 pregnancies in the UnitedStates; it is more common in Asia. The highest incidence is in older pregnant womenin the fifth and sixth decade. Moles may present in the fourth and fifth month of preg-nancy with a uterus that is large for dates and vaginal bleeding. No fetus is detectableby examination or ultrasoundl The "embryo" co-nsists of a 46lof karyotype derived Note

exclusively from the father. There may be elevated blood and urine (hCG) levels. A partial hydatidform

b. Pathology mole contains an embryo

( I ) Grossly, moles are usualJy in the uterus bur may be ectopic. The urerus is larger that is triploid or tebaploid

than expected, and the .unity i, fil.d rnrith -ultiple grapi-like cystic structurls. lt is thought that this is

A collapsed amniotic sac may be presenl. due to tlvo or more sperm

(2) Microscopicallt one sees a hydropic, cystic swelling of chorionic villi with fertilizingthe ovum'

epithel.ial hyperplasia and anaplasia; epithelium may contain both cyto- and syn-cftiotrophoblast.

c. Course and prognosis. Moles can be graded by degree of atypia and differentiation.Eighty percent are benign. Some may be precursors of malignant choriocarcinoma.Therapy is removal by curettage with periodic monitoring of hCG levels.

2. Invasive rnole (chorioadenoma destruens)

a, Clinical features. These moles cause encessive, irregular uterine enlargement andvaginal bleeding in pregnant women. hCG is elevated.

b. Pathology

( i ) Grossly, there is a hydropic mass within the uterine cayity, which may invade andperforate the wall.

(2) Microscopicalln one sees the c)'stic villi with proliferation of cyto- and qrrcy-tiotrophoblast. Microinvasion can be demonstrat€d.

c. Course and prognosis. Invasive moles may spread by local invasion or distantembolization. They do not grow at thes€ distant sites; henc€, they are not true metas-tases. Uterine rupture may be a lethal complication. The tumor responds tochemotherapy.

569

Reproductive System

3. Choriocarcinoma

a. Clinical features. This is an uncommon trophoblastic malignancy that may be pre-ceded by a hydatidiform mole (50olo), abortion (25o/o),pregnancy (22o/o), or other con-ditions (3o/o). Patients generally present with bloody vaginal discharge. hCG levels aremarkedly elevated.

b. Pathology

(1) Grossly, pale necrotic areas, hemorrhage, and rysts occur.

(2) Microscopic findings vary. Epithelial cells or atypical cuboidal and syncytialcells may occur but no villi. Invasion is obvious.

c. Course and prognosis. Choriocarcinoma metastasizes *id"ly to the lungs, vagina,brain, liver, and kidney. Tieatment includes surgery and chemotherapy, which mayhave dramatic results and cure some patients.

BREASTA. Acute mastitis

1. Clinical features. Fissures in nipples during early nursing or from skin disorders maypredispose to bacterial infection of the breast. Usual pathogens are Staplrylococcus aureusand Streptococcus.

2. Pathology. Mastitis is usually unilateral, with pus in the ducts. Necrosis may occur.

3. Course. Antibiotics and surgical drainage may be adequate therapy, but necrosis and sub-sequent fibrosis of a localized area of breast tissue may occur.

B. Mammary duct ectasia (plasma cell mastitis)

1. Clinical features. This disorder generally occurs in the fifth decade in multiparouswomen. It presents with pain, redness, and swelling around the areola.

2. Pathology. Involvement is usually unilateral, causing a thickened, indurated area of thebreast with thick secretions.

3. Course. Skin fixation, nipple retraction, and axillary lymphadenopathy may occur andmust be distinguished from malignanry.

C. Fibrocystic disease (cystic hyperplasia)

1. Clinical features. This is the most common breast disorder; it is responsible for 50olo ofbreast surgery, affecting approximately I0o/o of women. It usually develops during repro-ductive life and represents a distortion of the normal breast changes associated with themenstrual rycle. Patients often have lumpy, tender breasts.

2. Pathogenesis is thought to be due to high estrogen levels, e.g., estrogen therapy, or estrogen-secreting neoplasm, coupled with progesterone deficienry.

3. Pathology. Several morphologic patterns are recognized.

a. Fibrosis usually affects women 3549 years of age and is not premalignant.

(1) Grossly, fibrosis is usually unilateral, most often in the upper outer quadrant,forming a dense, rubbery mass.

(2) Microscopically, there is an increase in stromal connective tissue, which maycompress ducts and lobular buds. Cysts are rare.

,70

Pathology: Female

b. Cystic disease usually affects women 45-55 years of age and may predispose tomalignanry.

(1) Grossly, rystic disease is usually multifocal but is often bilateral. It causes gross

rysts and a nodular, firm breast to palpation. Cysts are filled with serous fluid,which may be hemorrhagic, and are easily aspirated.

(2) Microscopically, cysts are lined by cuboidal/ columnar or flattened epitheliumand may have papillary projections or piled up masses of cells. Occasionally,there are large, polygonal cells with round, dark nuclei and eosinophilic cyto-plasm, representing benign apocrine metaplasia. There may be an accompanyingstromal lymphocytic infiltrate ("chronic rystic mastitis").

c. Sclerosing adenosis usually affects women 3545 years of age and probably does notpredispose to cancer.

(1) Grossly, this disease is usually unilateral, often focal, and is most often found inthe upper outer quadrant. It causes a palpable, ill-defined, firm area.

(2) Microscopically, there are glandular patterns and nests of cells in a fibrousstroma. Adenosis (closely aggregated glands) may be difficult to distinguishhistologically from cancer because the mixture of epithelial and stromal cellssuggests an invasive, epithelial malignanry (Figure IV-7-6).

Figure lV-7-6. Sclerosing adenosis (microscopic).

d. Epithelial hyperplasia occurs in women over 30 years of age (usually 3545) and rep-resents an increased cancer risk.

(1) Grossly, findings are variable. Hyperplasia may be accompanied by adenosis,fibrosis, and rysts that produce ill-defined masses.

(2) Microscopically, the duct epithelium is multilayered and produces variable mor-phologies: glandular structures (cribriform patterns) or papillary configurations(ductal papillomatosis). There are often increased mitoses (atypical hyperplasia).

ffi

t7 l

Reproductive System

4. Course and prognosis. Fibrorystic disease is clinically important, because it may be mis-

taken for cancer, and it may predispose to cancer, particularly the epithelial hyperplasia

variant. Thble IV-7-2lists the features that differentiate the two diseases.

Thble lV-7-2. Features distinguishit g fibrocystic disease frombreast cancer.

Fibrocystic Disease Breast Cancer

Often bilateral Often unilateralMay have multiple nodules Usually single noduleMenstrual variation No menstrual variationCyclic pain and engorgement No cyclic pain or engorgementMay regress during pregnancy Does not regress during pregnancy

D. Gynecomastia

1. Clinical features. Gynecomastia is an enlargement of the male breasts that occurs in var-ious clinical situations (e.g., Klinefelter syndrome; testicular tumors [particularly Sertoli-Leydig cell tumors], puberry or old age) and is associated with increased sensitivity toestrogens (e.g., in hepatic cirrhosis, the liver cannot properly metabolize estrogens).

2. Pathology

a. Grossly, it may be unilateral or bilateral, but it is most often unilateral.

b. Microscopically, there is ductal epithelial hyperplasia and adjacent edema of theperiductular stroma.

3. Course depends on the etiology. Gynecomastia may be an important signal to the clini-cian that the patient has a high-estrogen state.

E. Thmors

1. Fibroadenoma

a. Clinical features. This is the most common benign breast tumor. It occurs in womenof reproductive age, generally before age 30, and may be related to increased estrogensensitivity. Fibroadenoma presents as a single movable breast nodule, not fixed to theskin.

b. Pathology

(1) Grossly, there is a small, freely movable nodule, often in the upper outer quadrant.Size may range up to 10 cm. The tumors are usually round and encapsulated witha grey-white cut surface (Figure I\f-7-7).

t72

Pathology: Female

ss**g*3#

Figure aV -7-7. Fibroadenoma (gross).

(2) Microscopically, fibroadenomas form glandular epithelial-lined spaces with afibroblastic stroma. Stromal proliferation may collapse gland lumina, or alterna-tively, glandular proliferation may predominate with scanty connective tissue stro-ma. Usually, there is a network of ducts within a proliferated, edematous stroma(Figure W-7-8).

+" .9,a 4

. t

h

Figure lV-7-8. Fibroadenoma (microscopic).

c. Course. Fibroadenomas may show menstrual variation and increased growth duringpregnancy. Postmenopausal regression is usual. Surgery is required for definitivediagnosis.

.\.

77t

Reproductive System

In a Nutshell

Risk Factors for BreastCancer. Increasing age (40+)

. Nulliparity

. Family history

. Early menarche

. Late menopause

. Fibrocystic disease

. Previous history of breastcancer

. Obesity

. High{at diet

2. Cystosarcoma phyllodes (Phyllodes tumor)

a. Clinical features. These are fibroadenoma-like tumors that have become large, cystic,and lobulated. They are distinguished from fibroadenomas by the nature of the stro-mal component. When hypercellular, the term "cellular fibroadenoma" is used. Whenthe stroma is both hypercellular and highly atypical, the tumor is called a sarcoma.

b. Pathology

( 1) Grossly, these tumors form an irregular mass, often fungating or ulcerated.

(2) Microscopically, there is a mlaroid stroma with increased cellulariry anaplasia,and increased mitoses. Malignant fibrous, cartilaginous, and bony elements maybe present.

c. Course. The tumor is initially localized but may spread latet usually to distant sitesbut not to local lymph nodes.

3. Intraductal papilloma

a. Clinical features. This forms a solitary lesion within a duct or ryst and is most com-mon in women 20-50 years of age. It may present with nipple discharge (serous orbloody), nipple retraction, or as a small subareolar mass.

b. Pathology

(1) Grossly,lesions are small (less than 1 cm) and are usually close to the nipple inmajor ducts. They may be sessile or pedunculated.

(2) Microscopically, there are multiple papillae.

c. Course. Current evidence suggests that single intraductal papillomas are benign, butmultiple papillomas are associated with an increased risk of cancer.

4. Carcinoma of the breast

a. Incidence. Breast carcinoma is the most common cause of cancer in women, althoughlung cancer causes more deaths. It is rarely seen in women under age 25.

b. Etiology. Risk factors include increasing age (particularly after 40), nullipariry familyhistory (especially in premenopausal cancer), early menarche/late menopause, fibro-

rystic disease (especially epithelial hyperplasia), and a previous history of breast can-cer. The lifetime risk of breast cancer for the average woman with no family history is8-l0o/o.


( 1) Locations of breast carcinoma are: 50% in the upper outer quadrant, 20o/o in cen-tral area, and 10o/o in other quadrants. Ninety percent arise in ductal epithelium,while 10olo arise in the lobules. Carcinoma is slightly more common in the leftbreast ( 1 10:100); it is bilateral or sequential in 4o/o of cases.

(2) Most patients present with a breast mass discovered either by self-examinationor on a routine physical examination by a physician.

(3) Depending on the size and invasiveness of the tumor, other clinical patterns mayoccur. The tumor may grow into the thoracic fascia to become fixed to the chestwall; it may extend into the skin, causing dimpling and retraction; it may causeobstruction of subcutaneous lymphatics, causing an orange-peel consistency toskin called "peau d'orange"; or it may invade Cooper ligaments within ducts tocause nipple retraction.

t74

Pathology: Female

d. Pathogenesis is multifactorial: genetic (e.g., family history), environmental (e.g.,radiation), and viral (e.g., mammary tumor virus in mice) influences may beinvolved. A possible hormonal role has been intensively studied, yielding the findingthat "unopposed estrogen" over prolonged periods may lead to ductal hyperplasiaand malignant transformation.

e. Noninfiltrating intraductal carcinoma

( 1) Grossly, there is a focus of increased consistenry in breast tissue. Intraductal car-cinomas, called "comedocarcinomas I' are so named because cheesy, necrotictumor tissue may be expressed from ducts.

(2) Microscopically, typical duct epithelial cells proliferate and fill ducts,leading toductal dilatation. They rarely have a papillary pattern (i.e., intraductal papil-lary carcinoma).

f. Infiltrating ductal carcinoma is the most common breast cancer.

(1) Grossly, these tumors typically have a rock-hard, cartilaginous consistenry andare usually 2-5 cm in diameter. They may be fixed to the chest wall with nippleretraction and skin dimpling. Foci of necrosis and calcification are common,aiding discovery on mammography.

(2) Microscopically, anaplastic duct epithelial cells appear in masses, nests, glands,cords, and tubes, invading the stroma. A fibrous reaction is responsible for thehard, palpable mass.

g. Medullary carcinoma with lymphoid infiltration. These have a better prognosis thaninfiltrating ductal carcinoma.

(1) Grossly, medullary carcinoma forms fleshy masses, often 5-10 cm in diameter.There is little fibrous tissue. Foci of hemorrhage and necrosis are common.

(2) Microscopically, there are sheets of large, pleomorphic cells with increasedmitotic activity and a lymphocytic infiltrate that separates the epithelial cellsfrom each other.

h. Colloid (mucinous) carcinoma occurs in older women. It is slow growing and has abetter prognosis than infiltrating ductal carcinoma.

( 1) Grossly, these are soft, large, gelatinous tumors.

(2) Microscopically, there are islands of tumor cells floating in a sea of mucin. Somemay resemble well-differentiated, mucin-producing adenocarcinomas.

i. Lobular carcinoma arises from terminal ductules. Ttrmors are multicentric and usu-ally have estrogen receptors.

(1) Grossly, the lobular carcinomas are rubbery and ill-defined as a result of theirmulticentric nature.

(2) Microscopically, tumor cells are small and may be arranged in rings aroundducts. In lobular carcinoma in situ, tumor cells are confined to lobules. In infil-trating lobular carcinoma, there is stromal infiltration, often showing malignantepithelial cells in single file.

Note

Two tumor suppressor genes-BRCAI on chromosome l7qand BRCA2 on chromosome13q-have recently beendiscovered. BRCAI has beencloned, and specific mutationsin high-incidence families havebeen characterized. Essentially,all cause protein synthesistermination, leading to theabsence of gene product.Patients carrying mutatedBRCAI are at extremely high(almost l00o/o) lifetime risk forbreast cancer, often occurringin the third and fourthdecades of life. Some patientsare also at increased risk forovarian carcinoma, and menmay be at increased risk forprostate cancer, although dataon this subject are notconclusive. Mutated BRCA2does not increase theincidence of ovarian cancer inwomen but does increase theincidence of breast cancer inboth women and men.

,75

Reproductive System

Figure lV-7-9. Paget disease of the breast (gross).

j. Paget disease of the breast is a form of intraductal carcinoma that involves theareolar skin and the nipple. It occurs in older women and has a poor prognosis.

(1) Grossly, the skin of the nipple and areola are ulcerated and oozing. There maybe a superimposed inflammation or bacterial infection (Figure IV-7-9).

(2) Microscopically, there is ductal carcinoma as well as large, anaplastic, hyperchro-matic "Paget cells," i.e., tumor cells invading the epidermis (Figure fV-7-10).

*,*

w #," &,, #, g l F

ry'+, .#

Figure lV-7-10. Paget disease of the breast (microscopic).

k. Metastatic tumors to the breast are rare. The most common are leukemia, lym-phoma,lung cancer, and melanoma.

l. Diagnosis. Mammography, a radiologic evaluation of the breast, is part of the clini-cal investigation of a breast mass. Sixty percent of breast cancers have foci of calcifica-tion (Figures IV-7-11 and lV-7-12).

*r,

Note

The American Cancer Societyrecommends annualmammography for allwomen over 40.

,76

Pathology: Female

Figure lV-7-11. Carcinoma of the breast (gross).

Figure lV-7-12. Carcinoma of the breast (microscopic)

m. Metastases. Most breast cancers disseminate via lymphatic or hematogenous routes toaxillary, supraclavicular, and internal thoracic nodes or the nodes of the contralateralbreast. The direction of spread depends on the anatomic location and lymphaticdrainage of the primary tumor.

n. Staging of breast carcinomas is based upon the size of the tumor and the degree towhich the tumor has spread to the surrounding tissues.

( 1) Stage I refers to a tumor less than 5 cm, with no metastases or nodal involvement.

(2) Stage II tumors are less than 5 cm and have local, moveable, nodal involvement,but not distant metastases.

(3) Stage III tumors have local nodal, pectoral, and/or skin involvement, but nodistant metastases.

T?*n ,

m.&^"

t77

Reproductive System

Note

Prognosis is alsoheavily influenced byhistologic type.

( ) Stage fV tumors may or may not have local involvement, but are characterizedby the presence of distantmetastases.

o. Prognosis depends on many factors, including the type and stage of the carcinoma.Overall S-year survival is 50%; a breakdown by stage is summarized in Thble IV-7-3.

Thble lV-7-3. Breast cancer5-year survival rate by stage.

Stage 5-Year Survival

IIIIIIIV

80-95o/o

65-85o/o

40-50o/o

l0-20o/o

p. Treatment

(1) Surgery. Segmental mastectomy (can be local excision, quadrant excision,partial removal of breast tissue, or "lumpectomy"), where only the tumor andits surrounding tissue is removed. Simple mastectomy is the removal of breasttissue; modified radical mastectomy is the removal of the breast tissue,axillary nodes, and pectoralis fascia; and radical mastectomy is the removal ofbreast tissue, axillary nodes, pectoralis fascia, and pectoral muscles. Therapyusually includes some combination of surgery, radiation, and chemotherapy.

(2) Estrogen receptors. The presence of cytoplasmic estrogen receptors may be auseful predictor of response to "hormonal therapy."Approximately two-thirds ofbreast cancers are estrogen-receptor positive; most of these will regress whenpatients are given antiestrogen compounds such as tamoxifen. In fact, patientswho are both estrogen- and progesterone-receptor positive have the bestresponse to tamoxifen. Adjuvant chemotherapy is clearly of benefit in post-menopausal cancer but not in premenopausal cancer.

!78

Reproductive Pharmacology

The reproductive or sex hormones consist of estrogens, progestins, and androgens. Synthetichormone analogs and their antagonists are available for endocrine and nonendocrine abnormalities,including replacement therapy, fertility control, treatment of infertility, and cancer chemotherapy.

ESTROGENSThe estrogens are steroid hormones produced predominantly by the ovaries, although theadrenals, placenta, and other organs may contribute. Estradiol is the principle ovarian estro-gen. Other endogenous estrogens include estriol and estrone.

A. Regulation of secretion. Synthesis and secretion are regulated by the hypothalamic-pitu-itary-ovarian axis. Synthesis by ovarian follicles is stimulatedbyFSH, which increases cAMPin follicular cells. Estrogens provide negative feedback to inhibit pituitary secretion of FSHand LH. However, the midrycle surge (or pulse) in estradiol stimulates the secretion of LH,which induces ovulation. Estrogens remain elevated in the luteal phase.

B. Mechanism of action. Estrogens work via a steroid hormone mechanism, entering the tar-get cells and binding to specific cytosolic receptors. The steroid-receptor complex is thentranslocated to the nucleus where it alters gene expression.

C. Physiologic effects

l. Stimulate the development of uterus, fallopian tubes, vagina, breast, and secondary sexcharacteristics

2. Cause endometrial growth during the menstrual rycle

3. Decrease serum cholesterol

4. Inhibit bone resorption

5. Estrogens increase linear bone growth with subsequent closure of the epiphyseal plate,effect a mild increase on fluid and salt retention, increase high-density lipoproteins(HDLs), and decrease low-density lipoproteins (LDLs). cr-Blood clotting factors II, VII,IX, and X are increased, and antithrombin III is reduced.

B. Pharmacokinetics. Estradiol has low bioavailability following oral administration; analogswith better bioavailability are usually used. Estrogens are also available for topical, intra-muscular, and transdermal administration. They bind in the blood to sex hormone-bindingglobulin.

Bridge toMolecular Biology

Steroid receptors are DNAbinding proteins that have azinc finger structure allowingthem to interfere with specificenhancers in spacer DNA orintrons of genes they regulateexpression of.

ln a Nutshell

Estrogens. Stimulate secondary sex

characteristics. Inhibit bone resorption. Have procoagulant effects. Can increase risk of endome-

trial carcinoma if given withoutprogestins

Bridge to Pathology

Endometrial hyperplasia is apossible precursor toendometrial carcinoma and isgenerally associated with highexposure to estrogens.

T79

Reproductive System

Cliniol Correlate C. Indications for use

For DostmenoDausal Women 1. Oral contraceptives, in combination with progestins

whose uterus has nol been 2. Postn€nopausal rq acernent therapy to reduce symptoms such as hot flashes and vagi-removed surgiolly, both nal atrophy; aiso to decrease the risk of osteoporosis and coronary artery dis€aseestrogen and a progestin are 3. Replacement therapy for primary hypogonadism and hypopituitarismrecommended. Thecombination reduces the risk 4. Dysmenorrhea and dysfunctional uterine bleeding

of endometrial arcinoma 5. Palliative treatment of prostatic carcinoma to reduce growth rat€ of metastasesasociated with unoooosed--l -. ,., "-"-- 6. Diethylstilbestml (DES), which can be given to prevent pregnancy when administered in

enroSen qlmulanon high dose 2,1-72 hours after intercourse; it is th"refore knor,r,o as the "morning-after pill."

D. Specific agents

l. Natur.l estrogens include estradiol and conjugated estrogens.

2. Synthetic estrogens include t}le oral preparations ethinyl estradiol and mestranol.Mestranol is converted in the body to ethinyl estradiol.

3. Nonst€roid estrogenic agents include DES and chlorotrianisene.

PROGESTINSProgesterone is a steroid horrnone synthesized predominandy by the corpus luteum during thepostovulatory or luteal phase of the menstrual cycle. During pregnancy, the placenta talcs overthe production of progesteron€. Th€ adrenal cortex is also a source of small amounts of pro-gesterone. Progestins are drugs with progesterone-like properties.

A. Regulation of secretion. Synthesis by the corpus luteum is stirnulated by LH, an effect medi-rted by cAMP.

B. Mechanisrn ofaction. Progestins act like estrogens to alter g€xre opression and protein synthesis.


1. Produce a secretory vascular uterine endometrium in preparation for implantation

2. Stimulate breast development in preparation for lactation

). Maintain pregnancy by inhibiting the sloughing of the endometrial lining

GliniOl Gorrelate 4. Increase body Gmperature (basal temperature is 0.5-1.0 degree higher in the postovulatory

phase)

Clucose intolerance, 5. Alter carbohydrate metabolism and enhance fat depositiondecreased HDL, and,--------;, ̂ ; 1-;-,- -, 6. Progestins are also androgenic and antiestrogenictncreasec LUL cnote$erolare seen with progestin. D. Pharmacokinetics. Progesteron€ is largd metabolized (conjugated) by the liver and is,

therefore, ineffective orally. Synthetic progestins are orally administered.

E. Indications for use

1. Oral contracE tives (usually in combination with an estrogen)

2. The treatment of dysrnenorrhea and dysfunctional uterine bleeding

3. The treatment of endometriosis (a condition in which endometrial tissue is present atsome ectopic site) to suppress ovarian function

580

Pharmacology

ORAI AND IMPIANTABLE CONTRACEPTIVE AGENTSA. Specific agents

1. Oral contraceptives are available as either a combination of an estrogen and a progestin,or as progestin only ("mini-pill"). The combination products may be biphasic or tripha-sic, in which the dose of progestin increases during the later days of the month to mimicthe natural menstrual cycle.

2. Progestin implants consist of levonorgestrel capsules, which are implanted under theskin of the upper arm, providing a slow release of progestin. Progestin implants areconsidered an effective and reversible contraception for up to 5 years.

3. Medroxyprogesterone acetate intramuscular depot injection provides contraception for3 months.

B. Mechanism of action

1. The estrogen component inhibits ovulation by negative feedback to inhibit the release ofFSH and LH.

2. The progestin component may, but does not always, inhibit ovulation. The progestinreduces the possibility of fertilization and implantation by effecting changes in fallopiantube motility, cervical mucus, and endometrium.

C. Side effects and toxicity

1. Nausea and vomiting, breast tenderness, increased skin pigmentation, hypertension, andbreakthrough bleeding correlate with the amount of estrogen given. Weight gain,depression, and hirsutism correlate with progestin content.

2. Headaches may occur but are often transient; however, migraine headaches may occur forthe first time or be exacerbated and associated with stroke. Oral contraceptives are con-traindicated in patients with a history of migraine headaches.

3. There may be withdrawal bleeding. Excessive spotting and late cycle spotting mayimprove by decreasing estrogen and increasing progestin.

a. Vaginal infections may occur.

5. There may be effects from changes in serum proteins; specifically, increased fibrinogenmay increase the erythrocyte sedimentation rate.

6. Cholestatic jaundice has been reported in patients taking progestins.

7. Cardiovascular effects of combination oral contraceptives

a. There may be thromboembolic disease. The risks of superficial and deep venousthrombosis and pulmonary embolism are related to estrogen content.

b. There is an increased risk of myocardial infarction that is related to estrogen content,usually after prolonged use. The risk is increased by cigarette smoking, hyperlipo-proteinemia, diabetes, hypertension, and a history of preeclampsia.

c. Stroke may occur. There is an increased incidence of thrombolytic and hemorrhagicstrokes, predominantly in women over 35 years old.

8. Sodium and water retention may occur.

9. Cancer risk

a. DES use during pregnancy has been associated with vaginal and uterine carcinoma infemale offspring.

Clinical Correlate

Some Contraindications toTaking Oral Contraceptives

. Thromboembolicdisease

. History of migraineheadaches

. Smoking

. Liver disease

. Cerebrovascular disease

. Estrogen-dependentneoplasms

18l

Reproductive System

Note

A partial agonist has efficacyalone, but behaves as ablocker in the presence of afull agonist (e.g. endogenousestrogens).

Bridge to Pathology

Board-like scenario. Youngwoman on oral contraceptivesplaying soccer drops during agame with a ruptured liveradenoma, causingintraperitoneal bleedi ng.

b. Because progestins oppose estrogen-induced cell growth, oral contraceptives do notincrease the incidence of endometrial cancer. They actually decrease the incidence by50o/o, an effect that lasts l5 years after the pills are stopped. Sirnilar data exist for theincidence of ovarian cancer. The use of oral contraceptives is not associated with a sig-nificant increase in breast cancer. The only cancer risk is that of iiver adenoma.

ESTROGEN ANTAGONISTS AND PARTIAT AGONISTSThere are two drugs in this category that play an important role in therapy.

A. Thmoxifen, a nonsteroidal drug, is important in the treatment of estrogen-sensitive breastcancer.

l. Mechanism of action. Thmoxifen is a competitive antagonist to estrogen at receptors inthe breast; it may be a partial agonist at other estrogen receptors (thus minimizing sideeffects due to estrogen deprivation).

2. Side effects and toxicity. The drug has a low incidence of adverse reactions. These mayinclude hot flashes, nausea, vomiting, rash, menstrual irregularities and bleeding, infre-quent depression, headache, hypercalcemia, edema, and blood dyscrasias.

3. Indications for use. The drug is successful in reducing the recurrence of estrogen-receptor-positive breast cancer, particularly in postmenopausal women.

B. Clomiphene, a nonsteroidal estrogen, is used in treatment of infertility.

1. Mechanism of action. Clomiphene is a partial agonist at pituitary estrogen receptors. Itdecreases the negative feedback of estradiol, leading to increased release of FSH and LH.

2. Indications for use. Clomiphene is used in women to improve follicular developmentand induce ovulation. It is used in men to increase spermatogenesis.

3. Side effects and toxicity. Adverse reactions include hot flashes, headache, constipation,allergic reactions. Overstimulation of the ovaries can lead to ovarian cysts and multiple-birth pregnancies.

C. Raloxifen is used after menopause to decrease osteoporosis.

ANTIPROGESTINSA. Mifepristone (RU486) is a competitive inhibitor of the progesterone receptor. The drug can

also bind to the glucocorticoid receptor. It is used as an abortifacient to terminate earlypregnancy. Drug administration is usuaily followed by a prostaglandin.

B. Danazol is a partial or weak agonist at androgen, glucocorticoid, and progesterone receptors.It appears to act centrally to reduce ovarian production of steroids. It is used in the treatmentof endometriosis and fibrocystic disease of the breast. Adverse reactions are due to its weakandrogenic properties.

!82

Pharmacology

ANDROGENS AND ANABOTIC STEROIDSA. Regulation of secretion

1. Testosterone is the principle androgen secreted by the testes (Leydig cells). Testosteroneand other androgens are also secreted by the adrenal cortex and in small amounts by theovaries. Once secreted, testosterone is 99olo bound to plasma proteins, mostly to sex hor-mone-binding globulin.

2. Secretion of testosterone is regulated by the hypothalamic-pituitary system. LH stimulatesthe Leydig cells to synthesize and secrete testosterone. Testosterone and FSH act toincrease spermatogenesis. Testosterone provides negative feedback to the pituitary.

B. Mechanism of action. Testosterone, similar to other steroid hormones, binds to cytosolicreceptors, which are translocated to the nucleus where they regulate gene expression. Insome organs (e.g., prostate), testosterone is converted via 5cr-reductase activity to dihy-drotestosterone, a more potent receptor agonist.


1. Testosterone is necessary for the development of secondary male sex characteristics andmale sexual behavior.

2. It is required for spermatogenesis.

3. Testosterone promotes protein anabolism and growth and enhances linear bone growthand muscular development.

4. It causes an increase in the size of the larynx and deepens the voice. It increases sebaceousgland activity, which may result in acne, and stimulates erythropoiesis (responsible for thehigher hematocrit in men than in women).

D. Indications for use

1. Androgens are used in replacement therapy for hypogonadism and hypopituitarism.

2. They are used to accelerate growth and to promote anabolism.

3. In breast cancer, androgens are used as palliatives.

4. Androgens are also used in the treatment of angioneurotic edema and endometriosis(danazol).

5. Specific agents

a. Compounds with androgenic and anabolic activity include testosterone and methyl-testosterone.

b. Synthetic analogs with greater anabolic than androgenic properties include flu-oxfmesterone, nandrolone, and oxandrolone. These "anabolic steroids" were firstproduced for treatment of patients with debilitating diseases or prolonged immobi-lization to prevent negative nitrogen balance.

E. Side effects and toxicity

1. Adverse reactions include masculinization in women and prostatic hypertrophy, pri-apism, and feminization in men. Testicular atrophy and gynecomastia are problems inchronic users.

2. The most common adverse reactions are edema, jaundice, local irritation, urinaryobstruction, and steroid fever.

3. Other adverse effects include premature epiphyseal closure in children,liver dysfunction,hypercalcemia, and alteration of serum lipids.

Clinical Correlate

Androgens have fallen out ofuse for the treatment ofanemia since the advent ofrecombinant erythropoietin.

585

Reproductive System

Note ANDROGEN ANTAGONTSTSSpironolactone. an aldosterone Androgen antagonists have been sl.nthesized for the treatment of prostate cancer and benignR blocker, is used for its prostatic hyperplasia.

antiandrogenic effecb like A. GnRH analogs (e,g.,leupmlide). Long-term therapy reduces the secretion of FSH and LH,Cyproterone acetate. thus leducing testosterone production. Used for advanced prostate canc€r.

B. Flutamide is a nonsteroid competitive antagonist at androgen r€c€ptors used in metastaticprostate canc€r to block t€stosterone.

C. Cyproterone acetate is an androgen receptor antagonist with progestin-like actiyity. It is

Gliniol Gorrelate being tested for the treatment of hirsutism in women.

D. Finasteride is an inhibitor of Scr-reductase and thus inhibits the production of dihy-The cr'-blocker terazosin is drotestosterone. It is us€d in the treatment ofbenignprostatichypertrophyand male patternalso used in the treatment of baldness.symptomatic prostaticLrpa"frr"

' E. Ketoconamle, an irnidazole-type antifungal agent, inhibits steroid synthesis and is used inmdrogen receptor-positive cancer tlerapy,

OTHER DRUGSA. Anastrozole is an aromatase inhibitor used in breast cancer.

B. Danazol inhibits ovarian steroid synthesis and is used in endometriosis and breast fibrocvsticdisease.

t84

2008 kaplan usmle step 1 home study program-brand new volume iv: organ systems book 2

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