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TRANSCRIPT
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E n d o c r i n o l o g y
American Manualof Examination
in Medicine(2CK)
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No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by anymeans, electronic, mechanical, photocopying, recording, or otherwise without prior permission of the
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ISBN full edition: 978-84-16276-21-9
DISCLAIMER
Medicine is a science subject to constant change. As research and clinical experience widen our
knowledge, treatments and pharmacotherapy changes are necessary. The editors of this work have
verified their results against reliable sources, in an effort to provide general and complete information,
according to the accepted criteria at the time of publication. Nevertheless, given the fact that human
error may occur or that some changes may take place in medical sciences, neither the editor nor any
of the contributors involved in the preparation –or publication- of this work can guarantee that thecontent herein is accurate and complete in each and every aspect. The editors and the contributing
sources cannot be held responsible for any errors, omissions or the outcome derived from the use
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Readers should also check with their own laboratory about normal values.
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E n d o c r i n o l o g y
American Manualof Examination
in Medicine(2CK)
AuthorJuan Simón Chacín
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01. Hypothalamic-Pituitary Pathology .................................1
1.1. Cushing’s Syndrome .........................................................................................................1
1.2. Acromegaly ....................................................................................................................................2
1.3. Hyperprolactinemia ..........................................................................................................2
1.4. Diabetes Insipidus................................................................................................................3
1.5. Syndrome of Inadequa teSecretion of Vasopressin SIAD H ..........................................4
02. Thyroid Pathology .................................................................................5
2.1. Thyroid Function Test ......................................................................................................5
2.2. Hyperthyroidism ....................................................................................................................5
2.3. Hypothyroidism ......................................................................................................................6
2.4. Thyroiditis .........................................................................................................................................6
2.5. Thyroid Nodule and Thyroid Cancer .........................................................7
03. Adrenal Pathology .................................................................................8
3.1. Adrenal Failure..........................................................................................................................8
3.2. Pheochromocytoma .........................................................................................................8
3.3. Primary Hyperaldosteronism PHA ..........................................................9
3.4. Congenital Adrenal Hyperplasia CAH ...........................................10
04. Alteration in Hydrocarbonate Metabolism ....10
4.1. Type 1 Diabetes Mellitus ........................................................................................10
4.2. Type 2 Diabetes Mellitus ........................................................................................11
4.3. Treatment of Diabetes Mellitus ....................................................................12
4.4. Metabolic Syndrome ....................................................................................................14
05. Bone Pathology and Phosphocalcic
Metabolism .........................................................................................................14
5.1. Osteoporosis ............................................................................................................................14
5.2. Paget’s Disease ....................................................................................................................15
5.3. Hyperparathyroidism ..................................................................................................15
06. Multiple Endocrine Neoplasia (MEN) ..........................16
Index
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Endocrinology
Chapter 01
Hypothalamic-
Pituitary Pathology
1.1. Cushing’s Syndrome
• Cushing’s syndrome (CS) is a set of diverse symptoms, due to an
excess in corsol producon by the adrenal cortex (endogenous
Cushing’s) or by sustained administraton of glucocortcoids (exog-
enous and facttous Cushing’s).
• The most frequent cause is iatrogenic administraon of steroids due
to another reason; the most frequent endogenous cause is Cushing’s
diseases (overproducon of ACTH due to a pituitary adenoma) in 65%
to 70% of the cases, autonomous producon of corsol as a result of
adrenal pathology (adrenal CS because of adenomas, adrenal hyper-
plasia and adrenal carcinoma) in about 15% to 20% and the ectopic CSas a result of paraneoplasc producon of ACTH (bronchial carcinoma
of small cells is the most frequent; carcinoid tumors, CMT and pheo-
chromocytoma) in 15%.
Clinical presentation (Figure 1)
Moon face
Acne
Central obesity
Muscle weakness
Capillary fragility
Hirsutism
Wine-red stretch marks
Figure 1. Clinical presentation of Cushing’s syndrome
• Characteristc features of Cushing’s Syndrome include (from the
most frequent to the least)
Symptoms: weight gain, menstrual cycle irregularity, hirsutsm,
psychiatric alteratons, muscle weakness.
Signs: central obesity, facial plethora, moon facies, hemato-
mas and capillary fragility, vinous red stretch marks, edemas
in lower extremites, proximal myopathy and hyperpigmenta-
ton.
The most specific are facial plethora, capillary fragility, muscle
weakness or proximal myopathy, wine-red stretch marks and,
weight gain with growth rate delay.
• Patents present in half of the cases, alteratons of carbohydrate
metabolism (DM and carbohydrate intolerance), high blood
pressure (HBP) and osteoporosis; and less frequently, nephro-
lithiasis.
• In ectopic CS cases, symptoms and signs typical of CS may appear
and cardinal manifestatons consist of glucose intolerance, hypopo-
tassemic alkalosis, proximal myopathy and cutaneous hyperpigmen-
taton.
Diagnosis
• Whatever the cause of excess cortsol producton, there will always
be an increased cortsol excreton, aboliton of its circadian rhythm
and absence of cortsol secreton inhibiton with a low dose of glu-
cocortcoids.
• Biochemical diagnosis of hypercortsolism requires two positve
tests of the following (they are regarded as “first line test”): high
corsoluria 24 h, high nocturnal salivary corsol (measured be-
tween 11 p.m. and midnight) and/or lack of suppression of basal
plasma cortsol afer administraton of low doses of dexametha-
sone: nocturnal suppression with 1 mg of dexamethasone (Nugent
test) and/or low-dose dexamethasone suppression test (classic test
of 2 mg DXM or low-dose Liddle test). • There are “second-line tests” to be performed on patents who
have had misleading results on a prior test and when there is a
high clinical suspicion of Cushing’s syndrome: high late-night se-
rum corsol (measured between 11 p.m. and midnight) and com-
bined suppression test with 2 mg of DXM + CRH smulus: useful
to diff erentate people suff ering from pseudo Cushing’s (it remains
suppressed afer CRH) from those with CS (they experience a high
plasma concentraton of cortsol and ACTH afer CRH administra-
ton).
• For eologic diagnosis or diagnosis for localizaton, the first step
will always be determining baseline ACTH to diff erentate between
ACTH-dependent CS (central or ectopic) and ACTH-independent CS
(adrenal). If ACTH is < 5 pg/mL (low or suppressed), it is ACTH inde-pendent, so the next step is to perform an adrenal imaging test (adre-
nal CT scan, MRN). If > 20 pg/mL, it is ACTH-dependent and the next
step is to perform a pituitary MRN.
• Intermediate results (from 5 to 20 pg/mL) will probably reveal an
ACTH-dependent CS, so a CRH test will be taken (central CS keeps
a hypothalamic pituitary-adrenal axis relatvely intact). Therefore,
afer CRH administraton, there is an increase in ACTH and cortsol
at baseline in most patents with hypothalamic dysfuncton or an
ACTH-secretng pituitary tumor (macroadenoma and microadeno-
ma).
• The 8 mg DXM Liddle’s test with a high dose (long high-dose
dexamethasone suppression test) is a useful test to discrimi-
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cal diabetes mellitus); hypercalciuria and nephrolithiasis. Hyperpro-
lactnemia is present in a third of the cases. Sleep apnea. Increase
in the frequency of nasal polyps and intracranial aneurysm. Three
to ten tmes higher risk of having premalignant polyps and colon
cancer.
Diagnosis
• Random determinatons of GH should not be used for the diagnosis
of acromegaly.
• Biochemical diagnosis is based on the presence of high IGF-I levels
for age and sex along with a GH that is not suppressed afer oral
glucose overload (OGO).
• Imaging studies (adrenal NMR) afer hormonal diagnosis, which
will reveal a selar lesion in most cases (macroadenoma is more fre-
quent).
• A complete assessment of pituitary funcon is necessary to rule out
the existence of panhypopituitarism.
• Every acromegaly suff erer must have a colonoscopy performed at
the tme of diagnosis and steps towards early detecon of pos-
sible complica
ons (i.e., sleep apnea, diabetes mellitus amongothers).
Treatment
• Transsphenoidal surgery is the choice in microadenomas and
macroadenomas that are potentally resectable. In macroad-
enomas with wide extraselar extension although surgery is not
curatve, it can improve response to medical treatment (“deb-
ulking”).
• The medical treatment of choice in acromegaly is the somatostan
analogs (octreotde, slow-release octreotde and lanreotde) which
suppress GH secreton. These drugs can be used as a therapeutc
first choice, when the surgical risk is unacceptable, the patents re-
ject surgery or a macroadenoma is present with scarce possibilitesof being completely resected with or without debulking. Pegviso-
mant, a GH receptor antagonist is another alternave. It is the sec-
ond treatment of choice afer somatostan analogs, in the event cu-
rave criteria is not met or because of the appearance of severe side
eff ects.
• Radiotherapy is utlized in diseased people who did not reach cure
afer surgery or when surgery is contraindicated or the patent re-
jects it. At present, radiotherapy is a second or third choice treat-
ment.
1.3.Hyperprolactinemia
• Increase in prolactn levels. The most frequent cause of hyperp-
rolactnemia is pregnancy and the most frequent pathologic pri-
mary source is drugs intake.
• The most common functoning pituitary tumor is prolactnoma.
Other tumors can cause hyperprolactnemia, because of com-
pression of the pituitary stalk (and loss of dopamine inhibitory
tone on lactotroph) cells, like nonfunctoning adenomas and
other selar masses. Hypothyroidism, chronic renal disease and
hepatc cirrhosis are also causes of hyperprolactnemia (Table
1).
nate patents with ACTH-secretng pituitary microadenoma. A
positve response occurs when cortsol in urine or plasma is re-
duced (> 90% of baseline) afer DXM administraton, while mac-
roadenomas and most ectopic ACTH-secretng tumors do not do
so.
• When a CS is ACTH-dependent and there is no clear tumoral image
in the pituitary gland (≥ 6 mm) or there are hypopotassemia and/or
metabolic alkalosis (more frequent in ectopic Cushing’s) a bilateral
catheterizaton of inferior petrosal sinuses must be performed. The
demonstraon afer CRH smulaon of an ACTH peripheral gradient
(higher level in petrosal sinus than in peripheral vein) enables locat-
ing the site of ACTH hypersecreon in the pituitary gland. If there is
no gradient: there is an ectopic source producing ACTH, hence, the
tumor should be sought (thoracoabdominal CT scan, octreoscan test
or PET scan).
Treatment
• Eologic treatment of choice is surgery in adrenal pathology (ad-
enomas and carcinoma) and in Cushing’s disease (via transsphe-
noidal approach). Also in ectopic tumors in which resecton is pos-sible.
• Pituitary radiotherapy is used in cases in which cure is not achieved
afer transsphenoidal surgery of Cushing’s disease.
• When etologic treatment is not possible or it did not turn out eff ec-
tve, it is necessary to resort to medical adrenalectomy (mitotane)
or to inhibitors of cortsol synthesis (ketokonazole, aminoglutethi-
mide or metopirone).
• Occasionally, bilateral surgical adrenalectomy is needed when de-
finitve treatments (surgery or radiotherapy) fail or side eff ects to
drug treatment develop. Then, a substtuton treatment is required
with glucocortcoids and mineral or cortcoids.
1.2. Acromegaly
• Debilitatng chronic disease because of an increased producton of
growth hormone (GH), habitually because of GH-secretng pituitary
adenomas. A total of 75% of them are macroadenomas (greater
than 1 cm).
• When GH excess develops before epiphyseal plate closure in chil-
dren, the linear growth increases and results in gigantsm.
Clinical presentation
• Symptoms: progressive growth and enlargement of hands, feet andperimeter, prognathism, exaggerated development of the tongue and
coarsening facial features. Weakness and tredness, profuse sweat-
ing, headache, carpal tunnel syndrome, muscle weakness and ar-
thralgia. Amenorrhea, hirsutsm.
• Signs: cavernous voice as a result of laryngeal hypertrophy, wet and
doughy hands, deepening of skin crease, acanthosis nigricans and
oily skin. Bitemporal hemianopsia because of compression of the
optcal chiasm. HBP. Myocardiopathy (ventricular hypertrophy) and
heart failure because of diastolic dysfuncton, goiter, hepatomegaly
and splenomegaly.
• People suff ering from this disorder may be insulin-resistant with
abnormal hydrocarbon metabolism (glucose intolerance and clini-
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PHYSIOLOGIC
HYPERSECRETION
· Pregnancy
· Lactancy · Stimulation of thorax wall
· Sleep
· Stress
LESION OF THE
HYPOTHALAMUS
OR PITUITARY
STALK
Tumors · Craniopharyngioma · Meningioma
· Dysgerminoma · Metastasis
· Empty Turkish saddle · Lymphocitary hypophysis
· Adenoma with stalk compression
· Granulomas
· Rathke’s cysts · Radiation
Traumatisms · Section of the
pituitary stalk· Suprasellar surgery
HYPOPHESEAL
HYPERSECRETION
· Prolactinoma · Acromegaly
SYSTEMIC
DISORDERS
· Chronic renal failure · Hypothyroidism
· Cirrhosis
· Comitial crisis
DRUGS
Dopamine receptor
antagonists
· Phenothiazines:
chlorpromazine· Butyrophenones:
haloperidol
· Thioxanthenes
· Metoclopramide
Dopamine synthesis
inhibitors
Methyldopa
Cathecolaminesdepletion
Reserpine
Opiates
H2 antagonists · Cimetidine
· Ranitidine
Imipramines Amitriptyline
Serotonin reuptake inhibitors
Calcium antagonists Verapamil
Estrogens and anti-androgens
Table 1. Etiology of hyperprolactinemia
Clinical presentation • Hyperprolactemia generates inhibion of hypothalamic release
of GnRH, with a decrease in LH and FSH (hypogonadotropic hypo-
gonadism), manifestng through sexual and reproductve functon
disorders.
• In premenopausal women: galactorrhea, anomalies in the men-
strual cycle, like oligomenorrhea, infertlity because of anovula-
tory cycles or menorrhea.
• In men: a decrease in libido, impotence and infertlity, as well as the
possible appearance of alteratons in the visual field (by chiasmatc
compression of a macroprolactnoma). In postmenopausal women
compressive symptoms are also predominant.
Diagnosis
• High prolactn baseline values.
Prolactn levels < 100 μg/L may be owing to microadenomas,
as well as lesions in the stalk and in the hypothalamus, and
to the remaining reasons for nonneoplastc hyperprolac-
tnemia.
Prolactn levels > 100 μg/L in the absence of pregnancy are very
likely to result from microprolactnoma.
Prolactn levels > 250 μg/L are virtually diagnostc of a PRL-pro-
ducing pituitary adenoma, usually a macroadenoma.
• Pituitary MRN to assess the existence of a lesion at that level.
Prolactnomas (much in the same way as other pituitary adeno-
mas) are classified into microadenomas (lesser than 1 cm) and
macroadenomas (greater than 1 cm).
Treatment
• Treatment indicatons for prolactnomas are stated in Table 2.
• Pharmacologic treatment is the treatment of choice: dopaminer-gic agonists (the most utlized are cabergoline, bromocriptne).
• Surgical treatment is reserved for patents with persistent visual
defects despite dopaminergic agonist treatment and for those
patents who do not tolerate dopaminergic agonists. Decompres-
sive surgery may also be necessary in tumors with a significant
cystc or hemorrhagic component to relieve visual symptoms and
headache.
PROLACTINOMAS: TREATMENT INDICATIONS
· Microprolactinomas. In the following cases:
- Women: desire for pregnancy, severe hypogonadism with highrisk of osteoporosis, bothersome galactorrhea, decrease in libido
- Men: decrease in libido or sexual potency, sterility
· Macroprolactinomas. They are always treated
Table 2. Indications for treatment of prolactinomas
1.4. Diabetes Insipidus
• Inability to generate concentrated urine because of the absence of
(partal or complete antdiuretc hormone secreton) or a defect in
its acton at renal level.
• Diabetes insipidus is subdivided into: Central ID: the neurohypophysis is incapable of releasing
ADH. Causes comprise idiopathic causes, brain or pituitary
tumors, infiltratve illnesses, cranio-cephalic traumatsms,
posterior to surgery or pituitary radiotherapy. Also necrosis
of vascular origin, infectons, alcohol, chlorpromazine and
phenytoin.
Nephrogenic ID: lack of ADH renal response. The most usual
reasons are hypercalciuria, lithium administraton, hypopotas-
semia and tubulointersttal nephropathy. Other related drugs
are demeclocycline, methoxyflurane, foscarnet, cidofovir, am-
photericin B, didanosine, ifosfamide, ofloxacin, orlistat and V2
receptor antagonists (vaptans).
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Clinical presentation
• Symptoms: Persistent polyuria (> 3 L/day in adults, > 2 L/day in
children) of hypotonic urine (low density < 1.010, generally di-
minished osmolality < 300 mOsm/kg) and polydipsia contnual
thirst.
• Sudden onset of symptoms, above all, in central DI.
• Normal functon of the thirst center enables polydipsia to adjust
to polyuria and avoid dehydraton, so most cases are normona-
tremic.
• When water access is not available (i.e., seniors, the insttutonal-
ized), significant dehydraton and hypernatremia, with alteraton of
the level of consciousness, comital crisis and even coma.
Diagnosis
• Dehydraon test or thirst test (Miller test): simple and reliable form
for the diagnosis of diabetes insipidus and distnguish ADH defi-
ciency from other polyuric syndromes. The test involves comparing
urine osmolarity afer deprivaton of water and the osmolarity ob-
tained afer DDAVP (ADH synthetc analog). In ID (both central and nephrogenic) hypotonic polyuria persists
afer dehydraton, while in primary polydipsia urine becomes
concentrated.
• Response to DDAVP administraon:
If the response implies urinary osmolarity doubles and diuresis
decreases, it is a central ID. If that is not the response, then it is
a nephrogenic ID.
• If the patent presents analytc alteratons compatble with dehy-
draton (elevated plasma osmolarity > 295 mOsm/L, hypernatre-
mia) the dehydraton test is not necessary (it can even be danger-
ous). The next step will be direct administraton of DDAVP.
• Brain MRN in central ID to rule out hypothalamic or pituitary le-sions.
Treatment
• Central ID: hormonal substtuton with DDAVP. If certain ADH re-
serve is conserved (partal CID) the response may involve carbam-
azepine, clofibrate and chlorpropamide.
• Nephrogenic ID: salt and water restricton, administraton of diuret-
ics that increase natriuresis, (thiazides). NSAIDs can be adminis-
tered as coadjuvant (indomethacin).
1.5. Syndrome of InadequateSecretion of Vasopressin
SIADH
• Hyponatremia secondary to free water retenton due to inappro-
priately high ADH secreton, in relaton to plasma osmolarity and
independent, at least partally, of osmotc control.
• The origin of this ADH can be the neurohypophysis, neoplas-
tc tssues or inflammatory tssues. SIADH causes are listed in
Table 3.
SIADH: ETIOLOGY
· Neoplasias: lung microcytic, brain and neck tumors, duodenum and
pancreas neoplasias, neuroblastoma of olfactory nerve, thymoma
· Nonmalignant lung diseases: pneumonia, asthma, atelectasis, acute
respiratory failure, neumothorax, mechanical ventilation
· Alterations of CNS: infections, ictus, traumatisms, psychosis, thyroid
surgery
· Drugs: chlorpropamide, carbamazepine and derivatives, clobrate,cyclophosphamide, tricyclics, MAOI, SSRI, vincristine, vinblastine,
oxytocin
· Others: hypothyroidism, adrenal failure, major surgery of thorax and
abdomen, HIV, hereditary SIADH (constitutive activation of V2 receptor
and mutations of hypothalamic osmoreceptors, temporal arteritis
Table 3. Causes of inadequate secretion of AVP (SIADH)
Clinical presentation
• Clinical presentaton depends, in general, on how fast plasma so-
dium levels go down.
• If hyponatremia is severe (< 125 mEq/L) or of an acute onset, thefollowing symptoms become predominant: brain edema cerebral,
like agitaton, irritability, confusion, coma and convulsions, together
with unspecific changes in EEG.
• If hyponatremia is mild (130-135 mEq/L) or of progressive devel-
opment, symptoms are more unspecific, for example, anorexia,
nausea and vomitng, headache, sensaton of instability.
Diagnosis
• Suspicion must be maintained on every patent with hyponatre-
mia (< 135 mmol/L), plasma hypoosmolality (< 275 mOsm/kg) and
without maximum urine diluon (> 100 mOsm/kg), but without
edemas, orthostatc hypotension, dehydraton signs, or thyroid or
adrenal hypofuncon (Table 4).• Other findings are detecton of low levels of ureic nitrogen, creat-
nine, ureic acid (< 4 mg/dL) and albumin in the presence of normal
renal functon and normal acid-base equilibrium and potassium.
MAJOR MINOR
1. Hyponatremia
2. Plasma hypo-osmolality
3. No edemas
4. No volume depletion (normal BP)5. Lack of maximum urine dilution
(urine osm > 100 mOsm/kg)
6. Exclusion of hypothyroidism and
adrenal failure
1. Pathologic hydric overload
2. High AVP levels in plasma and
urine
All major criteria are needed for diagnosis. Minor criteria are optional
Table 4. Diagnostic criteria for SIADH
Treatment
Identfy and correctly treat the triggering underlying cause whenever
possible.
• If there is acute hyponatremia with CNS alteraton, comital cri-
sis, subarachnoid hemorrhage or severe hyponatremia (< 125
mEq/L):
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Careful and progressive correcton with hypertonic saline serum
(correct Na+ 1-2 mEq/L/h in symptomatc patents 0.3 mmol/L/h
in asymptomatc suff erers with a maximum limit of 8 mEq/L/12
h, 12 mEq/L/24 h and 18 mEq/L in the first 48 hours). Do not
correct it faster to avoid central pontne myelinolysis (locked-in
syndrome).
• If there is chronic hyponatremia, the patent is asymptomac and
sodium levels are over 125 mEq/L:
Hydric restricton.
Salt contributon and low doses of furosemide.
Lithium or demeclocycline.
Vasopressin receptor antagonists (vaptans). Indicated in case of
SIADH of any etology refractory to other therapies.
Chapter 02
Thyroid Pathology
2.1. Thyroid Function Test
• Determinaon of thyroid smulang hormone (TSH): the best test
for the screening of thyroid pathology and assessment of its func-
ton. Elevated values are usually related to primary hypothyroidism
(with low T3 and T4) and low or suppressed values, with primary
hyperthyroidism (with high T3 and T4).
• Determinaon of total T4: it is not useful for the study of thyroid
pathology, as T4 circulates in plasma and it is almost completelybound to its carrier protein (TBG). T4 values can be altered by this
protein variaton.
• Determinaon of free T4: of choice afer TSH determinaton, for the
screening of thyroid pathology. See Table 5 for interpretaton.
• Thyroid gammagraphy: performed with iodine isotopes (I-131 and
I-123) or with Tc-99 in the form of pertechnetate. It is a useful test
for the etologic diff erental diagnosis of hyperthyroidism.
PRIMARY
hypothyroidism
CENTRAL
hypothyroidism
PRIMARY
hyperthyroidism
CENTRAL
hyperthyroidism
TSH N or
T4L
Table 5. Interpretation of thyroid function test (N: normal)
2.2. Hyperthyroidism
• Hyperthyroidism is the clinical and analytc situaton that results
from the eff ect of excessive amounts of thyroid hormones circulat-
ing throughout body tssues and it is present with high values of T3
and T4.
• Graves disease (GD) is the most common cause in middle-aged
adults. It has an autoimmune origin (presence of thyroid stmulat-
ing antbodies or TSI or TSH-R-Ab) that exists in associaton with:
hyperthyroidism, diff use goiter and extrathyroidal signs (ophthalmic
and derma signs). Not all characteristcs are necessary for diagnosis.
In a gammagraphy, Graves disease reveals a generalized increased
uptake.
• Toxic mulnodular goiter (TMG) or hyperfunctoning is the most
usual reason for hyperthyroidism in the elderly. Thyroid gammag-
raphy reveals a multnodular gland with several hyperfunctoning
nodules that alternate with other normofunctoning or hypofunc-
toning nodules.
• The toxic adenoma is observed in the gammagraphy as a single nod-
ule, which intensely concentrates the radiotracer and with almost
total suppression of the rest of the gland.
• (Postpartum, subacute) thyroidis may appear with an inital phase
of hyperthyroidism as a result of inflammaton and release of the
preformed hormone. Thyroid gammagraphy shows an abolished or
“white” gland.
Clinical presentation • Symptoms: plethoric aspect with nervousness, weakness, emoton-
al lability, decreases in performance, excessive sweatng and heat
intolerance. There are also increased intestnal transit, increased
appette with paradoxic weight loss, pruritus and alteratons in the
menstrual cycle (oligomenorrhea).
• Signs: wet skin, goiter that is diff use and spongy in GD (it is irregular
with a nodular surface in the SMB), arrhythmias (sinusoidal tachy-
cardia, atrial fibrillaton), distal tremor, acropachy, alopecia, palpe-
bral retracton, proximal myopathy, myoclonias and hyperreflexia.
Exophthalmoses, pretbial myxedema and thyroidal murmur can be
appreciated in Graves disease.
• “Apathec hyperthyroidism”: in advanced age, it can manifest
through weight loss, muscular weakness, depression, mental slow-ness, apathy and arrhythmias or heart failure.
Diagnosis
• Determinaon of TSH: it is the most useful isolated inital determi-
naton for diagnosis. TSH may be diminished or suppressed in pri-
mary hyperthyroidism.
• Determinaon of free T4: it is high in clinical hypothyroidism. It may
be normal in subclinical hyperthyroidism (with low TSH).
• Determinaon of free T3: it is indicated if TSH is low and T4 is nor-
mal.
• For the eologic diagnosis, elaboratng a detailed clinical record
and determining -according to clinical suspicion- of antthyroid an-tbodies (including TSI) +/- thyroid gammagraphy enables classifica-
ton of most cases of hyperthyroidism.
Treatment
• Symptomac: propranolol for the control of adrenergic symptoms.
• Anthyroid drugs (methimazole or propylthiouracil) in GD. They can
also be utlized in MTG.
• Definite treatment: radioactve iodine (I-131) is of choice in the USA
for the treatment of GD. Thyroidectomy can also be performed, es-
pecially in the presence of large goiters, failure or intolerance to
prior treatments.
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Complications
• Thyroid storm: emergency situaton and of increased mortality
(20% to 30%) characterized by irritability, delirium or coma, fever,
tachycardia, hypotension, vomitng and diarrhea. It requires emer-
gency treatment with i.v. propranolol, propylthiouracil and cort-
coids. Iodine or iodine contrasts can also be used.
2.3. Hypothyroidism
• Situaton that results from the lack of thyroid hormone eff ect on
body ssues and presents with low levels of free T3 and T4. Pri-
mary thyroid causes consttute more than 95% of the cases, but less
than 5% are of thyroid or hypothalamic origin. The most frequent
cause of hypothyroidism world-wide is iodine deficiency.
• Autoimmune etology (Hashimoto’s thyroidis) is the most com-
mon reason in developed countries. Hashimoto’s thyroidits pres-
ents with positve antthyroglobulin and antmycrosomal (antTPO)which precipitate thyroid destructon.
• There is also another important factor: postablave hypothyroid-
ism (radioiodine or surgery) or afer administraton of I-131 as a
treatment for hyperthyroidism.
• Other types of thyroidis -subacute and postpartum) usually ap-
pear with a hypothyroidism phase afer an inital phase of hypothy-
roidism. Hypothyroidism can be permanent.
• Other less frequent causes are external cervical irradiaton, drugs
like lithium, amiodarone or tyrosine kinase inhibitors (that work
as an oncologic treatment), infiltratve diseases, granulomatous
or metastatc thyroidits, and congenital alteratons in thyroid hor-
mone synthesis and thyroid agenesis.
Clinical Presentation
(Figure 2)
• Unspecific inital symptoms with progressive appearance: fatgue,
lethargy, constpaton, cold intolerance, rigidity and muscle con-
tracture, carpal tunnel syndrome and menstrual cycle disorders.
Progressive deterioraton of intellectual and motor actvites, for
example, dementa and abnormal involuntary movements, loss of
appette and weight gain.
• Signs: dry and coarse skin, loss of body hair, a deep voice and sleep
apnea may appear. Amimia, paleness, skin coldness, scarce body
hair, periorbitary edema and macroglossia. Prolonged relaxaton
phase of osteotendinous reflexes. Bradichardia and pericardial fluid
accumulaton (even obstructon of pericardial drainage). Adynamic
ileum, megacolon and intestnal obstructon.• Determining TSH: it is the most useful isolated inital determinaton
for diagnosis. THS is increased in primary hypothyroidism and it is
low or inappropriately normal in central hypothyroidism.
• Determinaon of free T4: it is low in clinical hypothyroidism. It may
be normal in subclinical hypothyroidism with a high TSH).
• For the eologic diagnosis, drawing up a detailed clinical record and
determining antthyroid antbodies enables classificaton of most
cases of hypothyroidism.
Treatment
• Hormonal replacement with levothyroxine (L-T4).
Alopecia
Macroglossia
Intolerance
to cold temperatures
Carpal
tunnel syndrome
Metrorrhagia
Coarse, dryand yellow skin
BradypsychiaMemory loss
Palpebral edema
CardiomegalyPericardial effusion
Constipation
Weakness,spasticity
Slowed Achillesreex
Weight gain
Figure 2. Clinical presentation of hypothyroidism
Complications
• Myxedematous coma: severe complicaton of hypothyroidism with
stupor and hypothermia, likely to be mortal. The most frequent
cause of myxedematous coma is cold temperature exposure or
performing surgery on a patent with untreated -or poorly treated-hypothyroidism. It can also appear in a hypothyroid suff erer under
treatment, who abruptly suspends medicaton. Mortality ranges
from 30% to 60%. It requires immediate treatment with intravenous
L-T4 together with hydrocortsone administraton -so that an adre-
nal crisis will not be triggered- untl a normal pituitary-adrenal axis
actvity is achieved.
2.4. Thyroiditis
• A set of heterogeneous eology processes and several clinical charac-teriscs that appear with thyroid inflammaton. The most common
types of thyroidis are (granulomatous subacute and viral thyroidis or
Quervain’s) thyroidis; autoimmune or Hashimoto’s thyroidis; post-
partum thyroidis postradiaon and amiodarone-induced thyroidis.
Clinical presentation
• Viral subacute (Quervain’s) thyroidits presents with a painful goiter,
general discomfort and concomitant -or recent- upper respiratory
tract infecton.
• The remaining types of thyroidits appear together with a painful
goiter.
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Diagnosis
• Thyroidits usually comprises two phases: 1) thyrotoxicosis followed
by 2) hypothyroidism, hence, the thyroid functon test varies ac-
cording to the phase in which diagnosis is made.
• Thyroid gammagraphy: presents with generalized hypocapta-
ton of the gland, by inflammaton during the hyperthyroidism
phase.
Treatment
• Symptomac: β-blockers in the hyperthyroidism phase. In milder
cases of Quervain’s thyroidits, symptoms are usually controlled
with ASA. More severe cases require cortcosteroids.
• If hypothyroidism: levothyroxine should be given, although this
phase may be temporary and not permanent.
• The use of anthyroid drugs is not indicated.
2.5.Thyroid Noduleand Thyroid Cancer
• The incidence of thyroid carcinoma in the populaton represents
only a fracton of patents that have thyroid nodules. In single nod-
ules, thyroid carcinoma incidence is approximately 5%; multnodular
goiters, thyroid cancer incidence are also 5% per individual nodule.
Clinical presentation
• They are usually asymptomac at the tme of diagnosis. They are in-
cidentally found through imaging tests, i.e., a CTA scan of the cervical-
thoracic region, a carotd Doppler ultrasound test) or thyroid palpaton.
• Hyperfunconing nodules are present with signs and symptoms of
hyperthyroidism.
• Large nodules and, especially, those adjacent to the trachea/esopha-
gus, can produce compressive symptoms (dysphagia, dyspnea and
cough).
• Clinical findings that suggest malignancy are: rapid growth of the le-
sion, fixaon to adjacent structures, vocal cords paralysis, Horner’s
syndrome, present adenopathies, and a history of radiaon in child-
hood, size > 4 cm, and family record of medullary thyroid cancer (MTC).
• Cervical examinaton will enable nodule localizaton and a descripton
of the nodule’s characteristcs: stony consistency, painless, aached
to superficial and/or deep planes, as well as the presence of cervical
anterior lymphoadenopathies, all signs suggestve of malignancy).
Diagnosis (Table 6)
• TSH determinaon: to rule out thyroid hyper or hypofuncton. Hy-
perfunctoning nodules are seldom malignant (< 1%).
• Thyroid ultrasound study: it makes it possible to assess the nod-
ule features as well as the remainder of the gland and the pres-
ence or absence of pathologic cervical ganglia. The presence of
microcalcificatons, hypoechogenicity, and the presence of an irregu-
lar rim and an increased intranodal vascularizaton are all ultrasound
signs of malignancy.
PAPILLARY FOLLICULAR MEDULLARY ANAPLASTIC LYMPHOMA
Epidemiology · Bimodal distribution:
2.nd and 3.rd decade/
middle age
· 70% follicularepithelium tumors
· Relation
to radiationin childhood
· Advanced age
· 15% to 20%
tumors of follicular
epithelium
Four ways:
· Sporadic (80%)
· MEN 2A
· MEN 2B · Familial no MEN
6.th, 7.th decades
· 5% follicular
epithelium tumors
· Women 55-75 years
of age
· 5% of all thyroid
tumors · Relation
to Hashimoto’s
thyroiditisand positive
antiperoxidase
antibodies
Derived from
follicular epithelium
Yes Yes No Yes No
Pathologic
anatomy
· Papillae with follicular
elements and cells
· “Sand-grain sized”calcications or
psammoma bodies
(typical, but rare)
Capsular and/or
capsule invasion is
what differentiates itfrom benign follicular
adenoma
· Cell C accumulation
with amyloid
substance · Multicentric
in familial forms
· Gigantic
and fusiform cells
· Hard to differentiatefrom lymphomas
or sarcomas
Diffuse β lymphoma
with large cells
Growth,
dissemination
and metastasis
Slow growth with
neighboring structures
invasion and lymphaticdissemination
Slow growth, but early
hematic dissemination,
with lung, bone andCNS metastasis
Calcied adenopathies
and metastasis to CNS
and bone
Rapid growth with
huge local invasion
ulcerating skin
-
Marker Thyroglobulin Thyroglobulin Calcitonin/ACE - -
I-131 Yes Yes No No No
Prognosis The best Hürthle subtype: worse
clinical course
Bad The worst (months
survival)
Variable
Table 6. Malignant tumors of the thyroid
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• These tumors are commonly associated with multple endocrine
neoplasias (MEN) 2A and 2B.
Clinical presentation
• Hypertension is the most frequent manifestaton. It is usually kept
in 60% of the cases. Hypertension is sometmes malignant and it is
resistant to conventonal treatment in almost every case.
• Paroxysms or hypertensive crises are characterized by a significant
increase in blood pressure accompanied by headache, profuse sweat-
ing, palpitaons, anguish, and imminent sensaon of death, paleness,
thoracic and abdominal pain, accompanied by nausea and voming.
• Paroxysms are triggered by postural changes, psychological stress,
physical exercises, Valsalva’s maneuver, some food and drugs; anes-
thesia and surgery. However, the triggering factor cannot be idenfied
on some occasions.
Diagnosis
• An increase in free catecholamines and/or metabolites (meta-
nephrines) in 24-hour urine or plasma. • CT and abdominal MRl are the imaging techniques most commonly
utlized to localize the tumor.
• Gammagraphy with MIBG (meta-iodobenzylguanidin), is the most
effi cient method to detect extra-adrenal pheochromocytoma (either
primary or metastac). Cytology of pheochromocytomas is contra-
indicated.
Treatment
• The treatment of choice is laparoscopic pheochromocytoma re-
secton. Surgery should be conducted in a specialized center, once
proper preoperave preparaon has taken place. Pre-op treatment
consists of:
α blockade with phenoxybenzamine at least 10-14 days beforesurgery.
β blockade if necessary with propranolol (to prevent tachycardias).
Preoperave volume load with salt, to prevent rebound hypo-
tension in the immediate postoperatve period.
• It is very important to be reminded that β-blockers are never to be
administered untl α blockade has been established, as a hyperten-
sive crisis would be triggered.
• In the event of a hypertensive crisis before the patent is fully estab-
lished on an α blockade therapy, i.v. phentolamine or nitroprussiate.
• When a pheochromocytoma is malignant and unresectable, medi-
cal treatment with α blockers is carried out. There is also chemo-
therapy administraton with the use of cyclophosphamide, vincris-tne and dacarbazine. MIBG administraton can be used if there is
positve tumor uptake, in repettve doses.
3.3. Primary
Hyperaldosteronism PHA
PHA occurs because of autonomous secreon of aldosterone through the
glomerulus zone of the adrenal gland. A 60% originates in an aldosterone-
secreng adrenal adenoma (Conn’s syndrome). PHA can also result from
adrenal bilateral micronodular or macronodular hyperplasia, unilateral
adrenal hyperplasia or familial etology, like glucocortcoid-remediable
PHA. An aldosterone-secretng adrenal carcinoma is very rare.
Clinical presentation
• HBP is the predominant and universal finding, with diastolic values
over 110 mmHg. There is greater prevalence of aff ectaton of target
organs (hypertensive retnopathy, cardiopathy and nephropathy) in
these kinds of patents.
• Because of increased renal excreton of potassium, hypopotasse-
mia occurs, which if marked, is present along with muscle weak-
ness, fatgue, cramps and in severe cases, muscle palsy, as well as
electrocardiographic changes. Polyuria and polydipsia because of
nephrogenic ID.
• PHA existence must be assessed in young patents who have their
debut with HBP without risk factors or a family history (see Table 7
for screening indicatons for PHA).
PHA: INDICATIONS FOR EARLY DETECTION
· Moderate/severe HBP (SBP ≥ 160 and/or DBP ≥ 100 mmHg)
· Hypertension resistant to pharmacologic treatment (SBP > 140or DBP > 90 mmHg despite the use of three antihypertensive drugs
· Patients with HBP and spontaneous or diuretic-induced
hypopotassemia
· HBP and adrenal incidentalomas · Patients with HBP and family history of HPB of early onset or
cerebrovascular accidents in family members < 40 years of age
· Hypertensive 1.st degree relatives of a patient diagnosed with PHA · HBP in children and young people (< 20 years of age)
Table 7. Indications for early detection of primary hyperaldosteronism
Diagnosis • General analycs: hypopotassemia, mild hypernatremia, metabolic
alkalosis, hypomagnesaemia.
• PHA screening: determinaton of baseline aldosterone (it must be
increased, > 15 ng/dL) and aldosterone/acvity quoent of plasma
renin > 30.
• Confirm biochemical diagnosis using the suppression test: saline
physiologic serum infusion (the correct aldosterone suppression
excludes diagnosis) or captopril test (ACE inhibiton causes -in
healthy people- a decrease in aldosterone, which does not occur in
primary hyperaldosteronism).
• Etologic diagnostc takes place afer biochemical diagnosis: abdom-
inal CT. Catheterism of adrenal veins is reserved (as it is invasive)
for lesions < 1 cm (or with a negatve CT) in individuals > 40 years ofage, in which the prevalence of nonfunctoning adrenal adenomas
is very high.
Treatment
• In unilateral pathology, as an adenoma, the treatment of choice is
laparoscopic extrpaton.
• PHA by bilateral hyperplasia is addressed with spironolactone (aldo-
sterone- receptor antagonist) or other potassium-sparing diuretcs,
like, triamterene or amiloride.
• PHA sensitve to glucocortcoids can be treated with small doses of
cortcosteroids or with potassium-sparing diuretcs.
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3.4. Congenital AdrenalHyperplasia CAH
• It consists of a group of adrenal steroidogenesis disorders stemming
from a hereditary deficiency of one of the enzymes of steroid bio-
synthesis, with subsequent “accumulaton” of cortsol precursors
prior to enzyme deficiency.
• Congenital Adrenal Hyperplasia (CHA) is the most frequent adrenal
disorder in childhood and it can be accompanied by severe deficien-
cies that endangers the life of a newborn, while partal defects are
manifested afer adolescence by hirsutsm and virilizaton in wom-
en.
• The most common form of CHA is 21-hydroxylase deficiency
(autosomal recessive heritage in 95% of cases), whose clinical
presentaton, diagnosis and treatment will be discussed below:
Clinical presentation
• Classic form: it presents with ambiguous genitalia in girls and
precocious puberty in children. In 80% of the cases it is associ-ated with a salt-wastng syndrome due to mineralocortcoids and
cortsol.
• Nonclassic form: hyperandrogenism, oligomenorrhea and subfertl-
ity in adolescents and grown women. It is very similar to polycystc
ovary syndrome.
Diagnosis
• Diagnosis is confirmed by an increase in baseline 17-hydroxiproges-
terone baseline and afer ACTH smulaon.
Treatment
• In the case of salt-wastng syndrome: repositon of salt and vol-ume; glucocortcoid administraton. If later, 21-hidroxilase syn-
drome becomes severe, mineralocortcoid replacement must be
administered.
• Surgical correcton of ambiguous genitalia in girls.
• The treatment and management of CAH will be discussed further on
in the Gynecology secton.
Chapter 04
Alteration in
Hydrocarbonate
Metabolism (Table 8)
Diabetes mellitus (DM) is a set of heterogeneous syndromes of mult-
factorial etopathogenesis, whose common nexus is chronic hyperglyce-
mia. Chronic macrovascular and microvascular complicatons develop
along the course of the disease.
DIABETES MELLITUS
TYPE 1
DIABETES MELLITUS
TYPE 2
Age < 40 years of age(typically children
or adolescents)
> 40 years of age
Morphotype Normal or low weight Overweight or obesity
Onset Abrupt, even with
ketoacidosis
Insidious, even
asymptomatic nding
Treatment Always insulin Diet, oral antidiabeticdrugs or insulin
Tendency to
ketosis
Yes No
Heritage Predisposition to HLA Concordance > 90%
of identical twins
Autoimmunity
against β cell
Yes No
Insulin resistance No Yes
Table 8. Differences between DM type 1 and 2
4.1. Type 1 Diabetes Mellitus
• It consttutes 5% to 10% of the total cases of DM.
• Result of the deficiency (usually absolute) in insulin secreton be-
cause of cell β cell destructon of the pancreas.
Clinical presentation
• Type 1 DM typically aff ects children and adolescents with normal
weight.
• Cardinal manifestaons: polyuria, polydipsia, polyphagia and weight
loss, whose appearance is usually rapid and of short evoluton.
• These patents need insulin administraton to prevent the appear-ance of ketoacidosis. Type 1 DB is subdivided into 1A (positve auto-
immunity) and 1B or idiopathic.
• Genetc predispositon associated with HLA-DR3 and DR-4.
Diagnosis
• Diagnostc criteria for diabetes mellitus:
Plasma glucose on an empty stomach > 126 mg/dL.
Plasma glucose two hours after oral glucose overload
(SOG) > 200 mg/dL.
Glycosylated hemoglobin (HbA1C) > 6.5%.
Plasma glycemia at random + compatble symptoms with DM >
200 mg/dL.
• Presence of anbodies pancreatc ant-islets, ant-IA2 (associated
protein with insulinoma 2), ant-GAD (descarboxylase of glutamic
acid) and ant-ZnT8 (zinc channel): The first three are more fre-
quently positve in people with DM1.
Treatment
• Insulin therapy in intensive paern (subcutaneous, bolus-baseline
paern or pump subcutaneous insulin infusion), simulatng physi-
ologic secreton of the pancreas: baseline insulin and insulin before
each meal (Figure 3).
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• Type 2 DM suff erers may develop hyperosmolar nonketoc hyper-
glycemia in cases of metabolic control, infectons or severe intercur-
rent pathology. Some patents may have their debut with this disease.
Diagnosis
• The same criteria as for diagnosis of DM1.
• Negave anbodies (although they are routnely requested).
• DM2 screening in the general populaton:
Every three years, asymptomatc people aged ≥ 45, and regard-
less of age in case of patents with overweight or obesity (BMI
≥ 25 kg/m2) and some other risk factor for DM type 2 develop-
ment (see Table 11).
1. Age ≥ 45
2. Regardless of age in individual with BMI ≥ 25 kg/m2 and someadditional risk factor:
· Sedentarism
· 1.st degree relatives with a record of diabetes
· Ethnic group at high risk (Afro-Americans, Hispano-Americans, native
Americans, Asian American and natives from the Pacic Islands) · People previously diagnosed with carbohydrate intolerance and
altered glucose in fastening or HbA1c ≥ 5.7% · Personal history of gestational diabetes or macrosomic fetus
· Arterial hypertension
· An increase in triglycerides or a decrease in HDL
· Women with polycystic ovary syndrome· Clinical conditions associated with insulin resistance
(i.e., severe obesity or acanthosis nigricans)
· Personal record of cardiovascular disease
Table 11. Screening indications for diabetes mellitusin asymptomatic adult patients (ADA, 2010)
Treatment
• Monitoring goals are the same as for Type 1 DM patents (see Table
11); given that the hypoglycemia risk factor is not high, especially in
elderly patents.
• Blood pressure should be controlled (objectve: < 140/ < 80 mmHg),
renal functon, lipid profile and early detecon of comorbilies
(microalbuminuria for diabetc nephropathy, examinaton of the
patent’s retna, by means of fundoscopy or nonmydriatc retnogra-
phy, complete neurologic examinaton , etc).
• Met ormin treatment may be commenced in a preventve man-
ner in paents with prediabetes (glycemia on an empty stom-
ach > 100 mg/dL, but < 126 mg/dL and/or afer two hours of OGO
> 140 and < 200 mg/dL) who are obese and who present another risk
factor of diabetes (HbA1c > 6%, HBP, a decrease in HDL, hypertriglycer-idemia, a history of DM in first degree relaves under 60 years of age).
4.3. Treatment of Diabetes Mellitus
Lifestyle
• Diet:
Low fat diet (< 30%), moderate in carbohydrates (< 55%) and
hypocaloric if there is overweight or obesity.
• Weight loss:
Goal: lose 5% to 10% of inital weight through diet and exercise.
• Exercise:
Exercise of moderate intensity, minimum 30 minutes a day, 5
days a week.
• Quit smoking habit.
Pharmacotherapy
See Table 12, next page.
Control of Comorbilities
• An-aggregaon:
Primary preventon: men > 50 years of age or women > 10 years
afer menopause (in general > 60) with some major cardiovas-
cular risk factor (family history of cardiovascular disease, hyper-
tension, dysplemia, smoking or albuminuria) or those patents
at risk of having a cardiovascular event, in ten years is higherthan 10%.
• Blood pressure:
Target 140/< 80 mmHg. ACEIs are the treatment of choice, but
ARA-2 if the former are not tolerated.
Acute Complications (Table 13)
• Diabec Ketoacidosis:
Typical, although not exclusive of DM type 1. It occurs because
of insulin deficiency and an increase in contrainsular hormones,
mainly glucagon. First manifestaton of DM type 1 in 25% to 30%
of cases. In known diabetc patents, precipitatng reasons are
usually abandonment of insulin treatment, dietary transgres-sions, infectons (30% to 40% of the cases), traumas, surgery,
gestaton, and endocrinopathies, like Cushing’s syndrome or
Graves-Basedow disease among others.
Clinical presentaton: nausea, vomitng and abdominal pain,
together with diabetc cardinal symptomatology. If not treat-
ed precociously, obnubilaton and coma will develop. During
physical examinaton, outstanding manifestatons are tachy-
pnea, Kussmaul respiraton and dehydraton signs, like dry
mucosa, hypotension and a decrease in ocular globe pres-
sure. Prerenal and renal failure may occur because of dehy-
draton.
Diagnosis: Hyperglycemia + metabolic acidosis with increased
anion gap, presence of increased ketonic bodies in blood andurine.
Treatment with intravenous insulinotherapy, serum therapy, in-
travenous potassium administraton, bicarbonate (if pH < 7) and
treatment of triggering cause.
• Hyperosmolar nonketoc hyperglycemia:
Typical, but not exclusive of DM type 2.
Insuffi cient response of insulin acton because of insulin resis-
tance, unable to counteract the increase in contrarregulatory
hormones caused by triggering stressing factors. Residual insulin
secreton is capable of minimizing or impedes ketosis, but not
preventng hyperglycemia.
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SULPHONYLUREAS MEGLITINIDES BIGUANIDESGLUCOSIDASE
INHIBITORSTIAZOLIDINEDIONES
IV-DPP
INHIBITORS
ANALOGOUS
OF GLP-1
Active
substance
· Glibenclamide
· Glipizide · Gliclazide
· Gliquidone
· Glimepiride
· Repaglinide
· Nateglinide
Metformin · Acarbose
· Miglitol
· Pioglitazone
· Rosiglitazone
· Sitagliptin
· Vildagliptin · Saxagliptin
· Exenatide
· Liraglutide
Mechanism
of action
Insulin secretion
stimulus insustained way
through bond to β
cell receptor
Insulin
secretionstimulus in
acute way
throughbond to β cell
receptor
Liver
resistanceto insulin
decreases
Transient
inhibitionof intestinal
α-glucosidase
They decrease
peripheral resistance(muscle and adipose
tissue) to insulin by
means of bond toPPAR-γ
They increase
endogenousGLP-1 half like
dipeptidyl
peptidase IV
Similar effect
to endogenousGLP-1
(increase in
insulin secretionmediated through
intake , slowing
gastric emptying)resistant to DPP IV
Side effects Severe and
sustained
hypoglycemia
Hypoglycemia
(infrequent)
· GI
discomfort
(the mostfrequent)
· Lactic
acidosis
(the mostsevere, but
rare)
GI discomfort · Hepatotoxicity
· Hydric retention
· Heart failure · Osteoporosis
in women
· Increase in
transaminase
(vildagliptin) · Discrete
increase in
respiratory
and urinarytract
infections
· Nausea
and vomiting
(frequent) · Pancreatitis
(very rare)
· Deterioration of
renal function
Contraindications · Pregnancy · Hepatopathy · RI
· Pregnancy · Liver disease · Severe RI
Situationspredisposingto lacticacidosis
Pregnantwomen andchildren
· Hepatopathy · Heart failure · Rosiglitazone
withdrawn inEurope due toan increase incoronary events
Pregnantwomenand children
Use not approvedalong with insulin
Use Secondtherapeutic stepin type 2 DM withpancreatic reserve
· Postprandialglycemiacontrol
· Elderlypeople with
some degreeof declinein renalfunction
First choicein type 2 DM
· Scarcelyeffective
· Control ofpospandrialhyperglycemia
Associated withmetformin orin case of itscontraindicationmild-moderate RI
· 2.nd therapeuticstep in type2 DM
· Sitagliptin
approved inmonotherapyand incombinationwith insulin
· Obesitytogether with
metformin
· Its use alsoapproved with
sulfonylureas
(increased risk
of hypoglycemiaand less weight
loss)
Table 12. Characteristics of oral antidiabetic drugs and noninsulin therapies in type 2 diabetes mellitus
PREVENTION (early phases) SYMPTOMATIC TREATMENT (advanced phases)
Diabetic retinopathy Strict glycemic control Photocoagulation
Diabetic
nephropathy
· Strict glycemic and HBC control · RAAS blockade (ACE inhibitors
or ARBs) if microalbuminuria or
macroalbuminuria or hypertension · Reduction of protein intake in chronic
kidney disease
Dialysis or kidney transplant
Neuropathy
and diabetic foot
· Strict glycemic control and foot care
· Smoking cessation
NEUROPATHY
· Pain: opiates, tricyclics, anticonvulsants, duloxetine and capsaicin · Orthostatic hypotension: postural measures, fludrocortisone
· Diarrhea: loperamide
· Gastroparesis: prokinetics and erythromycin
ULCERS
Debridement, rest, antibiotics and revascularization
Macroangiopathy · Strict HBC control
· Smoking cessation
· Antiplatelet therapy
· Lipid-lowering therapy
Arterial revascularization techniques
Table 13. Prevention and treatment of chronic complications in DM
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Mortality, given this clinical profile, ranges from 5% to 20% of
cases; underlying infecton process and general deterioraton of
the patent are also contributng factors.
Triggering factors: infecton (in approximately 60% of the cases),
leaving therapy or inadequate treatment. A 20% of the individu-
als suff ering from Hyperosmolar hyperglycemic state (HHS) have
not been previously diagnosed with DM.
Clinical presentaon: severe dehydraon. Alteraon of the level of
consciousness, from stupor up to coma (hyperosmolar coma). Neuro-
logic manifestaons (as convulsions or transient hemiplegia), as well
as microthrombosis and disseminated vascular coagulaon may oc-
cur.
Diagnosis: glycemia > 600 mg/dL, negave –or mildly posive- keton-
ic bodies can be traced in urine or serum, BP > 7.30, eff ecve serum
osmolality > 320 mOsm/kg and plasma bicarbonate (> 18 mEq/L).
Treatment: aggressive serum therapy, electrolytc replacement
and insulin therapy, as well as treatment of the triggering factor.
Complications of Insulin Treatment
• Somogyi phenomena: an increase in fastng glycemia because of anincrease in contrarregulatory cell in response to nocturnal hypogly-
cemia. Treatment involves reducing insulin dose to prevent noctur-
nal hypoglycemia.
• Dawn phenomenon. An increase in plasma glucose. Plasma glucose
increase in the first hours in the morning, in relaon to GH nocturnal
or circadian rhythm of corsol. Disncon from Somogyi phenom-
enon is made by determining glycemia at 3 a.m. Glucose will be low
if it is a Somogyi phenomenon and it will be normal if it is a dawn
phenomenon. Insulin should be increased if there is evidence of a
dawn phenomenon so normoglycemia levels are maintained.
4.4. Metabolic Syndrome
• Associaon of several cardiovascular risk factors, including abdom-
inal obesity, dyslipemia, hypertension and glucose alteraton, which
can coexist in the same aff ected person.
• Also called X syndrome, it has as a main pathophysiologic substrate
insulin resistance. There are many definitons of the metabolic syn-
drome (MS).
Diagnosis
Diagnosis criteria of ATP-III (2004) are as follow:
• Abdominal circumference: > 102 cm (> 40 inches) in men and > 88cm (> 35 inches) in women.
• Triglycerides > 150 mg/dL.
• HDL-cholesterol < 40 mg/dL in men and < 50 mg/dL in women.
• Blood pressure > 135/ > 85 mmHg or request anthypertensive med-
icaton.
• Fastng baseline insulin > 100 mg/dL.
• At least three out of five criteria are needed for MS diagnosis.
Treatment
• Weight loss should be encouraged, as well as specific treatment for
the remaining in comorbilites (HBP and dyslipidemia).
• For patents at high risk of developing DM type 2, start with met or-
min can be assessed.
Chapter 05
Bone Pathology
and Phosphocalcic
Metabolism
5.1. Osteoporosis
• Loss of bone mass equal to or higher than 2.5 SD (standard devia-ton) with respect to bone mass of young people of the same sex. It
is the more frequent metabolic bone disease.
• Most of the cases belong to the primary osteoporosis or they are
not associated to other diseases.
• Diseases present with secondary osteoporosis: hyperparathyroidism,
hyperthiroidism, hypercorsolism and hypogonadism. Other accom-
panying illnesses are also rheumatoid arthris, systemic mastocytosis,
mulple myeloma and chronic treatment with corcoids among others.
Clinical presentation
• It is an asymptomac disease untl fracture appears; backbone frac-
ture is the most common.
• Fractures in vertebral bodies and forearm distal radius (de Collesfracture) are frequent complicaton.
• Vertebral bone fracture causes back pain, of acute onset with fre-
quent irradiaton toward the abdomen and backbone deformity. It
usually occurs afer sudden flexions, but sometmes there is a trig-
gering factor. It happens more frequently in the middle and lower
dorsal vertebrae and in lumbar spine.
Diagnosis
• Dual radiologic densitometry (DXA): loss of bone mass equal to or
higher than 2.5 SD with respect to bone mass of young people (30-
35 years of age) of the same sex.
• Rule out secondary causes: full biochemical lab test that includesCa, P, TSH, PTH, 25(OH) vitamin D, 24-hour excreted calciuria, tes-
tosterone (men), serum proteinogram and screening of Cushing’s
syndrome if clinical presentaton is suggestve.
• Convenonal bone x-ray: it is lile sensitve for osteopenia diagno-
sis, as a loss greater than 30% of bone mass is needed to be radio-
logically detected.
Treatment
• Change in life style: do exercise. Abstnence of smoking habit.
• Calcium and vitamin D: this recommendaton applies for all patents
diagnosed with osteoporosis, regardless they receive additonal
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pharmacological treatment or not. Calcium and vitamin D favor a
reducton of fracture rates, hip fracture included.
• Biphosphonates: alendronate, risedronate, zoledronate, ibandro-
nate are all potent inhibitors of bone resorpton. They decrease ver-
tebral fractures and femur neck fracture.
• Selecve estrogen response modifiers or SERMs -raloxifene and
tamoxifen. They reduce replacement and loss of bone mass; dimin-
ishing the incidence of vertebral fractures, without having proven
their eff ect on the preventon of femoral neck fractures.
• Denosumab, monoclonal antbody with a high affi nity for RANKL. In
postmenopausic women, significantly reduce the risk for vertebral,
nonvertebral and hip fracture.
5.2. Paget’s Disease
The second most frequent osteopathy in developed countries.
• Characterized by an increase in bone resorpton, followed by a com-
pensatory increase in synthesis (bone replacement can be up to 20tmes over normal values).
• More frequent in men than in women and prevalence increases
with age, so the disease is usually present in the elderly.
• The presence of viral inclusion bodies (paramixovirus) in osteoclasts
enables supposing that a viral infecon could be the origin of Pag-
et’s disease in genetcally predisposed individuals.
• Primary bone pain is the more habitual clinical manifestaton.
• Other manifestatons are the gradual appearance of deformaons
or swelling in the limbs, problems with gait because of the diff er-
ence in limb length, headache and facial pain, backbone lower
extremites pain, hearing loss owing to direct aff ectaton of small
internal bones in the inner ear or to compression of the 7.th cranial
nerve in the internal auditory orifice.
• The most severe neurologic complicatons occur because of bonegrowth in the base of the cranium, which can compress the medulla
and can cause tetraplegia.
Diagnosis
• Biochemical: alkaline phosphatase is a good test choice for early
detecton and treatment response. Other parameters also help es-
tablish a diagnosis, i.e., an increase in other parameters of bone
formaton (osteocalcin, procollagene) and bone resorpton (hy-
droxyproline, acid phosphatase, pyridinoline, deoxypyridinoline and
peptde).
• Convenonal bone x-ray: characteristc radiologic alteratons, like
an increase in bone size, cortcal thickening and alteratons in thetrabecular paern, coexistence of lytc and blastc areas, fractures,
“vertebras with rim-like appearance” and circumscribed osteopo-
rosis.
• Bone gammagraphy: this enables checking the extent of the disease.
Treatment
• Asymptomac: they do not need treatment.
• Symptomac: (persistent pain, nerve compression, bone deformity
of rapid progression that results in gait diffi cultes, heart failure, hy-
percalcemia and hypercalciuria, bone fractures and reparaton for
orthopedic surgery). Biphosphonates is the treatment of choice.
Complications
• Increase in cardiac output: an increased blood flow in bone, with an
increase in the venous return network in aff ected areas, which may
give rise to heart failure in patents with prior cardiopathy.
• Pathologic fractures, arthropathy because of proximity (the most
frequent is the coxofemoral), compressive neurologic syndromes
and bucco-dental disorders.
• Nephrolithiasis because of hypercalciuria. It rarely causes hypercal-
cemia. There is also a greater incidence of hyperuricemia and gout.
• Sarcoma. Shown in 1% of the patents. Sarcoma is the most severe
complicaton and is usually located in the femur, the humerus, the
cranium, facial bones and pelvis.
5.3. Hyperparathyroidism (Table 14)
• Parathyroid glands produce parathyroid hormone (PTH), which,
together with vitamin D and calcitonin, is responsible for calciumand phosphorous metabolism. Hyperparathyroidism is defined as
elevated values of PTH in plasma, with diff erent eff ects on calcium
and phosphorous depending on the specific cause.
• Primary hyperparathyroidism: in 85% of cases, primary hyperthy-
roidism is caused by autonomous secreton by a single or multple
parathyroid adenomas, while hyperplasia is found in 15% of the
cases and parathyroid carcinoma in < 1%. Both forms of the disease
can appear in a sporadic way or as family disorders: MEN 1, MEN 2A,
familial hyperparathyroidism and jaw tumor syndromes.
• Secondary hyperparathyroidism: a physiologic increase in PTH in renal
failure or vitamin D deficiency is considered to prevent hypocalcemia.
• Terary hyperparathyroidism: the secondary increase in PTH over
tme in patents with chronic renal failure. In theory, it can lead to
hyperplasia of the parathyroid glands. Tertary hyperparathyroidismoccurs when one gland -or more- becomes autonomous (even re-
maining afer renal transplantaton).
PRIMARY
Hyperpara-
thyroidism
SECONDARY
Hyperpara-
thyroidism
TERTIARY
Hyperpara-
thyroidism
PTHi
Calcemia N or N or
Phosphatemia
Table 14. Differential diagnosis of hyperparathyroidism. Lab parameters(N: normal)
We will mainly discuss primary hyperparathyroidism:
Clinical presentation
• Most cases diagnosed are asymptomac and hypercalcemia is
found by chance.
• HBP is present in 50% to 70% of the patents. Peptc ulcer and gastri-
ts, acute pancreatts and cholelitasis are also present.
• Other manifestatons are: headache, asthenia, depression, anemia,
band keratopathy, constpaton, proximal muscle weakness, poly-
uria, gout, chondrocalcinosis, osteoporosis and increased cardio-
vascular risk, fatgue, depression and anxiety.
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• Bone disease. Appearance of bone cysts in long bones or “brown
tumors” (accumulaton of multnuclear giant osteoclasts). Other
changes are generalized or circumscribed osteopenia (salt and pep-
per skull) and subperiosteal resorpton phenomena (radial zone of
the middle phalanx of fingers) or generalized (clavicle). Bone dis-
ease may be silent or cause local pain and even pathologic fractures.
• Renal aff ectaon. Nephrolithiasis and nephrocalcinosis.
Diagnosis
• General analycs: hypercalcemia, hypophosphatemia, metabolic
acidosis, hypercalciuria and diminished phosphate tubular resorp-
ton.
• High values of intact PTH (PTHi) in relaton to plasma calcemia. Some
patents show inappropriately normal values, but never low or sup-
pressed.
• Localizaon diagnosis: they should only be requested if surgical
treatment is indicated, but not forced.
Cervical ultrasound and gammagraphy with Tc-sestamibi: current-
ly, the combinaon of both techniques off er greater diagnosc
yield and enables the performance of a minimally invasive surgery.
• Complicaons of diagnosis: bone densitometry (DEXA scan) to rule
out osteopenia or osteoporosis, in lumbar spine, hip and distal ra-
dius. Renal ultrasound test.
Treatment
• Parathyroidectomy if the patent meets surgical criteria (Table
15). If there is a parathyroid adenoma, an adenomatous gland
is removed. If any of the following occurs: parathyroid hyper-
plasia, total parathyroidectomy with implant in forearm muscles
or sternocleidomastoid muscle or subtotal parathyroidectomy
(leave a porton of the last gland).
• In severe, symptomatc acute hypercalcemia, treatment involvesabundant hydraton, loop diuretcs and i.v. Biphosphonates.
• In asymptomac paents, secure effi cient hydraton.
• Cinacalcet, a calcimimetc, increases circulatng calcium affi nity
by its receptor resultng in a significant decrease in calcium and
PTH levels. Therefore, it is indicated in secondary hyperparathy-
roidism in CRD and in primary hyperparathyroidism suff erers un-
suitable for surgery because of accompanying comorbilites or in
those aff ected by the disease who refuse surgery.
• To prevent secondary hyperparathyroidism development in CRD
patents, oral phosphorus chelants must be administered, but
the patent’s diet intake needs to be restricted.
· Under 50 years of age
· Age ≥ 50 with, at least, one of the following criteria:
- Serum calcium > 1 mg/dL over the upper limit of normality - Decreased creatinine clearance (< 60 mL/min)
- Mineral bone density under 2.5 ED on T-score
in backbone, hip, femoral head or 1/3 distal of radiusand/or any prior fracture because of fragility
Any primary hyperparathyroidism that presents signs or symptoms
related to hypercalcemia (i.e., nephrolithiasis) requires surgicalindication right from the start
Table 15. Indications for surgery in asymptomatic primaryhyperparathyroidism (Workshop, 2008)
Chapter 06
Multiple Endocrine
Neoplasia (MEN)
• Neoplastc syndromes that aff ect multple endocrine organs and
that have hereditary etology (autosomal dominant).
• MEN 1 (Wermer’s syndrome) associaon of hyperparathyroidism (the
most frequent manifestaon, because of parathyroid hyperplasia), pi-
tuitary adenoma and cell tumors of pancreac islets. “The 3 Ps”: para-
thyroid, pancreas and pituitary. Mulple Endocrine Neoplasia (MEN)
(Table 16).
• MEN type 2A (Sipple’s syndrome) confluence of medullary thyroid
cancer (or MTC, the most common manifestaton), pheochromocy-
toma (bilaterality is more frequent than sporadic pheochromocy-
toma) and hyperparathyroidism (the most frequent form is hyper-
plasia as in MEN 1) (Table 17).
• MEN type 2B consists of (aggressive) MTC with the presence of mu-cosa neuromas (tp of the tongue, eyelids and digestve tract).
• When MTC and pheochromocytoma converge, pheochromocytoma
should be surgically treated first.
ENDOCRINE MANIFESTATIONSNONENDOCRINE
MANIFESTATIONS
1. Parathyroid hyperplasia/adenoma (90%)
2. Enteropancreatic tumor (70%): · Gastrinomas (40%)
· Pancreatic polypeptide (20%)
· Insulinoma (10%)
· Other more rare (i.e., vipoma and
glucagonoma)3. Pituitary tumors (40%):
· Prolactin (20%)
· Acromegaly (5%) · Combination of prolactin and GH (5%)
· Nonsecretory (5%)
· Others (TSH and so on)
4. Nonfunctioning adrenal adenomas
1. Facial angiobromas
(85%)2. Collagenomas (70%)
3. Lipomas (30%)
Table 16. Associations in MEN 1
SYNDROME CHARACTERISTICS
MEN 2A · Medullary thyroid carcinoma
· Pheochromocytoma (50%) · Hyperparathyroidism (10%)
· Lichenoid cutaneous amyloidosis
· Hirschprung’s disease
Familial medullary
thyroid carcinoma
· Medullary thyroid carcinoma
· It can be associated with Hirschprung’s disease
MEN 2B · Medullary thyroid carcinoma (more precociousand aggressive than in MEN 2A)
· Pheochromocytoma (40% to 50%)
· Mucocutaneous ganglioneuromatosis (95%) · Marfanoid habitus (without ectopia lentis or
aortic anomalies)
Table 17. Associations in MEN 2