degenration and necrosis
TRANSCRIPT
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Presented by :
Dr. Kush Pathak
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DEGENERATION AND
NECROSIS
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Contents
1. Introduction
2. Causes of cell injury
3. Biochemical mechanism of cell injury
4. Reversible & irreversible cell injury
5. Degeneration6. Types of degeneration
7. Necrosis
8.Termination of necrosis
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Introduction
Cellsfunctions are complex and delicate.
Main functions of cells-
1 Maintenance of permeability of cell membrane- water &electrolyte balance.
2 Aerobic respiration & production of ATPmain function
of mitochondria.
3 Protein synthesis.
4 Preservation of integrity of genetic apparatus of cell.
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Normal homeostasis- when cell
is able to handle the normal
physiological demands.
When the physiological demand
exceeds normal / any
pathological stimuli may bring
about physiologic and
morphologic cellular adaptations
( hypertrophy,
atrophy,hyperplasia,
metaplasia)
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When stimuli still exceeds,
where cellular adaptation is not
possible it leads to cell injury.
Outcomes of cell injury
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Causes of cell injury
1 Hypoxia-
-common cause of cell injury
&
cell death.
Causes- cardiac failure,respiratory failure, anemia.
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2. Physical agents-
-mech trauma, radiation, electric shock.
3. Chemical agents-
-poisonous sub like cyanide, mercuric salts.
-high cons of O2
-hypertonic cons of glucose / salts.
4. Infectious agents--bacteria, virus, fungi causes cell injury.
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5. Immunologic reactions-
- Immune system protects the body against the foreign
material.
- Some immune reactions can cause cell injury eg-
anaphylaxis reactions.
6. Genetic defects-
Any alteration at the level of chromosome or DNA level can
cause cell injury.
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Mechanism of cell injury:
1. Cellular responses to injurious stimuli depends on type ofinjury, duration & its severity.
2. Same injury has different outcome , depending on the celltype
Striated skeletal muscle of leg
Complete
ischemia
Accommodate 2-3 hrswithout irreversibleinjury
Cardiac muscle
After 20-30 min
Cell dies
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3. Celluar functions are lost far before cell death occurs &
morphological changes of cell injury lag far behind both.
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1. ATP depletion-
Results in rapid shutdown of most critical homostatic
pathways
ATP required for cellular osmolarity, transport processes,
protein synthesis.2 O2 deprivation / reactive O2 species-
Lack of O2 and reactive O2 species are also responsible for
cell death.
- Free radicals causes lipid peroxidation & deleterious effects
on cell struc like DNA fragmentation, protein synthesis.
BIOCHEMICAL MECHANISM OF CELL INJURY
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3 Loss of Ca+2
- Cytosolic free Ca+2 is maintained by ATP dependant ca+2 transporters at
a cons 10,000 times lower than cons of extracellular Ca+2.
- Ischemia / toxins allow a net influx of extracellular ca+2 across the
plasma membrane followed by release of ca+2
for the intracellularstores.
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4. Defects in membrane permeability
Bacterial toxins, viral proteins , physical & chemical agents
leads to loss of membrane barrier
Breakdown of cons gradient necessary to maintain normal
metabolic activities
5 Mi h d i l d
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5. Mitochondrial damage
(A) Mitochondria required for oxidative metabolism(B) cytosolic calcium, oxidative stress, lipid breakdown products
Formation of high conductance channels of innermitochondrial membrane c/a mitochondrial permeabilitytransition
Non selective pores allow proton gradient across themitochondrial membrane, this prevents ATP generation
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normal physiological excess physiologicalstress
demand
Normal cell
normal homeostasis cellular adaptation
Reversible injury
Persistent stimuli
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irreversible injury
cell death
necrosis apoptosis
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Reversible cell injury
Degeneration
In Latin degeneration means- deterioration or passing
from higher to lower level.
A retrogressive reversible pathological change in cells or
tissues in consequence for which their functions are
impaired.
h l l h f ibl ll i j
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Morphology- the ultrastructural changes of reversible cell injury-1 plasma membrane alteration- blunting of microvilli, loosening of
intercellular attachments.
2 mitochondrial changes- swelling & appearance of phospholipids rich
amorphous densities.
3 Dilation of ER
4 Nuclear alteration
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Types of degeneration(a) Disturbances in protein metabolism-
1. Cloudy swelling
2. Hydropic degeneration
3. Hyaline degeneration
4. Zenkers degeneration
5. Amyloid degeneration
(b) Disturbances in carbohydrate metabolism
1. Mucoid degeneration
(c) Disturbances in fat metabolism
1. Fatty degeneration
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1 Cloudy swelling
- First manifestation of almost all forms of cell injury.
- Causes- back toxins, chemicals, burns, high fever- It results from impaired regulation of cellular volume, especially
for Na.
- Na regulation operates at 2 levels
- plasma membrane
- Na pump on plasma membrane
- Injurious agents may interfere with these regulatory mechanism &result in accumulation of Na in cell.
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Gross appearance-
- affected organ is enlarged
- cut surface appears opaque, cloudy & pale .
Microscopic feature-
-Cells presents with granular & eosinophilic material
cloudy swelling
(kidney)
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2. Hydropic degeneration / vacuolar degen
- Severe form of cloudy swelling characterized by vacuolization of cells due toimbibition of large quantity of water in cell cytoplasm.
Causes - viral infection
- in kidney due to water & electrolytic imbalance.
-in hepatic cells due to infective hepatitis.
Pathogenesis-
- Toxic agents which interfere with semi permeability of cell membrane
water imbibitions
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- damaged mitochondria impaired energyproduction
altered cell permeability
Na in cell & k in cell
water in cell
hydropic degeneration
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Gross app
-Affected organ is swollen
- Cut surface appears opaque, pale,soft
Microscopic features-
-Cells appear clear due to watercontent
-Cytoplasm is vacuolated
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3 Hyaline degeneration-
Hyalinederived from Greek wordhyalos ( glass)
Hyaline indicates a glassy, homogenous, translucent appearance ofcytoplasm.
Hyaline stains bright red with eosin, blue or green with trichrome stain.
Cell organelle mainly involved are smooth ER, agglomeration of SERcorresponds to hyaline bodies in light microscopy.
- 2 types cellular hyalinization
connective tissue hyaline.
Hyaline degenration
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(a) Cellular hyalinization-
- Hyaline or glassy appearance of cell is due to coagulated proteins.Seen in following condition
In kidneyin the cells of renal tubules in nephritis.
these droplets are small, spherical.
Hyaline droplets
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In liver in viral hepatitishyaline inclusions arefound
-in alcoholic cirrhosisappears as dark irregularnetwork in
cytoplasm c/a Mallory
bodies.
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(b) Connective tissue hyalinization
- Caused by agglomeration & swelling of collagen- Found in scar of fibrocollagenous tissue.
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4 Zenkers degeneration-Commonly seen in striated muscles- skeletal & cardiac muscle.
gross app-
Muscle is thin, translucent & glossy in appearance
Microscopic app--loss of cross striations
-muscle cells appear coarse & clumped due to coagulation of sarcoplasm.
If the damage to muscle cell is irreversible the change is followed bycoagulation necrosis.
5 A l id d ti
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5 Amyloid degeneration
amyl starch starch like
oid - resembling
-Appears as amorphous, homogenous, translucent, eosinophilic.
- Usually found in walls of bv & basement mem.
-It is composed of 2 types of complex proteins
fibril protein P component
90% 10%
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- with congo red & polarised lightamyliod shows apple greenbirefringence due to cross -pleated sheet configuration
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(a) Fibril protein-
- Fibrils are delicate, non branching filaments measuring 7.5- 10nm in diameter& having indefinite length.
- In x-ray crystallographic analysis, the fibrils presents as - pleated sheetconfiguration which produces periodicity. this is characteristic feature ofamyloid.
- 2 types of amyloid fibril protein are1 AL (amyloid light chain)
2 AA (amyloid associated protein)
(b) P component-
- Non fibrillar
-In electron microscopy appears as pentagonal profile.
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Pathologic effects of amyloid-
- creates pressure onadjacent cells & causesatrophy.
- on blood vessels
narrowing of the vessels.
Amyloid plaque
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6. Mucoid degeneration
The degeneration of connective tissue into a gelatinous or mucoid
substance.-Mucous- is viscous watery secretion of mucous glands in a loosecombination of proteins & mucopolysaccharide.
- Mucin- is a glycoprotein & chief constituent of mucous.
Mucoid degeneration is excessive secretion of mucous associatedwith degeneration of cells
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- mucous is produced by epithelial cells of mucous membrane,mucous glands & CT cells in fetus.
- Epithelial mucin
Catarrhal inflammation of mucous membrane of respiratory
tractobstruction of duct leading to mucocele in oral cavity
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- CT mucins eg
-mucoid degeneration in some tumorsin myxomas,
neurofibromas
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7. fatty degeneration
Abnormal accumulation of small droplets with in the previouslyinjured/ diseased parenchymal cells, where normally fat is notvisible
- organs involved are liver, kidney, heart
etiology-
-anoxia-toxic agents like chloroform
- starvation
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(a) Fatty degeneration of liver
gross app-
-enlargement of liver
-appears pale , soft
- cut surface shows yellowish areas
Microscopic features:
-In fatty degeneration, small fat droplets appear in cytoplasm withoutdisplacement of nucleus.
-In fatty in filteration fat droplets fuse & push the nucleus in one corner givingsignet ring appearance.
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Fatty change in liver
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(b) Fatty degeneration in heart
The accumulation of fat globules within the cells of a bodily organ, suchas the liver or heart, resulting in deterioration of tissue and diminished
functioning of the affected organ
gross app-
-fatty yellow band alternating with healthy band of myocardium or it can bediffuse degeneration of entire myocardium
-loss of muscular tone
microscopic app--fat droplets arranged in rows along the length of muscle cell
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Irreversible cell injuryNecrosis
- Necrosis refers to a sequence of morphological changes that followS cell death inliving tissue.
gross app-
-normal translucency of living tissue is lost. Tissue appears opaque, yellowish in
color
morphological appearance in necrosis is result of
-enzymatic digestion of the cell
-denaturation of protein
This process requires hrs to develop, so there is no detectable change in cells in earlystages.
Morphological changes-
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Morphological changes
(a) Cytoplasmic changes-
Dead cells show eosinophilia.
Cells may have a glassyhomogenous app than viable cells ,mainly due to of glycogen particle
enzymes degrade the organelles ofcytoplasm, cytoplasm becomesvacuolated & appears moth eaten.
Nuclear changes-
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Nuclear changes-
Seen due to non specific breakdownof DNA
(a) karyolysis
-basophilia of the chromatin fadessecondary to DNAase activity
-nuclear chromatin undergoesdissolution gradually
(b) pyknosis
-nuclear shrinkage & basophilia
-DNA condenses into a solidshrunken mass & loss of nucleardetails
(c) karyorrhexis
-pyknotic nuclei fragments & totallydisappears
h d d ll h d h l h
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- once the dead cells have undergone these early changes, mass ofnecrotic tissue exhibits distinctive morphological patterndepending on enzymatic catabolism / protein denaturation.
- when denaturation predominates coagulation necrosis develops
- in case of enzymatic degradation liquefaction necrosis develops.
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Diagnosis of necrosis by biochemical means
- as necrosis occurs various solu sub like enzymes, diffuse out of
cells & absorbed in blood stream . Their detection aids in clinicaldiagnosis.
eg- 1 after skeletal muscle necrosis- raised plasma level of cratininephosphokinase (cpk)
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2. - In myocardial infarction - in SGOT (glutamateoxaloacetate transaminase)
- in CPK (Creatinine phosphokinase)
- in LDH (lactate dehydrogenase)
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1 Coagulation necrosis
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1. Coagulation necrosis-
Caused by irreversible injury, characterized by coagulation ofproteins of dead cells by intracellular enzymes
cause- sudden cessation of blood flow (ischemia)- hypoxia
Pathogenesis
injury hypoxia
ATP synthesis
Ph (acidosis)
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degeneration of structural proteins & enzymaticproteins
which blocks the proteolysis of cells
gross app
- foci of coagulative necrosis is yellowish, softer & shrunken.
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microscopic app
- Hallmark of coagulative necrosis is the conversion of normal cellsinto their tomb stones ie., outline of cells are retained so that celltype can be recognized but their cytoplasmic & nuclear details arelost.
- cells appear more eosinophilic
- nuclear changes pyknosis followed by karyolysis
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Normal myocardial cells
Coagulative necrosis
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Large area of coagulativenecrosis
Coagulaulated kidney
f t d f i i i fil d b i fl ll d d ll
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fate necrosed foci is infilterated by inflammatory cells . dead cells arephagocytosed leaving granular debris & fragments of the cells
2. Liquefaction necrosis (colliquative)
- Chacterized by rapid enzymatic digestion & complete destruction of cells & tissue.
cause- hypoxic death of cells in brain
- focal bacterial & fungal infection
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Pathogenesishydrolyticenzymes of cells
complete digestion &destruction of cells & tissues
gross app-
Affected areas is soft withliquified center containingnecrotic debris. Later a cyst wallis formed.
Liquifaction necrosis in brain
microscopic app-
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microscopic app-
Liquifaction necrosis
3 C i
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3. Caseous necrosis
- Is distinctive form of necrosis seen in foci of tuberculous infection.
- In casseous necrosis, cellular structure are lost with production ofcheesy material
Gross app
- Foci of casseous necrosis resembles dry cheese & are soft, granular &yellowish.
- Appearance is partly attributed to lipopolysaccarides present in capsule
of tubercle bacilli
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Microscopic app
Necrosed foci are structure less,eosinophilic
Surrounding tissue showsgranulomatous inflammatory
reaction
Consisting of epithiloid cellswith interspread giant cells oflangerhans & peripherally
lymphocytes
4 Fat necrosis
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4. Fat necrosis- Special form of necrosis which affects adipose tissue
cause
-acute pancreatitis
-trauma to pancreas
pathogenesis acute pancreatitis / trauma
Injury to acinar cells
Release of pancreatic lipase
Digestion of pancreas itself + surrounding adipose tissue
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protease & lipases liquify plasma mem of fat cells
release of triglycerides
triglycerides free fatty acid + glycerol
- damaged adipose cells assume cloudy app due to remaining free fatty acids
- fatty acid can complex with Ca to form Ca soaps
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gross app-appears as yellowish, white firm
deposits.
-formation of Ca soaps imparts firm& chalky white app to necrosed foci.
microscopic app--necrosed cells have cloudy app,
surrounded by inflammatoryreaction.
-formation of Ca soaps is identified as
amorphous, granular & basophilicmaterial.
5. Fibrinoid necrosis
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5 Fibrinoid necrosis
- Is characterized by deposition of fibrin like material .
cause
- hypertension
- peptic ulcer
- autoimmune disease
site
- wall of arterioles / small arteries
microscopically- appears as bright, eosinophilic, hyaline like deposition in vessel wall or
on luminal surface of a peptic ulcer
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Fibrinoid degeneration
i i f i
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Termination of necrosis
- occurs when necrotic area is small
liquefaction by leucocytes / autolysis
lymphatic absorption
- sometimes necrosis is asso with sec infection with pyogenicorganism
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absorption abscess formation
Necrosis
encapsulation calcification fibrosis
when necrotic area dead tissue -repair by filling
is large , repair takes attracts gaps with fibrous
place from periphery Ca from blood + fatty tissue in brain, liver &
to provide a capsule acids heart
of fibrous
tissue
- insoluble Ca soaps
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References
1. Robbins Basic Pathology, 6th Edition.
2. Pathology Rubin & Farber , 1st Edition.
3. Text Book of Pathology, N.C.Dey , 6th Edition.
4. Text Book of Pathology , Harsh Mohan , 3ed Edition.
5. Text Book of Pathology , William Boyed , 8th Edition.
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Thank you