Presented by : Dr.

Kush Pathak

DEGENERATION NECROSIS

AND

Contents
1. Introduction 2. Causes of cell injury 3. Biochemical mechanism of cell injury 4. Reversible & irreversible cell injury 5. Degeneration 6. Types of degeneration 7. Necrosis 8.Termination of necrosis

Introduction
Cells functions are complex and delicate.
Main functions of cells-

1 Maintenance of permeability of cell membrane- water & electrolyte balance. 2 Aerobic respiration & production of ATP main function of mitochondria. 3 Protein synthesis. 4 Preservation of integrity of genetic apparatus of cell.

 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)

Outcomes of cell injury

When

stimuli still exceeds, where cellular adaptation is not possible it leads to cell injury.

Causes of cell injury

1 Hypoxia-

-common cause of cell injury &

cell death. Causes- cardiac failure, respiratory failure, anemia.

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.

5. Immunologic reactions- Immune system protects the body against the foreign

material.

- Some immune reactions can

anaphylaxis reactions.

cause cell injury eg-

6. Genetic defectsAny alteration at the level of chromosome or DNA level can cause cell injury.

1. Cellular responses to injurious stimuli depends on type of

Mechanism of cell injury:

injury, duration & its severity. 2. Same injury has different outcome , depending on the cell type Striated skeletal muscle of leg
Complete
ischemia

Cardiac muscle
After 20-30 min
Cell dies

Accommodate 2-3 hrs without irreversible injury

3. Celluar functions are lost far before cell death occurs & morphological changes of cell injury lag far behind both.

BIOCHEMICAL MECHANISM OF CELL INJURY

1. ATP depletionResults in rapid shutdown of most critical homostatic pathways ATP required for cellular osmolarity, transport processes, protein synthesis. O2 deprivation / reactive O2 speciesLack 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.

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 intracellular stores.

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. Mitochondrial damage
(B) cytosolic calcium, oxidative stress, lipid breakdown products
(A) Mitochondria required for oxidative metabolism

Formation of high conductance channels of inner mitochondrial membrane c/a mitochondrial permeability transition

Non selective pores allow proton gradient across the mitochondrial membrane, this prevents ATP generation

normal physiological
demand

excess physiologicalstress

Normal cell
normal homeostasis cellular adaptation

Reversible injury Persistent stimuli

irreversible injury

cell death

necrosis

apoptosis

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.

Morphology- the ultrastructural changes of reversible cell injury1 plasma membrane alterationintercellular attachments. 2 mitochondrial changes- swelling & appearance of phospholipids rich blunting of microvilli, loosening of

amorphous densities.
3 Dilation of ER 4 Nuclear alteration

Types of degeneration
(a)

Disturbances in protein metabolism1. 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

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.

Gross appearance-

- affected organ is enlarged

Microscopic feature-

- cut surface appears opaque, cloudy & pale .

-Cells presents with granular & eosinophilic material

cloudy swelling
(kidney)

2. Hydropic degeneration / vacuolar degen

- Severe form of cloudy swelling characterized by vacuolization of cells due to
imbibition 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

- damaged mitochondria

impaired energy production

altered cell permeability

Na in cell & k in cell

water in cell

hydropic degeneration

Gross app -Affected organ is swollen - Cut surface appears opaque, pale, soft Microscopic features-Cells appear clear due to water content

-Cytoplasm is vacuolated

3 Hyaline degenerationHyaline derived from Greek word hyalos ( glass) Hyaline indicates cytoplasm. a glassy, homogenous, translucent appearance of

Hyaline stains bright red with eosin, blue or green with trichrome stain. Cell organelle mainly involved are smooth ER, agglomeration of SER corresponds to hyaline bodies in light microscopy. - 2 types cellular hyalinization connective tissue hyaline.

Hyaline degenration

(a) Cellular hyalinization- Hyaline or glassy appearance of cell is due to coagulated proteins.
Seen in following condition
In kidney in the cells of renal tubules in nephritis.

these droplets are small, spherical.

Hyaline droplets

In liver in viral hepatitis hyaline inclusions are found -in alcoholic cirrhosis appears as dark irregular network in cytoplasm c/a Mallory bodies.

(b) Connective tissue hyalinization

- Caused by agglomeration & swelling of collagen - Found in scar of fibrocollagenous tissue.

Zenkers degeneration

-Commonly seen in striated muscles- skeletal & cardiac muscle.

gross appMuscle 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 by coagulation necrosis.

Amyloid degeneration
amyl starch
oid - resembling -Appears as amorphous, homogenous, translucent, eosinophilic.

starch like

- Usually found in walls of bv & basement mem.

-It is composed of 2 types of complex proteins

fibril protein 90%

P component 10%

- with congo red & polarised light amyliod shows apple green birefringence due to cross pleated sheet configuration

(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 sheet configuration which produces periodicity. this is characteristic feature of amyloid. - 2 types of amyloid fibril protein are 1 AL (amyloid light chain) 2 AA (amyloid associated protein)

(b) P component- Non fibrillar -In electron microscopy appears as pentagonal profile.

Pathologic effects of amyloid- creates pressure on adjacent cells & causes atrophy. - on blood vessels narrowing of the vessels.

Amyloid plaque

6.

Mucoid degeneration

-Mucous- is viscous watery secretion of mucous glands in a loose

combination of proteins & mucopolysaccharide. - Mucin- is a glycoprotein & chief constituent of mucous. Mucoid degeneration is excessive secretion of mucous associated with degeneration of cells

The degeneration of connective tissue into a gelatinous or mucoid substance.

- mucous is produced by epithelial cells of mucous membrane, mucous glands & CT cells in fetus.

- Epithelial

mucin Catarrhal inflammation of mucous membrane of respiratory tract obstruction of duct leading to mucocele in oral cavity

- CT mucins eg
-mucoid degeneration in some tumors in myxomas, neurofibromas

7. fatty degeneration
Abnormal accumulation of small droplets with in the previously injured/ diseased parenchymal cells, where normally fat is not visible - organs involved are liver, kidney, heart

etiology-

-anoxia

-toxic agents like chloroform

- starvation

(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 without displacement of nucleus. -In fatty in filteration fat droplets fuse & push the nucleus in one corner giving signet ring appearance.

Fatty change in liver

(b) Fatty degeneration in heart

The accumulation of fat globules within the cells of a bodily organ, such as 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 be diffuse degeneration of entire myocardium -loss of muscular tone microscopic app-fat droplets arranged in rows along the length of muscle cell

Irreversible cell injury Necrosis

- Necrosis refers to a sequence of morphological changes that followS cell death in living 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 early stages.

Morphological changes-

(a) Cytoplasmic changesDead cells show eosinophilia.

Cells may have a glassy homogenous app than viable cells , mainly due to of glycogen particle enzymes degrade the organelles of cytoplasm, cytoplasm becomes vacuolated & appears moth eaten.

Nuclear changesSeen due to non specific breakdown of DNA (a) karyolysis -basophilia of the chromatin fades secondary to DNAase activity -nuclear chromatin undergoes dissolution gradually (b) pyknosis -nuclear shrinkage & basophilia -DNA condenses into a solid shrunken mass & loss of nuclear details (c) karyorrhexis -pyknotic nuclei fragments & totally disappears

- once the dead cells have undergone these early changes, mass of necrotic tissue exhibits distinctive morphological pattern depending on enzymatic catabolism / protein denaturation. - when denaturation predominates coagulation necrosis develops - in case of enzymatic degradation liquefaction necrosis develops.

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 clinical diagnosis. eg- 1 after skeletal muscle necrosis- raised plasma level of cratinine phosphokinase (cpk)

2. - In myocardial infarction oxaloacetate transaminase)

-

in SGOT

(glutamate

in CPK (Creatinine phosphokinase) in LDH (lactate dehydrogenase)

Types of necrosis

1. Coagulation necrosis
2. Liquefaction necrosis 3. Caseous necrosis 4. Fat necrosis 5. Fibrinoid necrosis

1. Coagulation necrosisCaused by irreversible injury, characterized by coagulation of

proteins of dead cells by intracellular enzymes

cause- sudden cessation of blood flow (ischemia) - hypoxia Pathogenesis injury hypoxia
ATP synthesis

Ph (acidosis)

degeneration of structural proteins & enzymatic proteins

which blocks the proteolysis of cells

gross app - foci of coagulative necrosis is yellowish, softer & shrunken.

microscopic app - Hallmark of coagulative necrosis is the conversion of normal cells into their tomb stones ie., outline of cells are retained so that cell type can be recognized but their cytoplasmic & nuclear details are lost. - cells appear more eosinophilic - nuclear changes pyknosis followed by karyolysis

Normal myocardial cells

Coagulative necrosis

Large area of coagulative necrosis

Coagulaulated kidney

fate necrosed foci is infilterated by inflammatory cells . dead cells are

phagocytosed 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

Pathogenesis hydrolytic
enzymes of cells
Liquifaction necrosis in brain

complete digestion & destruction of cells & tissues

gross appAffected areas is soft with

liquified center containing necrotic debris. Later a cyst wall is formed.

microscopic appLiquifaction necrosis

3. Caseous necrosis
- Is distinctive form of necrosis seen in foci of tuberculous infection. - In casseous necrosis, cellular structure are lost with production of cheesy 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

Microscopic app
Necrosed foci are structure less, eosinophilic Surrounding tissue shows granulomatous inflammatory reaction Consisting of epithiloid cells with interspread giant cells of langerhans & peripherally lymphocytes

- Special form of necrosis which affects adipose tissue

cause -acute pancreatitis -trauma to pancreas

4. Fat necrosis

pathogenesis acute pancreatitis / trauma

Injury to acinar cells

Release of pancreatic lipase

Digestion of pancreas itself + surrounding adipose tissue

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

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 inflammatory reaction. -formation of Ca soaps is identified as amorphous, granular & basophilic material.

- Is characterized by deposition of fibrin like material .

cause

5. Fibrinoid necrosis

- 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

Fibrinoid degeneration

Termination of necrosis
- occurs when necrotic area is small

liquefaction by leucocytes / autolysis

lymphatic absorption - sometimes necrosis is asso with sec infection with pyogenic organism

absorption

abscess formation

Necrosis
encapsulation when necrotic area is large , repair takes place from periphery to provide a capsule of fibrous tissue calcification fibrosis

dead tissue -repair by filling attracts gaps with fibrous Ca from blood + fatty tissue in brain, liver & acids heart

- insoluble Ca soaps

References
1.
2.

Robbins Basic Pathology, 6th Edition.

Pathology Rubin & Farber , 1st Edition.

3.
4. 5.

Text Book of Pathology, N.C.Dey , 6th Edition.

Text Book of Pathology , Harsh Mohan , 3ed Edition. Text Book of Pathology , William Boyed , 8th Edition.

Thank you