Dr Neha MahajanMD Pathology

Autolysis

Necrosis

Gangrene

Apoptosis

It is disintegration of the cell by its own hydrolytic

enzymes liberated from lysosomes.

Can occur in living body or postmortem.

Morphologically, autolysis is identified by

homogenous & eosinophilic cytoplasm with loss

of cellular details & remains of cell as debris.

Def: It is defined as focal death along with degradation

of tissue by hydrolytic enzymes liberated by cells and is

accompanied by inflammation.

Causative agents:

Hypoxia

Chemical and physical agents

Microbial agents

Immunological injury

MORPHOLOGY

Cytoplasm

Increased eosinophilia due to loss of RNA

Glassy homogenous appearance due to loss of glycogen

particles

Vacuolated or moth eaten appearance

Myelin figures

Electron microscopy- discontinuities in plasma & organelle

membranes, marked dilation of mitochondria,

amorphous densities

Nucleus

Pyknosis

Nuclear shrinkage due to condensation of nuclear

chromatin

Karyolysis

Chromatin fades- loss of DNA due to enzymatic

degradation by endonucleases

Karyorrhexis

Pyknotic nucleus undergo fragmentation

Coagulative

Liquefactive

Caseous

Fatty

Fibrinoid

Gangrenous

Most common type due to ischaemia

Organs- heart, kidney, spleen

Grossly- foci of necrosis

Early pale, firm & slightly swollen and shrunken

Later yellowish softer & shrunken

Microscopy-

Conversion of normal cells into their tombstones i.e cell

outline preserved but nuclear details lost

Cells swollen, more eosinophilic with nuclear changes

Wedge shaped kidney infarct

Microscopy of edge of infarct showing normal kidney and necrotic cells in infarct

It is characterised by digestion of the dead cells,

resulting in transformation of the tissues into liquid

viscous mass

Seen in focal bacterial and fungal infections

Examples- infarct brain, abscess cavity

Grossly- affected area is soft with liquefied centre

containing necrotic debris, cyst wall

Microscopically- cystic space shows necrotic cell debris

and macrophages

Liquefactive necrosis.Infarct brain showing dissolution of tissue

Liquefactive necrosis in the brain

Combines featues of coagulative and liquefactive necrosis

Example:

◦ tuberculosis lesions

◦ fungal infections

Coccidioidomycosis

Blastomycosis

Histoplasmosis

Gross- Dry cheese, soft, granular and yellowish

Microscopy- necrosed foci are structureless eosinophilic with

granular debris surrounded inflammatory cells (granulomas)

Caseous necrosis:confluent cheesy tan granulomas in the lung in a patient with tuberculosis

Pulmonary tuberculosis:tubercle contains amorphous finely granular, caseous ('cheesy') material typical of caseous necrosis.

Focal area of fat destruction, resulting from release of

pancreatic lipases

Traumatic fat necrosis

Gross- fat necrosis seen as yellowish white and firm

deposits, chalky white appearance.

Microscopy-

Necrosed fat cells have cloudy appearance & are

surrounded by inflammatory reaction.

Fat necrosis secondary to acute pancreatitis

It is characterised by depostion of fibrin like material

which has staining properties of fibrin

Seen in immunological tissue injury( immune complex

vasculitis,autoimmune diseases,arthus reaction)

Arterioles in hypertension and peptic ulcer

Fibrinoid necrosis: afferent arteriole and part of the glomerulus are infiltrated with fibrin, (bright red amorphous material)

Fibrinoid necrosis- wall of artery shows circumferential bright pink area of necrosis

Gangrene is a form of necrosis of tissue with superadded putrefaction

Usually coagulative type due to ischaemia

Example- gangrene of bowel

gangrene of limb

Gangrenous or necrotising inflammation- gangrene lung, gangrenous appendicitis

Types- Dry gangrene

Wet gamgrene

Gas gangrene

It begins in the distal part of a limb due to ischaemia.

Examples- dry gangrene in toes & feet of an old person

due to arteriosclerosis

Thromboangitis obliterans( Buerger`s disease)

Raynaud`s disease

Trauma

Ergot poisoning

Line of separation is formed between gangrenous and

viable part.

Gross- Affected part is dry, shrunken and dark black (foot

of mummy)

black due to liberation of Hb from haemolysed RBC`s

which is acted upon by H2S produced by bacteria

resulting in formation of black iron sulphide.

Line of separation- separation with falling off the

gangrenous tissue

Microscopy-

Necrosis with smudging off tissue. Line of separation

consists of inflammatory granulation tissue.

Dry gangrene

It occurs in moist tissues and organs such as mouth,

bowel, lung, cervix, vulva,etc

Examples:

Diabetic foot

Bed sores

Wet gangrene develops due to blockage of venous and

less commonly arterial.

Affected part is stuffed with blood- growth of putrefactive

bacteria

No clear cut line of demarcation, may spread to

peritoneal cavity causing peritonitis.

Gross-

Affected part is soft, swollen, putrid, rotten and dark.

Microscopy-

Coagulative necrosis with stuffing of affected part with

blood.

No clear cut line of demarcation.

Feature DRY GANGRENE WET GANGRENE

SITE Commonly limbs More common in bowel

MECHANISM Arterial occlusion More commonly venous obstruction

MACROSCOPY Organ dry, shrunken and black

Part moist, soft,swollen,rotten and dark

PUTRFACTION Limited due to very little blood supply

Marked due to stuffing of organ with blood

LINE OF DEMARCATION Present at the junction between healthy and gangrenous part

No clear cut line of demarcation

BACTERIA Bacteria fail to survive Numerous present

PROGNOSIS Generally better due to little septicemia

Generally poor due to profound toxemia

It is form of wet gangrene caused by gas forming

clostridia.( gram positive anaerobic bacteria)

Gross-

Affected tissue swollen, oedematous, painful and

crepitant due to accumulation of gas bubbles within the

tissues.

Later tissue becomes dark black and foul smelling.

Microscopy-

Muscle fibres show coagulative necrosis with liquefaction,

oedema and leucocytic infiltrate

Def: Apoptosis is a pathway of cell death that is

induced by a tightly regulated suicide program in

which cells destined to die activate enzymes that

degrade the cells' own nuclear DNA and nuclear

and cytoplasmic proteins.

CAUSES OF APOPTOSIS

Physiological

Pathological

Apoptosis in Physiologic Situations

The programmed destruction of cells during embryogenesis, including implantation, organogenesis, developmental involution, and metamorphosis.

Involution of hormone-dependent tissues upon hormone withdrawal.

Cell loss in proliferating cell populations, such as immature lymphocytes in the bone marrow and thymus that fail to express useful antigen receptors, B lymphocytes in germinal centers, and epithelial cells in intestinal crypts, so as to maintain a constant number (homeostasis).

Elimination of potentially harmful self-reactive lymphocytes.

Death of host cells that have served their useful purpose.

Apoptosis in Pathologic Conditions

DNA damage. Radiation, cytotoxic anticancer drugs, and hypoxia can damage DNA, either directly or via production of free radicals. If repair mechanisms cannot cope with the injury, the cell triggers intrinsic mechanisms that induce apoptosis.

Accumulation of misfolded proteins. Cell death in certain viral infections. Pathologic atrophy in parenchymal organs

after duct obstruction, such as occurs in the pancreas, parotid gland, and kidney.

MORPHOLOGIC AND BIOCHEMICAL CHANGES IN APOPTOSIS

Morphology Cell shrinkage. Cell smaller, cytoplasm dense and the

organelles, though relatively normal, are more tightly packed.

Chromatin condensation. This is the most characteristic feature of apoptosis. The chromatin aggregates peripherally, under the nuclear membrane, into dense masses.

Formation of cytoplasmic blebs and apoptotic bodies.Extensive surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments.

Phagocytosis of apoptotic cells or cell bodies, usually by macrophages. Apoptotic bodies are rapidly ingested by phagocytes and degraded by the phagocyte's lysosomalenzymes.

On histologic examination, in tissues stained with

hematoxylin and eosin, the apoptotic cell appears as

a round or oval mass of intensely eosinophilic

cytoplasm with fragments of dense nuclear

chromatin.

FEATURE APOPTOSIS NECROSIS

Definition Programmed & coordinated cell death

Cell death along with degradation of tissue by hydrolytic enzymes

Causative

agents

Physiological & Pathological processes

Hypoxia,toxins

Morphology •No inflammatory reaction•Death of single cells•Cell shrinkage•Cytoplasmic blebs on membrane•Apoptotic bodies•Chromatin condensation•Phagocytosis of apoptotic bodies bymacrophages

•Inflammatory reaction present•Death of many adjacent cells•Cell swelling initially•Membrane disruption

•Damaged organelles•Nuclear disruption•Phagocytosis of cell debris by macrophages

Molecular

changes

•Lysosomes & other

organelles intact.

•Genetic activation by proto

oncogenes & oncosupressor

genes & cytotoxic T cell

mediated target cell killing.

•Lysosome breakdown with liberation

of hydrolytic enzymes.

•Cell death by ATP depletion,

membrane damage, free radical

injury.

Activation of Caspases.Initiator caspases- caspase-8 and caspase-9.

Executioners caspase-3 and caspase-6

DNA and Protein Breakdown.

“Typical DNA” ladders-apoptotic cells. “Smeared” pattern of DNA fragmentation necrosis.

Membrane Alterations and Recognition by Phagocytes.

Movement of some phospholipids (notably phosphatidylserine) from the inner leaflet to the outer leaflet of the membrane- recognised by phagocytes

Annexin V

Initiation phase

1.Intrinsic pathway

2.Extrinsic pathway

Execution phase

Activation of caspases

Initiators:

Absence of stimuli required for normal cell survival

(absence of certain hormones, growth factors, cytokines)

Regulators of Apoptosis:

Pro apoptotic genes: Bax, Bak,Bid,Bim

Anti apoptotic genes: Bcl-2,Bcl-X

Activation of Caspases:

Caspase 9

FAS receptor activation

Activation of caspases

Caspase 8, 10

Two initiating pathways converge to a cascade of

caspase activation, which mediate final phase of

apoptosis

Mitochondrial(Intrinsic)- caspase 9

Extrinsic- caspase 8 & 10

Executioner caspases- caspase 3 & 6

Apoptosis summary

Growth factor deprivation.

DNA damage.

Protein misfolding.

Apoptosis induced by TNF receptor family.

Cytotoxic T lymphocyte mediated apoptosis.

Disorders associated with dysregulated apoptosis.

Necrosis

Coagulative

Liquefactive

Caseous

Fatty

Fibrinoid

Gangrenous

Gangrene

Dry

Wet

Gas

Apoptosis

SUMMARY

Questions

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