NECROSISGANGRENEAPOPTOSIS

PATHOLOGIC CALCIFICATIONS

DR. AKSHAY AGARWAL

DEGENERATION

Definition : It is defined as a retrogressive change in the cell following a cell injury , more so in the cytoplasm than the nucleus, caused by a factor which is not stong enough to cause cell death.

It is a reversible cell injury.

FOUR TYPES :

1. Cellular swelling

2. Fatty change

3. Hyaline change

4. Mucoid change

CELLULAR SWELLING It is the most common and earliest form of cell injury .

Results from impaired regulation of cellular volume

GROSS: The affected organ is enlarged , pale , the cut surface bulges out .

MICROSCOPY :The cells are swollen with cytoplasmic granularity and they compress the surrounding microvasculature.

HYDROPIC CHANGE : Small clear vacuoles are seen in the cells

Organs affected:

Kidney (Large white kidney ) , islets of Langerhans in DM

FATTY CHANGE Occurs due to intracellular accumulation of neutral

fats.

CAUSES:

Excess alcohol consumption,obesity malnutrition ,starvation ,diabetes mellitus, chronic ilnesses , late pregnancy, hypoxia , hepatotoxins [ carbontetra chloride , chloroform , ether,aflatoxins ] certain drugslike estrogen steroids tetracycline etc.

Liver is the most common organ affected . Other organs affected are heart, kidney and skeletal muscle.

FATTY LIVER

Gross :The organ is enlarged yellow tense glistening capsule and rounded margins. C/S – bulges and pale yellow and greasy to touch.

MICROSCOPY

Fat in the cytoplasm of the hepatocytes is seen as clear area which may vary from minute droplets in the cytoplasm of a few hepatocytes [microvesicular] to distension of the entire cytoplasm of most cells by coaslesced droplets [macrovesicular] pushing the nucleus to the periphery of the cell.

Occ. the adjacent cell containing fat, rupture producing fatty cysts

Special stains such Sudan III & IV,Sudan black Oil red O can be employed to demonstrate fat in the tissue

HYALINE CHANGE

Hyaline is a glassy homogenous material that stains pink in H&E sections.

Two types :

1. Intra cellular (epithelial )

2. Extra cellular (connective tissue)

Intra cellular (epithelial ) hyaline :

1. Zenkers degeneration in typhoid.

2. Mallory’s hyaline in ALD

3. Russel bodies in plasma cells

Extra cellular (connective tissue) hyaline

1. Hyaline degeneration of splenic capsule , leiomyomas of uterus.

2. Hyaline arterisclerosis in HT and DM.

3. Copora amylacea in prostate.

MUCOID CHANGE

Epithelial mucin:

Catarrhal infection, cystic fibrosis, mucin secreting tumors.

Connective tissue mucin:

Myxiod degeneration in tumors , dissecting aneurysm of aorta

DEF OF NECROSIS

Focal death along with degradation of tissue by hydrolytic enzymes liberated by cells. accompanied by inflammatory reaction.

NECROSIS

DEF.-It refers to spectrum of morphological changes that follows cell death in living tissue largely resulting from progressive degradative action of enzymes on lethally injured cell.

Irreversible cell injury.

Nucleus – pyknosis, karyolysis, karyorrhexis.

Cytoplasm – homogenous ,intensely eosinphilic.

TYPES

Coagulative Necrosis

Liquefactive Necrosis

Caseous Necrosis

Fat Necrosis

Fibrinoid Necrosis

COAGULATIVE NECROSIS

Mc , caused by sudden cessatiion of blood flow.

Organs commonly affected are kidney , heart , spleen.

Gross :they are pale or anemic & wedge shaped with the base resting under the capsule & apex pointing towards the medulla.

Microscopy: the hallmark of coagulative necrosis is that architectural outlines of cells may be preserved although the cellular details are lost.

LIQUEFACTIVE NECROSIS

Occurs commonly due to ischemic injury and bacterial and fungal infections.

Due to degradation of tissue by the action of powerful hydrolytic enzymes.

Eg : infarct brain , abcess cavity

well defined,soft with liquified centre containing necrotic debris later a cyst wall is formed

-The cystic space contains necrotic cell debris & macrophages containing phagocytosed material.The cyst wall is formed by proliferating capillaries ,inflammatory cells and proliferating glials cells.

CASEOUS NECROSIS

It is found in the centre of tuberculous foci

It combines features of both coagulative ana liquefactive necrosis.

GROSS :The necrotic areas appear dry, cheesy, soft and yellowish

Microscopy :The necrosed foci are structureless ,granular eosinophilicThe surrounding tissue shows chacteristic granulomatous reaction

CAUSES hypoxia,chemical and physical agents.

Microbial agents and immunologic injury.

Changes---cell digestion by lytic enzymes.& denaturation of proteins. manifested morphologically by changes in nucleus &cytoplasm.

CYTOPLASM ---EOSINOPHILIC/WITH VACUOLATION OR DYSTROPHIC CALCIFICATION.

NUCLEUS—PYKNOSIS/KARYOLYSIS/KARYORRHEXIS.

Types of necrosis 5 types.

1)Coagulative necrosis---common type. caused by ischaemia. less commonly by bacterial or chemical agents.

Organs—HEART,KIDNEY & SPLEEN.

GROSS: Focii of coagulative necrosis ;pale firm &slightly swollen. With progression, becomes yellowish softer & shrunken .

Microscopy — cells can be recognized as merely having ghost architecture. the nuclear and cytoplasmic characters are lost. Cells swollen &more eosinophilic along with nuclear changes described. It is infiltrated by inflammatory cells.

Dead cells are phagocytosed./granular debris/fragments of cells.

Heart, coagulative necrosis

(myocardial infarct) - Gross, cross section

Heart, acute myocardial infarct - High power

2)Liquifactive necrosis--- combination of ischemic injury and bacterial or fungal infection. action of strong powerful hydrolytic enzymes. eg; infarct brain, abscess.

Gross— soft with liquefied centre containing necrotic debris. Later cyst wall is formed.

Microscopy— necrotic cell debris/macrophages with phagocytosed material. Cyst wall—proliferating capillaries, inflammatory cells, and gliosis in case of brain. fibroblasts.

Brain, old (cystic) infarct - Gross, coronal cut surface

Brain, liquefactive necrosis, old cerebral infarct

3)caseous necrosis---tuberculous infection.

Gross—resembles cheese are soft granular &yellowish

Microscopy--

Focus is structureless eosinophilic, contains granular debris. granulomatus inflammatory reaction with epitheloid cells, langhans giant cells.or forein body giant cells. peripheral mantle of lymphocytes.

Caseous Necrosis

4)fat necrosis —acute pancreatic necrosis,traumatic fat necrosis.

Gross-yellowish white &firm deposits.micro—cloudy appearance with inflammatory cells.

5)Fibrinoid necrosis —fibrin like material.seen in examples of immunologic injury.

Micro—brighitly eosinophilic hyaline material in vessel walls etc.

P – 215/73. Mesenteric fat necrosis

Omentum, fat necrosis in a case of pancreatitis - Gross

PATHOLOGIC CALCIFICATION

When calcium getrs deposited at sites other than bone and enamel it is called as pathologic or heterotopic calcification.

Two types :

1. Dystrophic

2. Metastatic

DYSTROPHIC

Deposits of Ca salts in dead and degenerated tissue.

Ca metab . is normal

Sr Ca levels normal

Causes : necrosis,infarcts,

thrombi,atheromas , Monckebergs sclerosis etc

METASTATIC

Deposits of Ca salts in normal tissue

Deranged

Hypercalcemia

Hyperparthyroidism,bony destructive lesions ,prolonged immobilisation etc

APOPTOSIS. Programmed & co-ordinated cell death.

Physiologic & pathologic processes.

Morphology: 1.No inflammatory reaction.

2.Death of single cells.3.Cell shrinkage.4.Apoptotic bodies.5.Cytoplasmic blebs & chromatin condensation.

Molecular Changes: 1. Lysosomes & other organelles intact.

2.Genetic activation by protooncogenes; onco-suppressor genes& cytotoxic T-cell mediated target cell killing

“ A FORM OF CELL DEATH DESIGNED TO ELIMINATEA FORM OF CELL DEATH DESIGNED TO ELIMINATE

UNWANTED HOST CELLS THROUGH ACTIVATION OFUNWANTED HOST CELLS THROUGH ACTIVATION OF

COORDINATED , INTERNALLY PROGRAMMED SERIES COORDINATED , INTERNALLY PROGRAMMED SERIES

OF EVENTS REGULATED BY A SET OF GENE PRODUCTSOF EVENTS REGULATED BY A SET OF GENE PRODUCTS ”

DEFINITION

GENETICALLY DETERMINED

BIOLOGICALLY MEANINGFUL

ACTIVE , SELF , DESTRUCTIVE PROCESS

PRO-APOPTOTIC ANTI-APOPTOTIC

Bax , Bad , Bcl-XS , Bak Bcl-2 ,

Bcl-xl

EF , P53 , C-myc A-1 , MCL-

1

NUR-77 , Cyclin-A BAG , PRb

ICE , Ned-2

GENETIC BASIS OF APOPTOSIS

DURING DEVELOPMENT

HOMEOSTASIS OF CELL POPULATION

AS A DEFENCE MECHANISM IN

IMMUNE REACTIONS

CELL DEATH BY DISEASE or

NOXIOUS AGENTS

IN AGING

DURING EMBRIOGENESIS

Implantation

Organogenesis

Developmental involution

Metamorphosis

HORMONE – DEPENDENT INVOLUTION

Menstual loss

Ovarin foll icular atresia during Menopause

Regression of lactating breast after weaning

Prostatic atrophy after castration

CELL DELETION IN INTESTINAL CRYPT EPITHELIA

CELL DEATH IN TUMORS

DEATH OF NEUTROPHILS IN ACUTE INFLAMMATION

DEATH OF IMMUNE CELLS

IN DUCT OBSTRUCTION

VIRAL HEPATITIS ( Councilman bodies )

CELL DEATH PRODUCED BY INJURIOUS STIMULI

( In low doses )

CELL SHRINKAGE

CHROMATIN CONDENSATION

FORMATION OF CYTOPLASMIC BLEBS

and APOPTOTIC BODIES

PHAGOCYTOSIS OF APOPTOTIC CELLS

MORPHOLOGIC EVENTS

PROTEIN CLEAVAGE

PROTEIN CROSS – LINKING

DNA BREAKDOWN

PHAGOCYTIC RECOGNITION

BIOCHEMICAL FEATURES

MECHANISM OF APOPTOSIS

SIGNALING PATHWAY

CONTROL and INTEGRATION STAGE

EXECUTION PHASE

REMOVAL OF DEAD CELLS

SIGNALING PATHWAYS

MORPHOGENS

GROWTH FACTORS

TNFR SUPERFAMILY

DIFFERENTIATION FACTORS

SIGNAL DETERMINANTS (+ or - )SURVIVAL APOPTOSIS

CONTROL AND INTEGRATION STAGE

FAS – FAS LIGAND MODEL

CYTOTOXIC T – LYMPHOCYTE

Bcl – 2 FAMILY PROTEINS

MITOCHONDRIAL MEMBRANE DAMAGE

FORMATION OF PORES

DECREASED MEMBRANE POTENTIAL

MITOCHONDRIAL SWELLING

INCREASED PERMIABILITY

CYTOCHROME – C RELEASE

BINDS - Apaf –1

TRIGGERS INITIATOR CASPASE

APOPTOSIS

EXECUTION PHASE

INITIATOR CASPASE EXECUTION CASPASE

CASPASE 9 ACTIVATE CASPASE 3

BINDS Apaf-1 ACTIVATE CASPASE 6

ACTIVATION OF CAS 8 NUCLEAR & CYTOPLASMIC

CHANGES

APOPTOSIS

APOPTOSIS NECROSIS Cell shrinkage Cell swelling

No inflammatory response Inflammatory response

Death of single cells Death of many contiguous cells

Cytoplasmic blebbing Plasma membrane disruption

Chromatin condensation Nuclear swelling & lysis

Intact lysosomes & other Lysosomal breakdown

organelles

Fragmentation of nucleus & Cell lysis & disentegration

cytoplasm

Phagocytosis by adj ‘ cells Phagocytosis by infl ‘ cells

Physiological & path ‘ stimuli Hypoxia , toxins mainly

Apoptotic bodies Damaged organelles

Programmed cell death Cell death by ATP depletion

Necrosis ApoptosisMorphological changes

Loss of membrane integrity

Begins with swelling of cytoplasm and mitochondria

Ends with total cell lysis

No vesicle formation, complete lysis

Disintegration (swelling) of organelles

Membrane blebbing, but no loss of integrity

Aggregation of chromatin at the nuclear membrane

Begins with shrinking of cytoplasm and condensation of nucleus

Ends with fragmentation of cell into smaller bodies

Formation of membrane bound vesicles (apoptotic bodies)

Mitochondria become leaky due to pore formation involving

proteins of the bcl-2 family.

Necrosis ApoptosisPhysiological significance

Affects groups of contiguous cells

Evoked by non-physiological disturbances (complement

attack, lytic viruses, hypothermia, hypoxia, ischemica,

metabolic poisons)

Phagocytosis by macrophages

Significant inflammatory response

Affects individual cells

Induced by physiological stimuli (lack of growth

factors, changes in hormonal environment)

Phagocytosis by adjacent cells or macrophages

No inflammatory response

GANGRENE necrosis of tissue with superadded putrifaction.usually coagulative.

3types.

DRY GANGREN—seen in distal part of limb due to ischemia. eg toes & FEET IN ATHEROSCLEROSIS

THROMBOANGITISOBLITERANCE.RAYNAUDS.

GROSS-DRY,SHRUNKEN,DARK BLACK.MICRO—SMUDGING OF TISSUE/INFL.GRANULATION TISSUE.

Foot, dry gangrene – Clinical presentation

Wet gangrene —moist tissues. Diabetic foot.high growth of bacteria.bed sores.venous blockage commonly than arterial.due to thrombosis,embolism.

Gross —soft swollen ,putrid rotten dark. eg-bowel gangrene.

Micro —coagulative necrosis with blood,. uleration, inflammatory infiltrate. No clear line of demarcation.

P – 779/83. Extensive Gangrene of small intestine.

Gas gangrene special form of wet gangrene—gas forming clostridia

infectswounds. ms., colonic operation.

GROSS—Swollen, oedematous, crepitant/ dark black, foul smelling.

Microscopy—ms. fibres show coagulative necrosis with liquefaction. gm +bacilli can be identified.

Thank You