Introduction

• Pathology –
• scientific study (logos) of suffering
(pathos).
 Subdivisions of clinical
Pathology:
• Histopathology
• Cytopathology
• Haematology
• Microbiology
• Immunology
• Chemical Pathology
• Genetics
• Toxicology
• Forensic Pathology
 Learning Pathology:

• General Pathology
– Common changes in all tissues.
• E.g.. Inflammation, cancer, ageing.
• Systemic Pathology
– Specific changes in organs.
• E.g.. Goiter, pneumonia, breast cancer.
 What is Disease ?

• dis + ease (not at ease…)

 Disease process

• 1) etiology
• 2) pathogenesis
• 3) morphologic changes
• 4) clinical significance- c/f ,functional
changes, course & prognosis of disease.
One agent  One disease - Malaria
Several agents  One disease -
Diabetes
One agent  Several diseases -
Smoking
 What is Diagnosis?
• The formal name(s) used to describe a patient’s
disease.
• Based on the symptoms & Signs and the results
of Pathology tests
• Needs Knowledge of different diseases, their
characteristics.
• Important for management & knowing
prognosis.
 Scope of Pathology
• Clinical Pathology
• Experimental Pathology
• Molecular Pathology
• Forensic Pathology
• Chemical / Microbiology
• Immunopathology
• Genetics & Disease.
When we know
“Where, Why, When & What,
then we can answer
the all important question
How to solve ?
Cell Injury
 Causes of cell injury

• Oxygen deprivation.
• Physical agents
• Chemical agents & drugs
• Infectious agents
• Immunologic reactions
• Genetic derangements
• Nutritional imbalances
 Cellular responses to injury

• Cellular adaptations – atrophy, hypertrophy,

hyperplasia & metaplasia
• Cell injury – reversible & irreversible
• Cell death – necrosis & apoptosis
• Intracellular accumulations
• Pathologic calcifications
• Cell aging
 Mechanisms of cell injury
• ATP depletion-
• 1) oxidative phosphorylation of ADP-
major pathway
• 2) glycolytic pathway- minor pathway
• O2 & O2 derived free radicals- partially
reduced reactive O2 forms – byproduct of
mitochondrial respiration..
 Contd…

• Loss of calcium homeostasis

• increase in intracellular Ca-
Defects in membrane permeability.
• Irreversible mitochondrial damage-
mitochondrial permeability
transition & release of cytochrome c
 Reversible cell injury

• Depletion of ATP will-

• Reduce activity of plasma memb energy
-dependent Na pump – Cell swelling.
• anaerobic glycolysis- acc of lactic acid
• Decreased intracellular pH
• Structural disruption of protein synthetic
aaparatus
 Reversible changes

• Cell swelling
• Mitochondria, ER swollen
• loss of microvilli
• “blebs” at cellular surface
• “Myelin figures” in the cytoplasm
• If O2 is restored all these changes are reversible.
 Irreversible cell injury

• Inability to reverse mitochondrial dysfunction -

marked ATP depletion
• Extreme disturbances in memb. function.
• Cytoskeletal abnormalities-actn of proteases.
• Detachment of cell memb from cytoskt –rupture.
 Contd…
• Injury to lysosomal memb. – leakage of
their enzymes.
• Reactive O2 species- highly toxic to cell
memb& other constituents.
• Lipid breakdown products- unesterified
FFA accumulate due to phospholipase
action-damage cell memb
• Rupture of cell membrane
 Ischaemia - reperfusion injury

• Generation of oxygen free radicals

• Increased Ca concentration in Mitochondria
• Mitochondrial permeability transition
• Inflammation
Free radical – induced cell injury
• Free radicals(FR) – chemical species that
have a single unpaired electron in an outer
orbit.
• Reactions with adjacent molecules.
• Initiate autocatalytic reactions.
• Propagation
 Sources of free radicals
• Radiation
• Enzymatic metabolism of exogenous chemicals or drugs
• Reductn-oxidation reactions occuring in normal metabolism
• Transition metals donate or accept free electrons
• Nitric oxide(NO) –converted to highly reactive peroxynitrite anion.
 Effects of free radicals

• Lipid peroxidation of membranes

• Oxidative modificatn of proteins-enhances
degradatn of critical enzymes
• Lesions in DNA
 Inactivation of free radicals

• Antioxidants- Vit A,E&C & glutathione in

cyto.
• Binding of ions to storage & transport
proteins(transferrin,ferritin etc)
• Enzymes(catalase, superoxide dismutases
glutathione peroxidase)
 Morphology of Reversible cell injury

• 1) cellular swelling – occurs in imbalance of

ionic/fluid homeostasis,
• Hydropic change/Vacuolar degeneration.
• 2)fatty change- occurs in hypoxic,toxic or
metabolic injury
• mainly seen in hepatocyte &myocardial cell
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 Cell Death
• Necrosis
• Apoptosis
 Necrosis
• Morphological changes which
• follow pathological cell Death
• in living tissue,
• Caused by progressive degradative action of
enzymes on the lethally injured cell
• Always surrounded by inflammation
 Morphology

• Cytoplasmic changes –
• Increased eosinophilia –
• glassy homogenous app of cell .
• Moth –eaten app of cyto
• Finally calcification of dead cells
 Contd…

• Nuclear changes-
• 1) karyolysis – fading of basophilia of
chromatin.
• 2) pyknosis – nuclear shrinkage
• 3) karyorrhexis – fragmentation of
pyknotic nucleus
Types of necrosis
 1) coagulative necrosis

• Denaturation of cytoplasmic proteins.

• Preservation of basic outline of coagulated
eosinophilic cells with absent nucleus.
• eg. myocardial infarction
• Characteristic of hypoxic death of cells in
all tissues except brain
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Click image to return
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 2) Caseous necrosis
• Foci of tuberculous infectn
• (caseous- white & cheesy)
• Amorphous granular debris enclosed in
inflammatory border kn as granulomatous
reaction
• Here tissue architecture is completely
destroyed (unlike coagulation necrosis)
 3)Liquefactive necrosis

• Focal bacterial infections (abscesses) &

hypoxic death of Brain
• Digestion of dead cells by hydrolytic
enzymes,transformation of tissue in a liquid
viscous mass
• If acute inflammation- material is creamy
yellow- presence of dead white cells- PUS
 4) Fat necrosis
• Seen in focal areas of fat destruction
• Enzymatic-
• Acute pancreatitis-– abdominal emergency.
• Identified by surgeon as fat saponification (chalky
white areas)
• Traumatic-
• Breast tissue or subcutaneous tissue
• shadowy outlines of necrotic fat cells with basophilic
calcium deposits surrounded by inflammatory reaction.
 Gangrene

• Ischemic necrosis - with superadded

infection by putrefactive microorganisms
• Common organisms -
• anaerobic bacteria( clostridia,
streptococci, bacteriods etc)
 Types of gangrene
• Dry gangrene-
• in atherosclerotic , senile or gangrene due to burger’s
disease (TAO)
• Wet gangrene-
• in DM, gangrene of bowel asso with volvulus,
intussuceptn or strangulated hernia.
• Black disclouration- due to comb of H2S released by
bacterial action on proteins with Hb iron.
Wet gangrene
 Apoptosis

• a form of cell death designed to

eliminate unwanted host cells through
activation of a coordinated, internally
programmed series of events
controlled by a set of gene products
 Physiologic apoptosis

• During embryogenesis
• Hormone –dependent involution in adult
• Cell deletion in proliferating population
 Pathologic apoptosis
• cell death in tumors
• cell injury in certain viral diseases.
• death of immune cells –after cytokine depletn &
deletn of autoreactive T –cells in thymus
• Cell death by injurious stimuli in low doses
• Atrophy of parenchymal organs after duct
obstruction
 Morphology in apoptosis

• 1) Cell shrinkage- small cell with dense

cyto, tightly packed organelles
• 2)chromatin condensation- peripheral
aggregatn of chromatin into dense masses,
• 3) Formation of cytoplasmic blebs &
apoptotic bodies
• 4) Phagocytosis of apoptotic cells or bodies
by adjacent healthy cells
 Contd…

• Plasma membranes remain intact during

apoptosis until the last stages.
• No inflammation
• H&E-Single cells or cluster of cells – app
round or oval mass of intensely eosinophilic
cytoplasm with dense nuclear chromatin
fragments.
 Biochemical features
• Death trigerring signals- can be lack of growth
factor or a ligand-receptor interaction or a specific
injurious agent.
• Control phase –
• direct control by adapter proteins
• Bcl-2 family of proteins in mitochondria.
• Execution phase –
• protein cleavage-by family of cystiene proteases-
caspases
• Phagocytosis of apoptotic bodies
 Contd…

• Phagocytic recognition- apoptotic cells

express --
• phosphatidylserine
• thrombospondin
I hear, I forget
I see, I remember
I do, I understand…