CELLULAR RESPONSES

TO STRESS/NOXIOUS
 INTRODUCTION
 Cells exist in a state of homeostasis {balance between the internal and
external environment}.

 Alteration in any of the environment can lead to disruption. The

environmental alteration can be physiologic or pathologic.

 Cells respond to these environmental changes in the following ways:

 Adaptation 4. Aging
 Injury 5. Intracellular accumulations
 Death 6. Pathologic calcifications
FACTORS THAT INFLUENCETHE TYPE OF CELLULAR
RESPONSE
 Certain factors influence the type of response of a cell exhibit wghen exposed
to environmental changes.
 1. Agent related factors
Certain features of the noxious agent influence cellular responses
A. DURATION: Brief period of ischaemia can cause reversible injury, but
prolonged duration leads to irreversible injury or death.

B. DOSE; Moderate amount of pressure during weight-lifting can cause muscle

hypertrophy, while severe amount of pressure can cause muscle injury.

C. VIRULENCE/NATURE: Some agents are so toxic that they can only cause
cell injury. Eg Acid.
 HOST-RELATED FACTORS

 1. Type of cell: Based on proliferative ability, cels in the body

can be divided into three groups{labile, stable and permanent
cells}. Labile cells respond to stress by hyperplasia, while
permanent cells (eg skeletal muscle) respond by hypertrophy.
 Another example is that Cells adapt differently to oxygen needs.
Heart muscle adapt better to hypoxia than brain cells

 2, Genetic make upof the individual: Exposure of individuals

to similar dose of a toxin can lead to the death of one individual,
while the oter survives.
FACTORS THAT CAUSE
CELULAR RESPONSES
 Stress/stimuli that can cause environmentalalterations can be
classified into physiologic or pathologic stimuli
 1. PHYSIOLOGIC STRESS
 They are changes in the environment which are within
acceptable ranges. It includes
a. changes in demand(Increased or decreased demand can
influence cellular response)
b. Changes in cellular stimulation by hormones or growth factors
increased or decreased)
c. Chronic irritation: Eg Normal level of gastric acid irritating the
oesophagus
 2. PATHOLOGIC STIMULI
They are stimuli that cause severe disturbances in the environment. It can be
A. Inherited conditions
B. Acquired conditions:
i. Chemicals(drugs,industrial chemicals)
ii. Hypoxia
iii. Physical factors (temperature extremes{cold,heat}, mechanical {trauma,falls},
Electrical
iv. Microbes
v. Immunologic factors(Hypersensitivity reactions, autoimmunr disease}
vi. Nutritional imbalances{excess or deficiency}
CELLULAR ADAPTATION
 INTRODUCTION
 It is a type of cellular response characterized by reversible changes in sie,
number, phenotype and metabolic activity of the cells following changes in the
environment.
 Cells can adapt to environmental changes by modifying mrtabolism or growth
pattern.
 Adaptation leads to attainment of new steady state aimed at preserving cellular
functions and survival
 Cells may adapt by changes in protein synthesis( increased or decreased},
enzyme induction (increased or decreased], product secretion(increased or
decreased) and metabolic regulation (down-regulation of enzyme).
CLASSIFICATION OF CELLULAR
ADAPTATION
 There are four major types
 Hypertrophy Hyperplasia
 Atrophy Metaplasia
 A. HYPERTROPHY
 It is the increase in size of an organ/tissue due to increase in size of
the constituent cells.
 TYPES OF HYPERTROPHY
 Based on the cause;
i. Physiologic hypertrophy: it is hypertrophy resulting from
changes in physiologic requirement
ii. Pathologic hypertrophy: it is hypertrophy resulting from
disease
 Mechanism of hypertrophy
 i. increased protein synthesis
 Ii. Switch from adult to fetal type protein. Eg In skeletal muscle there is a
switch from beta-isoform of myosin (adult type) to alpha isoform(fetal type)
 Iii. Induction of repressed fetal/embryonic genes
 CAUSES
 i. Increased functional demand eg exercise, Hypertension
 Ii. Increased hormonal stimulation
 EXAMPLES
 i. physiologic hypertrophy. Eg Skeletal muscle enlargement following weight
lifting, Uterine enlargement in pregnancy
 Ii. Pathologic hypertrophy eg Cardiac enlargement following hypertension,
smooth muscular hypertrophy following gastric pyloric stenosis
 HYPERPLASIA
 It is the increase in the size of an organ or tissue due to the increase in the
number of constituent cells. It occurs in rapidly dividing cells
(labile calls)
 It can coexist with hypertrophy in the same organ/tissue.
 TYPES
 i. physiologic hyperplasia: it has two types
 A. Hormonal physiologic hyperplasia (hormone induced)
 B. compensatory physiologic hyperplasia (occurring as a compensation to
organ damage)
 Ii. Pathologic hyperplasia
 CAUSES
 I. Hormonal/growth factor stimulation
 Ii. Partial resection. Eg liver resection
 Mechanism of hyperplasia
 Stimulation of cell proliferation by growth factors or resected tissue
 Examples
 i. Physiologic hyperplasia
 Breast enlargement at puberty or pregnancy
 Liver regeneration following partial hepatectomy
 Ii. Pathologic hyperplasia
 Endometrial hyperplasia (oestrogen related0
 Benign prostatic hyperplasia (androgen related)
 Warts (viral-induced proliferation}

 NOTE.: Conditions where hypertrophy and hyperplasia coexist are

 Uterine enlargement at pregnancy
 Benign Prostate enlargement
 METAPLASIA
 It is the replacement of an adult/well-differentiaited cell by another adult/well-differentiated cell
type. It usually occurs in response to chronic irritation. The new cell that occur is better able to
withstand the adverse environment.
 TYPES
 i. Epithelial metaplasia: it is metaplasia involving epithelium. there are two types:
 A. Squamous metaplasia: it is the replacement of columnar or transitional epithelium by stratified
epithelium
 B. Columnar metaplasia: It is the replacement of squamous epithelium by columnar epithelium
 Ii. Mesenchymal metaplasia: it is metaplasia involving mesenchymal cells
 CAUSES;
 I. smoking
 Ii. Stones
 Iii. Micro-organism eg Schistosoma hematobium
 Iv. Vit A Deficiency
 E. Gastric acid
 MECHANISM:
 Reprogramming of stem cells
 EXAMPLES
 i. Epithelial metaplasia

 A. Squamous metaplasia
 -Squamous metaplasia in bronchi following smoking or vit A deficiency
 -Squamous metaplasia in excretory ducts(salivary glands, bile ducts,
pancreas) following stones
 -Squamous metaplasia in urinary bladder following schistosomiasis

 B. Columnar metaplasia eg Columnar metaplasia in oesophagus following

gastro-oesophageal reflux disease) {Barrett’s oesophagus}
 2. Mesenchymal metaplasia eg. Osteoid metaplasia in muscle (myositis
ossificans), chondroid metaplasia.
 ATROPHY
 It is the decrease in te size of an organ/tissue due to the decrease in size or
number of the constituent cells. Usually the cell loss in atrophy is replaced by
fatsor fibrous tissue.
 CLASSIFICATION
 i. Physiologic atrophy: it is atrophy occurring during physiologic condition. It can be
seen in normal development or hormonal withdrawal.
-Breast atrophy after cessation of lactation
-Uterine shrinkage after birth
-Thyroglossal duct atrophy during fetal development

ii. Pathologic atrophy: It is atrophy associated with pathologic conditions.

CAUSES
i. Hormonal withdrawal v. Immobilisation
ii. Aging vi. Malnutrition
iii. Ischaemia
iv. Denervation eg poliomyelitis
 Mechanism of atrophy
 i. Decreased protein synthesis
 Ii. Increased protein degradation eg proteolysis by ubiquitin-proteasome
pathway
 Iii. Organelle degradation: It involves autophagic vacuoles fuse with
lysosome. It usually forms residual bodies called lipofuscin
 EXAMPLES
 Skeletal muscle atrophy in malnutrition or following poliomyelitis
 Senile brain atrophy
 NOTE:
 1. Atrophic tissue/organ is not dead, rather it has diminished function
 2.Lipofuscin is a brownish pigment found in membrane-bound vesicles called
residual bodies. It is seen in atrophy.
 CELL INJURY
 It is the damage to a cell due to exposure to noxious stimuli. It results from a
biochemical and functional abnormalities in the several cellular components.
 It occurs in two scenarios:
i. When adaptive limit exceeded
Ii. Exposure in inherent injurious stimuli
 CAUSES
i. Chemicals v. Nutritional imbalance
Ii Hypoxia vi. Aging
Iii. Immunologic factors vii. Genetic factors
Iv. Physical factors
 TYPES:
Based on the ability to return to normal:
i. Reversible cell injury
Ii. Irreversible cell injury
 CELLULAR TARGETS
They are components to cells usually targeted during cellular injury. They are : i.
Membranes{cell memb, lysosomal memb, mitochondrial memb)
ii. Mitochondria
iii.proteins
iv. DNA
MECHNISM OF CELL INJURY:
i. ATP depletion v.Protein misfolding
ii. Mitochondrial damage vi. Free radical injury
iii. Calcuim influx vii. Membrane damage
iv. DNA damage
 ATP DEPLETION
 It is a mechanism of cellular injury that caused by decreased ATP production. ATP is the
currency of the cell is required for cellular processes. It is usually associated with
hypoxic and chemical injury.
 ATP is produced in cells in two major pathways:
 i. Oxidative phosphorylation of ADP (occurs in the mitochondria). It is the most
important source of ATP production and called aerobic respiration
 Ii. Glycolytic pathway (aka ANAEROBIC RESPIRATION)
 MECHANISM:
 ATP depletion leads to the following:
 A. FAILURE OF SODIUM PUMP:
Normally, sodium pump is responsible for pumping 2Na out of cells and bringing in 3
potassium ion. Thus failure of sodium pump leads to sodium accumulation inside the
cells leading to the obligatory water into the cells. He consequences are cellular
swelling and dilation of endoplasmic reticulum.
 B. FAILURE OF CALCUIM PUMP
 Normally, calcium pump is a pump on cell membrane responsible for pumping calcium
from the cell into extracellular space. It helps to keep intracellular calcium
concentration low. Thus failure of the pump leads to accumulation of calcium, The
consequences of calcium accumulation are enzyme inactivation or apoptosis.

 C. INCREASED ANAEROBIC GLYCOLYSIS

 The depletion of ATP leads to increase in ADP which stimulates anaerobic glycolysis.
The consequences are Lactic acid accumulation ( because lactate is end product of
anaerobic glycolysis), decreased PH ( It results of decreased enzyme activity and
nuclear clumping) and glycogen depletion.

 D. DETACHMENT OF RIBOSOMES
 There is detachment of ribosomes from the endoplasmic reticulum. The consequences
are decreased protein synthesis and lipid depiosition.
DIAGRAM OF ATP DEPLETION MECHANISM
 FREE RADICAL MECHANISM
 Free radicals are highly reactive chemicals species with unpaired electron in their
outer orbit. They react with organic and inorganic molecules initialing autocatalytic
reactions (ie reactions in which the molecule they react with become free radicals)

 TYPES
 i. Oxygen derived free radicals
-hydroxyl radicals (OH)
-Superoxide (O2)
-Peroxynitrite anion(ONOO)
 Ii. Non-oxygen derived radicals eg Hydrogen radicals, carbon trichloride radical
 Normally, free radicals are produced in cells following some physiologic processes but
the body has system in place to remove the free rdicals. This prevents accumulation
of free radicals.
 When the balance between production and removal of free radicals is tilted in favour of
production is the oxidative stress.
 PRODUCTION OF FREE RADICALS:
 i. Reduction-oxidation reactions eg oxidative phosphorylation, inflammation, xanthine oxidase
 Ii. Hydrolysis of water eg radiation. It gives rise to hydroxyl radical and hydrogen radicals.
 Iii. Metabolism of exogenous chemicals/drugs eg carbon trichloride radicals from carbon
tetrachloride
 Iv. Transition metal reaction(iron, copper) eg fenton reaction

 REMOVAL:
Free radical removal occur in two major ways:
i.NON-ENZYMATIC
-spontaneous decay eg superoxide decays to oxygen and hydrogen peroxide in the presence of
water
-Transport proteins: They remove free radicals by chelating them, eg transferrin, ceruloplasmin
binds to iron and copper respectively.
-Antioxidant eg Vit A,C and E.
-Storage proteins Eg Ferritin
 Ii. ENZYMATIC MECHANISM:
 The following enzymes are implicated in the removal of free radicals namely:
-Catalase: it reduces hydrogen peroxide radical to oxygen and water
-Superoxide dismutase: It reduces superoxide radicals.
-Gluthathione peroxidase
 MECHANISM:
 Free radicals cause cell injury by reacting with three major components of the cells
namely lipids, proteins and DNA. It causes the following:
i. Lipid peroxidation ( it results in membrane damage)
Ii. protein oxidation( it results in enzyme inactivation and membrane damage)
Iii. DNA oxidation(it results in DNA breaks and DNA adducts}
 REVERSIBLE CELL INJURY
 It is a type of cell injury capable of reversing once the initiating stimuli is removed. It is
usually caused by mild stimuli and transient stimuli.
 CAUSES
 As mentioned under cell injury.
 MORPHOLOGY
 The two most common morphologic finding are cellular swelling and fatty change.
 A. CELLULAR SWELLING:
 It is the first manifestation of Reversible cell injury in most cells. It is usually difficult to
appreciate on light microscopy, but can be seen grossly if many cells are involved. It is also
called cloudy swelling.
 GROSS:
 i. Organ is enlarged
 Ii. Organ is pale
 LIGHT MICROSCOPY::
 Affected cells are swollen with indistinct cell margin. Also, clear vacuoles in cytoplasm may
be seen called vacuolar degeneration or hydropic changes
 ULTRASTRUCTURAL FEATURES:
i.Plasma membrane changes (blebs, blunting. Microvilli loss)
Ii. Mitochondria changes(mild swelling, small amorphous densities)
Iii.Endoplasmic reticulum changes(dilation, detachment of ribosomes and
polysomes)
 2.FATTY CHANGE
It is accumulation of fats in parenchymal cells. It is seen in hypoxic or toxin induced
cell injury. It affects liver (mainly), heart and muscle.
 GROSS:
Organ is enlarged and greasy in appearance
 LIGHT MICROSCOPY:
i. small clear vacuoles in cytoplasm ( Cells with vacuolated cytoplasm due to fat are
called foam cells}
Ii. Clear cytoplasm with eccentric nuclei
 IRREVERSIBLE CELL INJURY
 It is a type of cell injury that continues even after removal of initiating stimulus. It is
usually caused by severe or persistent noxious stimuli.
 CAUSES; As mentioned under cell injury
 MORPHOLOGY
 Ultrastructural features
 i. severe mitochondrial swellings
 Ii. Large amorphous densities in mitochondria
 Iii. Lysosomal swelling
 CONCLUSION:
 The point of no return at which reversible becomes irreversible is unclear because
there is no reliable morphologic or biochemical correlates of irreversibility. It is thought
to be significant membrane damage (plasma or lysosomal) and significant
mitochondria dysfunction. Ultimately, regardless of efforts taken irreversibly injured
cell will die (cell death).
CELL DEATH
 It is the cessation of life in a cell. It is associated with cessation of biochemical functions
and morphologic changes in a cell.
 TYPES: i. Necrosis ii. Apoptosis
 NECROSIS
 It is the death of cells in a living tissue resulting from either protein denaturation or
enzymatic digestion of cellular components. It is unprogrammed and associated with
inflammation of surrounding tissue
 TYPES
i. Coagulative necrosis iv. Fibrinoid necrosis
Ii. Liquefactive necrosis v.Fat necrosis
Iii. Caseous necrosis
 A. COAGULATIVE NECROSIS
It is a type of necrosis characterized by preservation of architecture of dead tissue. The
preservation of architecture lasts for several days. It is caused by ischaemia.: It occurs by
protein denaturation. The light microscopy shows intensely eosinophilic cells without
nucleus.
 LIQUEFACTIVE NECROSIS
 It is a type of necrosis characterized by digestion of dead cells forming a liquid
substance. It is caused by enzymatic digestion. It is caused by ischemia of brain and
infections. A typical example of liquefactive necrosis is pus formation in tissues.
 NOTE: Ischaemia causes necrosis in most tissues except brain where it causes
liquefactive necrosis.
 C. CASEOUS NECROSIS
 It is a type of necrosis characterized by presence of cheese like materials in
necrosed tissue.it is seen in caseating granulomatous inflammation eg Tuberculosis,
Tuberculoid leprosy
 D, FAT NECROSIS
 It is a type of necrosis characterized by necrosis of fat cells by enzymes. It is caused
by acute pancreatitis with involvement of peritoneum. In this situation , lipase
released by pancreatic cells liquefy membranes of fat cells in the peritoneum to
release fatty acids which combine with calcium to form calcium soaps (chalky-white
appearance). (FAT SAPONIFICATION)
 Grossly, it is chalky white deposits in the peritoneum. Microscopically, it hsows
necrosed fat cells with basophilic deposits surrounded by inflammatory reactions.
 E. FIBRINOID NECROSIS
 It is a type of necrosis characterized by presence of fibrin-like materials. It is usually seen in
immune-mediated reactions. It commonly occurs in walls of blood vessels. Microscopy shows
amorphous eosinophilic materials in affected tissue

 MORPHOLOGY OF NECROSED TISSUE

 i. MICROSCOPY:
-INCREASED CYTOPLASMIC EOSINOPHILIA
-NUCLEAR CHANGES – KARYOLYSIS(LYSIS OF NUCLEUS)
 Ii. Ultrastruture:
-Discontinuation in membranes (plasma and organelle membrane)
-Large amorphous densities in mitochondria.

FATE OF NECROSED TISSUE

i.Removal by phagocytes (neutrophil or macrophages)
ii. Dystrophic calcifications
iii. Gangrene : it is the death of cells due to vascular occlusion or superimposition of infection
on dead tissue
 APOPTOSIS
 It is a programmed cell death resulting from the activation of tightly regulated intracellular
suicide program.
 CLASSIFICTATION
 i.Pathologic apoptosis:
it is apoptosis occurring in physiologic conditions. In situations like this, apoptosis is used to
maintain steady-state number of cells in tissue by removal of cells that are no longer needed.
 Ii. Physiologic apoptosis
It is apoptosis occurring in disease conditions
MECHANISM
There are two major pathways for activation of apoptosis based on the origin of the signal for
apoptosis. They are namely intrinsic and extrinsic pathways.
A. INTRINSIC PATHWAY (AKA MITOCHONDRIAL PATHWAY)
It is apoptotic pathway arising from signals within the cells usually mitochondria.it is
initiated by release of pro-apoptotic proteins (eg cytochrome c) from the mitochondria into the
cytoplasm. It is associated with activation of caspase 9. It is usually caused by conditions
associated with DNA damage such as radiation, toxins and free-radicals.
 B. EXTRINSIC PATHWAY (AKA DEATH RECEPTOR PATHWAY)
 It is the pathway of apoptosis initiated by binding of molecules to cell surface
receptors eg death receptors such as Fas it involves activation of caspase 8 and 10
 Regardless of whether it is intrinsic or extrinsic pathway they converge at common
pathway
 C. COMMON PATHWAY
It involves the activation of executioner caspases (caspase 3 and 6). They are
called executioner caspases because they activate enzymes that cause cell death. The
enzymes are Dnases (cause DNA fragmentation) and proteases (cause cytoskeletal
protein destruction).
 REMOVAL OF APOTOTIC (DEAD) CELLS
 The apoptotic cells form blebs which fall off forming fragments called apoptotic
bodies. The bodies are phagocytosed by macrophages.
 By definition, apoptotic bodies are membrane bound fragments derived from
apoptotic cells. A typical example is councilman bodies seen in viral hepatitis.
 MORPHOLOGY OF APOPTOSIS
 i. Light microscopy
Oval mass of intensely eosinophilic cytoplasm with fragments
 Ii. Ultrastructure
-cell shrinkage
-cytoplasmic blebs (surface blebs)
-apoptotic bodies
-nuclear changes-karyorrhexis(nuclear fragmentation),or pyknosis(nuclear shrinkage)
 EXAMPLES OF APOPTOSIS
 I. PHYSIOLOGIC APOPTOSIS
-Cell death during embryogenesis
-involution of hormone-dependent tissue following hormone withdrawal eg endometrial
cells death during menses, ovarian follicle atresia in menopause
-Regression of lactating beast after weaning
-Lymphocytic loss in thymus, bone marrow and germinal centre of lymph node
 Ii. PATHOLOGIC APOPTOSIS
-Cell death during acquired DNA damage eg Radiation induced death
-cell death due to misfolded protein accumulation eg degenerative diseses of
CNS
-viral induced cell death eg CD 4 destruction by HIV
-Pathological atrophy following duct obstruction
DIFFERENCE BETWEEN APOPTOSIS AND
NECROSIS
PARAMETER APOPTOSIS NECROSIS

mechanism Programmmed Unprogrammmed

Number of cells Single cell Group of cells

Inflammation of surrounding absent Present

tissue

Cell membrane Intact Distorted/damaged

Cell content Cell content don’t leak out Leaks out

INTRACELLULAR
ACCUMULATIONS
It is the abnormal accumulation of substances within the cells. The
accumulation can occur in the cytoplasm, lysosome or nucleus. The
substance that accumulate may be:
i. Normal cell constituents eg macromolecules (lipids, carbohydrate and
protein)
Ii. Abnormal substances: it can either be endogenous products eg lipofuscin or
exogenous eg pigments.

 CLASSIFICATION
 Based on the type of substances accumulating
i. Lipid accumulations eg steatosis
Ii, Carbogydrate accumulations eg glycogen storage disease
Iii. Protein accumulations iv pigments
 MECHANISM:
 Four mechanism are implicated:
i. Inadequate removal of Normal endogenous substances: due to excessive production Eg Russel
bodies or Excessive filtration (eg proximal tubule accumulation and Eg liver steatosis
Ii. Enzyme defects/ deficiency eg lysosomal storage diseases It can lead to formation of toxic
metabolites (eg homogentisic acid) and absence of end=products (eg albinism)
Iii. Defects in protein folding or transport: it is usually due to gene mutation.eg mutated alpha 1-
antitrypsin results in slow folding of AAT causing accumulation of partially folded AAT which cannot
be excreted. This results in low level of of AAT in plasma causing clinical condition. Alzheimer's
disease is due to protein misfolding.
Iv. Ingestion of indigestible materials: Abnormal exogenous substance not digestible by enzymes
eg Tattos, Anthracosis (carbon particle accumulation)

CONSEQUENCES:
The effect of substance accumulation are
i. No cellular injury (early stage and scant accumulations)
ii. Reversible cell injury
iii. Irreversible cell cell injury
iv. Cell death
LIPID ACCUMULATIONS

 It is the accumulation of lipids witin cells

 The types of lipids implicated are
 Triacylglyceride eg Steatosis (fatty change, liver is commonest
site)
 Cholesterol and its esters eg Atherosclerosis, Niemann-pick
disease
 Phospholipids eg Gauchers disease
 Gangliosides eg Tay saccchs
 Mucopolysacharides eg mucopolysaccharidosis
 They form part of lysosomal storage diseases (diseases due to
deficiency of lysosomal enzyme and accumulation occur in
lysosome)
 EARLY PHASE OF
FATTY LIVER LATER STAGE (NUCLEI
NORMAL LIVER (NUCLEUS IS HAS BEEN PUSHED
CENTRAL) TO THE SIDE
CARBOHYDRATE ACCUMULATION
 It is the abnormal accumulatyion of carbohydrate in cells.

 It is seen in patients with abnormality in glucose and glycogen metabolism

 Examples are glycogen storage diseases, glucose accumulation in proximal

tubules in Diabetes Mellitus

 Site include liver, skeletal muscle and proximal tubule cells

 It appears as clear vacuoles in affected cells. It can be confused for lipid

accumulations in the liver.
CARBOHYDRATE ACCUMULATIONS
PROTEIN ACCUMULATION

 It is the abnormal accumulation of proteins within cells

 It includes
 RUSSEL BODIES (It is immunoglobulin accumulation in plasma
cells. Seen in multiple myeloma
 Mallory body : It is a pinkish material in liver cells. it is due ton
intermediate filament accumulation in liver cells. Seen in
alcoholic liver disease
 Protein accumulation in proximal tubule cells : it is seen in
marked proteinuria eg nephrotic syndrome
KIDNEY SHOWING NORMAL PROXIMAL TUBULE SHOWING
PROXIMAL TUBULES AND PROTEIN ACCUMULATION
GLOMERULUS
 RUSSEL BODY (pinkish
MALLORY BODY (Pinkish accumulations in plasma
materials in liver cells) cells
 PIGMENT ACCUMULATION
 Pigments are coloured substances.
 TYPES:
 Endogenous pigment
 melanin accumulation (Skin hyperpigmentation in Addison”s disease, Melasma)
 hemosiderin accumulation eg bronze skin appearance in Haemochromatosis
 lipofuscin known as wear and tear pigment . It is a brownish pigment seen in some cells. It
is not injurious to the celi, but a sign of lipid peroxidation, atrophy and aging.
 It is seen in heart and liver of elderly people.
 homogentisic acid eg Ochronosis (Homogentisic acid deposition in tissues such as cartilage.
It is caused by deficiency of Homogentic acid oxidase
 Exogenous pigment
 They are pigments from outside the body
 carbon particles eg Anthracotic patches in lungs, Coal worker pneumoconiosis
 Tattoo Pigments
 HAEMOCHROMATOSIS
MELASMA (FOCAL AREA OF (BRONZE SKIN DUE TO
FACIAL HYPERPIGMENTATION. HAEMOSIDERIN
SEEN IN PREGNANCY) DEPOSITION)
 OCHRONOSIS
LIPOFUSCIN (GROWNISH PERI- (HOMOGENTISIC ACID
NUCLEAR PIGMENT) DEPOSITION)
PATHOLOGICAL CALIFICATION
 It is the abnormal deposition of calcium salts in tissues. This excludes the deposition
of calcium in bones or enamel because they are considered normal.

 CLASSIFICATION
 Bases on the nature of tissue:

 1. DYSTROPHIC CALCIFICATION
 It is a type of pathologic calcificatiob characterised by deposition of calcium salts in
dead or dying tissue.

 2. METASTATIC CALCIFICATION
 It is a type of pathologic calcification characterized by calcium deposition in normal
tissue.
 A. DYSTROPHIC CALCIFICATION
 Definition as stated above. It can occur intra- , extracellular or both.
 CAUSES
 -Any condition that causes necrosis
 -Aging
 -Damaged heart valves
 -Dead parasites
 - tumours
 PATHOGENESIS
 It involves: i. initiation phase ii. Propagation phase
 i. initiation phase:
 The different aetiologic agents causes cell membrane damage releasing of
phospholipid. Phosphatase associated with membranes act on the phospholipids to
give rise to phosphate group and lipids. Calcuim ion then binds to phosphate to form
calcium salts.
 Ii. PROPAGATION PHASE:
 Repeated cycles of calcium binding to phosphate occur producing deposits on the membrane. Structural
changes occur in the deposits forming microcrystals. The crystals are propagated by calcium binding to
phosphates leading to crystal growth.
 MORPHOLOGY
 GROSS:
-White granules or clumps in affected tissues
-Gritty sensation when scrapped with scalpel
 Microscopy:
-Basophilic amorphous structures
-psammoma bodies (concentric lamellated appearance)
-Dumb-bell appearance (seen in asbestosis)
NOTE: Psammoma bodies are seen in papillary cancers (eg thyroid, renal,ovarian cancers) and
meningioma
EXAMPLES:
-Calcification in coagulative or fat necrosis
-Calcification in atheromatos plaques
_ Calcifications in aging vessels
-Calcification in cancers
CALCIFICATION (BLUISH PSAMOMMA BODY (CONCENTRIC
STRUCTURES ) CALCIFICATION)
 METASTATIC CALCIFICATIONS
As defined earlier. It is usually associated with hypercalcemia.
 CAUSES
Any condition that causes hypercalcemia such as
i. Hyperparathyroidism
Ii. Bone destruction such as malignancy of bone (primary and secondary),
conditions with accelerated bone turnover eg Paget's disease, immobilization
Iii. Vit D related disorders eg Vit D intoxication, sarcoidosis
Iv. Renal failure
 MECHANISM:
 Increased precipitation of calcium phosphate leads to formation of
microcrystals
 MORPHOLOGY
Grossly, any tissue in the body can be affected but mainly kidney, lungs,
gastric mucosa and arteries. Microscopically it is similar to dystrophic
DIFFERENCE BETWEEN DYSTROPHIC
AND METASTATIC CALCIFICATIONS
PARAMETER DYSTROPHIC METASTATIC

TYPE OF TISSUE DYING OR DEAD TISSUE NORMAL TISSUE

SERUM CALCUIM LEVEL NORMAL INCREASED

DISTRIBUTION USUALLY LOCALISED OCCURSIN MANY

TISSUE
PATHOGENESIS INCREASED BINDING OF INCREASED
PHOSPHATASE TO PRECIPITATION OF
NEROTIC TISSUE CALCUIM PHOSPHATE
FOLLOWED BY CALCUIM DUE TO
BINDING HYPERCALCEMIA
 CELLULAR AGING
 It is the progressive decline in functions of a cell over time. It results from progressive
accumulation of sub-lethal DNA damage over time.
 CAUSES
 It can be as a result of genetic abnormalities eg Lamin A gene mutation (implicated in progeria),
WRN gene mutation (Werner syndrome (implicated in adult progeria), Bloom syndrome (BLM
gene mutation)
 Environmental factors.( Sun-exposure, smoking, excessive alcohol and Stress
 MECHANISM
 Cellular aging occur via any of the following:
i. Increased Cellular senescence:
Cellular senescence is permanent cell arrest. It occurs when a cell has exhausted its ability to
divide.
Normally, a cell has a fixed number of times it can divide (about &) times) after it, the cell
enters senescence.
Aging occurs when there is increased cellular senescence.
Senescence occurs by shortening of telomere and activation of tumour suppressor genes
 ii. Increased misfolded proteins
During protein synthesis in cells, sometimes protein misfolding can occur. These
misfolded proteins can cause apoptosis, thus they are usually destroyed.
Impaireddegradation of misfolded protein cam lead to aging.
iii.Increasd DNA damage:
it can be due to conditions damaging DNA ( Radiation, chemicals, free radicals and
biologic agents ) or defect in DNA repair mechanism.
Evidence in support of this mechanism is the fact that most cases of prematyre aging
involve inherited conditions that affect DNA repair genes, eg werner syndrome, Bloom
syndrome.
iv. Increased calorie intake: Excessive ating increases risk of premature aging while
Calorie restriction (eating less) decreases aging

 CONCLUSION:
Cellular aging results from progressive accumulation of sublethal injury. The rate of aging
depends on balance between cumulative metabolic damage and response to the damage.
SAM BERNS AT 17 YEARS. ONE OF
THE POPULAR CASE OF PROGERIA