Yidnekachew s(MD)
- The normal cell is confined to a fairly normal
range of function & structure.
- It is nevertheless able to handle normal
physiologic demands, maintaining steady
state called homeostasis.
- More severe physiologic stresses & some
pathologic stimuli may bring about a number
of physiologic & morphologic cellular
adaptations.
 If the limits of adaptive response to a
stimulus are exceeded, or the cell is exposed
to an injurious agent or stress , a sequence of
events follows that is termed cell injury
 The stimuli might result in
a)
b)
c)
Reversible cell injury
Irreversible cell injury
Cell death

Cell death might be through
1) Apoptosis
2) Necrosis
Adaptation
Reversible Injury
Normal cell
Irreversible injury
Cell Death
- It is a new but altered steady state which
preserves the viability of the cell & modulates
its function as it responds to a stimuli.
 It is an increase in number of cells in an organ or
tissue , usually resulting in increased volume of the
tissue or organ.
 Hyperplasia takes place if the cellular population is
capable of synthesizing DNA or able to undergo
mitotic division (labile and stable cells).
 It usually, occurs together with hypertrophy
 It can be physiologic or pathologic.
1)


Hormonal hyperplasia which increases the
functional capacity of a tissue when needed.
Due to ↑local production of growth factors, ↑GF
receptors or activation of particular intracellular
signaling pathway.
In hormonal hyperplasia the hormones
themselves act as GF.
 e.g.
 Breast glandular hyperplasia during puberty
and pregnancy
 Uterine enlargement during pregnancy( due
to hyperplasia and hypertrophy of the smooth
muscle cells)
2. Compensatory hyperplasia, which increases
tissue mass after damage or partial resection
Eg.
- Liver regeneration after partial resection
- After unilateral nephrectomy , when the
remaining kidney undergoes compensatory
hyperplasia
 The exact mechanism of compensatory
hyperplasia is unknown but it is thought to
be
A) Proliferation of the remaining cells
B) Development of new cells from stem cells
 Most are caused by excessive hormonal stimulation
or growth factors acting on target cells
 eg. Endometrial hyperplasia (due to imbalance b/n
Estrogen and Progesterone),

benign prostatic hyperplasia (due to androgen)
 N.B. Its response to normal regulatory mechanisms
distinguishes benign pathologic hyperplasia from
cancer( Hyperplasia ceases when the inducing agent
is withdrawn but carcinomas progress despite
removal of the inducing agent)
 However, Pathologic hyperplasia constitutes a
fertile soil in which cancerous proliferation
may eventually arise.
e.g. Endometrial hyperplasia might progress to
carcinoma
 Hyperplasias are important in connective
tissue cells during wound healing in which
proliferation of fibroblasts and blood vessels
aid repair.
Normal bone marrow
biopsy
Hyperplastic marrow
Normal epidermis
Hyperplastic epidermis
-
It refers to an increase in the size of cells , resulting in
an increase in the size of the organ
-
The increase in size is due to synthesis of more
structural components
-
-
It can be physiologic or pathologic & is caused by
increased functional demand or by specific hormonal
stimulation
Example:
◦ The enlargement of the left ventricle in
hypertensive heart disease
◦ The increase in skeletal muscle during
strenuous exercise

During muscle hypertrophy a) alpha-myosin
heavy chain is replaced by beta –myosin
heavy chain which has slow and energy
conserving contraction.
b) Production of atrial natriuretic peptide by
both atrium and ventricle like fetal period( in
normal adult it is only produced by atrium)
 ANP decreases hemodynamic load by ↑renal
sodium excretion, ↓volume & pressure.
- Shrinkage in the size of the cell by loss of cell
substance
- Atrophy can be physiologic or pathologic
- Physiologic atrophy is common during early
development .
 E.g Early embryonic structures such as thyroglossal
duct undergo atrophy during fetal development.
 Uterus decreases in size shortly after parturition.


can be local or generalized
Common causes of atrophy are the following
◦ Decreased work load (Atrophy of disuse)
◦ Loss of innervation (denervation atrophy)
◦ Diminished blood supply
◦ Inadequate nutrition( e.g marasmus)
◦ Loss of endocrine stimulation (breast & Uterus
after menopause)
◦ Aging ( especially in organs with permanent cells
brain and heart)
Pressure atrophy

Mechanisms
1) Acid hydrolases like cathepsin in lysosomes
degrade endocytosed protein from
extracellular environment)
2) Ubiquitin-proteasome pathway
 For degrading cytosolic and nuclear proteins
 Protein to be degraded is conjugated with
ubiqutin and then degraded by proteasome.
 Thyroid hormones, TNF stimulate and insulin
inhibit this pathway.
Proliferative endometrium
form reproductive woman
Atrophic endometrium
from 75 years old woman
- It is a reversible change in which one adult
cell type is replaced by another cell type.
- It is adaptive substitution of cells that are
sensitive to stress by cell types better able to
withstand the adverse environment.
Squamous metaplasia
-The most common type
 Is when mucin producing columnar
epithelium is replaced by stratified
squamous epithelium.
1)
 The influences that predispose to metaplasia
, if persistent, may induce malignant
transformation in metaplastic epithelium
e.g.
a) Respiratory epithelium in heavy smokers
b) Stones in salivary gland and pancreatic
gland ducts
c)Vitamin A deficiency
2) Columnar metaplasia
 Metaplasia from squamous to columnar type
(Barret esophagus) may also occur.
 To diagnose BE presence of goblet cell is a MUST.
 Esophageal squamous epithelium is replaced by
intestinal – like columnar under the influence of
refluxed gastric acid(GERD)
 Cancers may arise that are typically glandular
carcinoma (adenocarcinoma)
BE
Low and High
grade dysplasia
Normal
ADENOCARCINOMA
3)Connective tissue metaplasia
It is the formation of cartilage , bone or
adipose tissue (mesenchymal tissue) in
tissues that normally do not contain these
elements.
e.g.
Myositis ossificans – bone formation in
muscle after bone fracture
Dysplasia
 Disordered cell growth or proliferation.
 This is farther down the road toward neoplasia, but
dysplasia is still a potentially reversible process.
 Cellular adaptations which can undergo
neoplastic transformation are
1)Hyperplasia -e.g. Endometrial hyperplasia into
endometrial carcinoma
2) Metaplasia -e.g. Columnar metaplasia of the
esophagus into adenocarcinoma
3)Dysplasia – e.g. Cervical epithelial dysplasia into
squamous cell carcinoma
 Cell injury results when cells are stressed so
severely that they no longer able to adapt or the
cells are exposed to inherently damaging agents.
 These alterations may be divided into the
following stages
1) Reversible cell injury – is manifested as
functional & morphologic changes that are
reversible if the damaging stimulus is removed
2) Irreversible injury or cell death – with continuing
damage , the injury becomes irreversible
41
 Oxygen deprivation
 Hypoxia is a deficiency of oxygen , which causes cell
injury by reducing aerobic oxidative respiration.
 Hypoxia should be distinguished from ischemia , which
is loss of blood supply from impeded arterial flow or
reduced venous drainage in tissue
Causes of hypoxia include
 Cardiorespiratory failure,
 Anemia,
 Carbon monoxide poisoning
 Thrombosis/Embolism
 Atherosclerosis
 Physical agents – mechanical trauma,
extremes of temperature, sudden changes in
atmospheric pressure
 Chemical agents & Drugs
 Infectious agents
 Immunologic reactions( HSR and autoimmune
diseases)
 Genetic derangements
e.g Sickle cell anemia, down’s syndrome
 Nutritional imbalance
e.g. PEM, vit deficiency, anorexia nervosa
 Principles that are relevant to most forms of
cell injury
 The cellular response to injurious stimuli
depends on the type of injury, its duration &
its severity.
 The consequences of cell injury depend on
the type, state, & adaptability of the injured
cell
Cell injury results from functional & biochemical
abnormalities in one or more of several essential
cellular components.
The most important targets of injurious stimuli are

1) Aerobic respiration involving mitochondrial
oxidative phosphorylation & production of ATP
2) The integrity of cell membranes
3) Protein synthesis
4) The cytoskeleton
5)The integrity of the genetic apparatus of the cell
 Biochemical mechanisms that are responsible
for cell injury induced by different stimuli
a) Depletion of ATP
b) Mitochondrial damage
c) Influx of intracellular calcium & loss of
calcium homeostasis
d) Accumulation of oxygen –derived free
radicals (oxidative stress)
e)Defects in membrane permeability
Reversible injury
-Two patterns of reversible cell injury can be
recognized under the light microscope
1) Cell swelling ( hydropic changes)
- The first manifestation of injury
- It is the result of loss of function of plasma
membrane energy-dependent ion pumps
 Cellular swelling (synonyms:
hydropic change,
vacuolar degeneration, cellular edema) is an acute
reversible change resulting as a response to nonlethal
injuries.
 It is an intracytoplasmic accumulation of water due to
incapacity of the cells to maintain the ionic and fluid
homeostasis.
 It is easy to be observed in parenchymal organs : liver
(hepatitis, hypoxia), kidney (shock), myocardium
(hypoxia, phosphate intoxication).
 It may be local or diffuse, affecting the whole organ
 Grossly -the affected organ is enlarged, pale and soft.
 Mic -The cells are enlarged, with a clear cytoplasm
(due to the presence of small clear or pale vacuoles,
with indistinct shape and limits) and a normal nucleus
in central position; blood capillaries are compressed,
explaining the organ's pallor.
.
2) Fatty change
- It is manifested by the appearance of small &
large lipid vacuoles in the cytoplasm & occurs
in hypoxic & various toxic injury.
- It is principally seen in cells involved in &
dependent on fat metabolism such as
hepatocytes & myocardial cells.
Intracellular accumulations of a variety of materials can occur in
response to cellular injury. Here is fatty metamorphosis (fatty change)
of the liver in which deranged lipoprotein transport from injury (most
often alcoholism) leads to accumulation of lipid in the cytoplasm of
hepatocytes.
- After irreversible cell injury cell death is
inevitable either by necrosis or apoptosis/
both of them may occur together.
Necrosis
- It refers to a spectrum of morphologic changes
that follow cell death in a living tissue resulting
from the progressive degradative action of
enzymes in lethally injured cells.
- Necrosis is cell death occurring in the setting of
irreversible exogenous injury.
- Necrotic cells aren’t able to maintain membrane
integrity & their contents leak out & elicit
inflammation in the surrounding tissue
Morphology
- The morphologic features of necrosis is the
result of denaturation of intracellular proteins
& enzymatic digestion of the cell.
- These processes require hours to develop so
there would be no detectable change
immediately.
 Necrotic cells show increased eosinophilia
due to loss the normal basophilia imparted by
RNA in the cytoplasm.
Nuclear changes
 Karyolysis – The basophilia of the nucleus
fades
 Pyknosis- Nuclear shrinkage & increased
basophilia
 Karyorrhexis – Nuclear fragmentation
Normal myocardium
Myocardium with
Coagulative necrosis
Morphologic patterns of necrosis
Coagulative necrosis
- Most often results from sudden interruption
of blood supply to an organ.
- It is, in early stages, characterized by general
preservation of tissue architecture atleast for
few days.
 The necrotic cells are removed by
fragmentation & phagocytosis of the cellular
debris by scavenger leukocytes & by action of
Proteolytic lysosomal enzymes brought in by
the immigrant white cells.
 Coagulative necrosis is characterstic of
hypoxic death of cells in all tissues except
brain.
Gross, cross section: A pale, whitish infarct is surrounded by a zone of hyperemia
(vascular dilatation).
Very low power glass slide: The area of coagulative necrosis is bright pink
compared to the lighter pink viable myocardium. The bluish areas on each side of
the necrotic zone represent the granulation tissue response to the necrosis.
This is the typical pattern with ischemia and
infarction (loss of blood supply and resultant
tissue anoxia). Here, there is a wedge-shaped
pale area of coagulative necrosis (infarction) in
the renal cortex of the kidney.
Liquefactive necrosis
 It is characterized by digestion of tissue.
 It shows softening & liquefaction of tissue.
 It characteristically results from ischemic
injury to the CNS.
 It also occurs in suppurative infections
characterized by formation of pus.

This is liquefactive
necrosis in the brain in
a patient who suffered
a "stroke" with focal
loss of blood supply to
a portion of cerebrum.
This type of infarction
is marked by loss of
neurons and neuroglial
cells and the formation
of a clear space at the
centre left.
Gangrenous necrosis
 It is due to vascular occlusion & most affects
the lower extremities & the bowel.
 It Is called wet gangrene if it is complicated
by bacterial infection which leads to
superimposed Liquefactive necrosis.
 Dry gangrene if there is only Coagulative
necrosis without Liquefactive necrosis.
Caseous necrosis
 It is type of necrosis most often seen in foci
of tuberculous infection.
 The term Caseous is derived from the cheesy
white gross appearance of the area of
necrosis
 On microscopic examination, the necrotic
focus appears as amorphous granular debris
enclosed within a distinctive inflammatory
border known as a granulomatous reaction
Fat necrosis
 Focal areas of fat destruction, typically
occurring as a result of release of activated
pancreatic lipases into the substance of the
pancreas & the peritoneal cavity. This occurs
in acute pancreatitis.
 The activated enzymes liquefy fat cell
membranes &The lipases split the triglyceride
contained with in fat cells.
 The released fatty acids combine with calcium
to produce grossly visible chalky white areas
(fat saponification)
 On histological examination , foci of shadow
outlines of necrotic fat cells with basophilic
calcium deposits & surrounded by an
inflammatory reaction
Pancreas with fat necrosis
Fat saponification with
calcification and
inflammation
Fibrinoid necrosis
Fibrinoid necrosis is caused by immune-mediated vascular
damage.
 It is marked by deposition of fibrin-like proteinaceous material
in arterial walls, which appears smudgy and eosinophilic on
light microscopy.

 Necrosis can be followed by
A)
B)
C)
Release intracellular enzymes into the blood
(creatinine kinase or troponin in myocardial
infarction ) –clinically very important
Inflammation or
Dystrophic calcification ( if necrotic cells
are not phagocytosed , they tend to attract
calcium salts )
- It is a pathway of cell death that is induced
by tightly regulated intracellular program in
which cells destined to die activate enzymes
that degrade the cells’ own nuclear DNA &
nuclear & cytoplasmic proteins
Apoptosis in physiologic situations
1) Programmed destruction of cells during embryogenesis
2) Hormone –dependent involution in the adult such as
endometrial cell breakdown during menstrual cycle , the
regression of the lactating breast after weaning
3) Cell deletion in proliferating cell populations
4) Death of host cells that have served their useful purpose
such as neutrophils in acute inflammatory response
5) Elimination of potentially harmful self reactive
lymphocytes
6) Cell death induced by cytotoxic T cells that serves
eliminate virus infected & tumor cells
Apoptosis in Pathologic conditions
 Cell death produced by a variety of injurious
stimuli such as radiation & cytotoxic
anticancer drugs
 Cell injury in certain viral diseases such as
viral hepatitis
 Pathologic atrophy in parenchymal organs
after duct obstruction
 Cell death in tumors
The following morphologic features
characterize cells undergoing apoptosis
 Cell shrinkage
 Chromatin condensation
 Formation of cytoplasmic blebs & apoptotic
bodies. The apoptotic cell undergoes
fragmentation into membrane bound
apoptotic bodies
 Phagocytosis of apoptotic cells or cell bodies
usually by macrophages
 On histologic examination , apoptosis
involves single cells or small cluster of cells .
 The apoptotic cells appear as a round or oval
mass of intensely eosinophilic cytoplasm with
dense nuclear chromatin fragments
Feature
Necrosis
Apoptosis
Cell size
Enlarged (swelling)
Reduced (shrinkage)
Nucleus
Pyknosis Karyorrhexis –
Karyolysis-
Fragmentation into
nucleosome size
fragments
Plasma membrane
Disrupted
Intact; altered
structure, especially
orientation of lipids
Cellular contents
Enzymatic digestion;
may leak out of cell
Intact; may be
released in apoptotic
bodies
Adjacent inflammation
Frequent
No
Physiologic or
pathologic role
Invariably pathologic
(culmination of
irreversible cell injury)
Often physiologic,
means of eliminating
unwanted cells; may
be pathologic
after some forms of
 Certain conditions are associated with
distinctive alteration in cell organelles or the
cytoskeleton.
Lysosomal catabolism
 Primary lysosomes are membrane bound
intracellular organelles that contain different
enzymes .
 They fuse with membrane bound vacuoles
that contain material to be digested forming
secondary lysosomes.
1) Heterophagy

It is the process of lysosomal digestion of
materials ingested from the extracellular
environment.
 Extracellular materials are taken up through
general process of endocytosis.
 Uptake of particulate material is known as
phagocytosis; uptake of soluble smaller
macromolecules is called pinocytosis.
 It is common in professional phagocytes such as
neutrophils & macrophages
2) Autophagy
It refers to lysosomal digestion of the cells’
own components
 Lysosomal enzymes digest all proteins & CHO
 but Some lipids may remain undigested by
lysosomal enzymes & persist in cells as
residual bodies
 eg. Lipofuscin pigment – It represents
undigested material derived from intracellular
lipid perioxidation .

 Autophagy is a common phenomenon
involved in
a) Removal of damaged organelles during cell
injury and the cellular remodeling of
differentiation
b) Cells undergoing atrophy induced by
nutrient deprivation or hormonal involution.
 Lysosomes may sequester abnormal
substances which cannot be completely
metabolised.
1) Hereditary lysosomal storage disorders,
caused by deficiencies of enzymes that
degrade various macromolecules,
 It result in the accumulation of abnormal
amounts of these compounds in the
lysosomes of cells all over the body,
particularly neurons, leading to severe
abnormalities.
2) Acquired or drug-induced (iatrogenic)
lysosomal diseases.
 E.g.
Chloroquine ↑ internal pH of the
lysosomes, thus inactivating its enzymes
↓Tissue damage in inflammatory reactions,
which are mediated in part by enzymes
released from leukocytes;
 This action is the basis of the use of the drug
(Chloroquine) in autoimmune diseases like
rheumatoid arthritis, SLE,…
 The same inhibition of enzymes, however,
can result in abnormal accumulation of
glycogen and phospholipids in lysosomes,
causing toxic myopathy and neuropathy.
 The smooth ER is involved in the metabolism of
various chemicals & cells exposed to these
chemicals show hypertrophy of the ER as an
adaptive response that may have functional
consequences.
 E.g. protracted use of barbiturates leads to a
state of tolerance , with decrease in the effects
the drug & the need to use increasing doses .
 This is due to hypertrophy of smooth ER
hepatocytes that metabolize the drug
of
 It consists of
1) Microtubules,
2) Microfilaments (thin actin and thick myosin)
3) Various classes of intermediate filaments
Microtubules
 Defect in microtubules can
a) Inhibit sperm motility causing male sterility
b) Immobilize the cilia of respiratory epithelium causing
interference with the ability to clear inhaled bacteria,
leading to bronchiectasis (kartagener’s syndrome –
immotile cilia syndrome )
c) Microtubules are also important for leukocyte
migration & phagocytosis.
 Drugs such as colchicine bind to tubulin & prevent the
assembly of microtubules .
 It is used in acute attacks of gout.
D) They are also important component of the mitotic
spindle .
 Drugs (eg vinca alkaloids) can be antiproliferative & so
act as antitumor agents
 Thin filaments

They are important for leukocyte movement
or for phagocytosis to occur adequately.
 Some drugs & toxins can affect these
processes
 Intermediate filaments
These components provide a flexible
intracellular scaffold that organizes the
cytoplasm & resist forces applied to the cell.
 Intermediate filaments are divided into five
classes
1) Keratin filaments (characteristics of
epithelial cells)
2) Neurofilaments (neurons)
3) Desmin filaments (muscle cells)
4) Vimentin filaments (connective tissue cells)
5) Glial filaments (astrocytes)

 Mallory body (alcoholic hyaline) is
eosinophilic intracytoplasmic inclusion in
liver cells that is characteristic of alcoholic
liver disease and it is composed
predominantly of keratin intermediate
filaments.
Intracellular Accumulations
 One of the manifestations of metabolic
derangements in cells is the intracellular
accumulation of abnormal amounts of various
substances
- They fall into three categories
1) A normal cellular constituent accumulated in
excess such as lipids, water, CHO or proteins
2) An abnormal substances , either exogenous
such as mineral or product of infectious
agents or endogenous such as product of
abnormal synthesis or metabolism
3) Pigments
 Accumulation may be permanent or transient
 It may be harmless to the cell or very toxic
 In cytoplasm(especially in phagolysosome) or
within nucleus
Lipids
Fatty change (Steatosis)
 It implies abnormal accumulation of
triglycerides within parenchymal cells
 It is caused by an imbalance between the
uptake, utilization, & secretion of fat
 It is often seen in liver because it is the major
organ involved in fat metabolism. It also
occurs in heart, muscle & kidney.
 The causes of steatosis include
A) Alcohol abuse and toxins( hepatotoxic),
B) Protein malnutrition(decrease apoprotein
production),
C) Diabetes mellitus, obesity and starvation
( increased FFA release) , &
D) Anoxia( prevent FFA oxidation)
Morphology
- Fatty change is most often seen in the liver &
heart
- It appears as clear vacuoles within
parenchymal cells.
- Intracellular accumulation of water or
polysaccharides (glycogen) may also produce
clear vacuoles .
- To distinguish b/n them, special stains are
used
 Fat – Sudan IV or oil Red-O both impart
orange –red color to the contained lipids
 Glycogen – periodic acid –Schiff (PAS)
 Water – when neither glycogen or fat can be
demonstrated , it is presumed to contain
water
Cholesterol
1) Atherosclerosis – Cholesterol & cholesterol
esters fill smooth muscle cells &
macrophages within the intimal layer of the
aorta & large arteries
2) Xanthoma – intracellular accumulation of
cholesterol within macrophages in the
subepithelial connective tissue of the skin &
in tendons.
3) Cholesterolosis – focal accumulation of
cholesterol laden macrophages in the lamina
propria of the gallbladder
Proteins
 Intracellular accumulation of proteins usually
appear as rounded, eosinophilic droplets,
vacuoles or aggregates in the cytoplasm
 Excess protein accumulation has various
causes
 Reabsorption droplets in proximal renal
tubules are seen in renal diseases associated
with protein loss in the urine (proteinuria)
 Synthesis of excessive amounts of normal
secretory protein such as plasma cells
engaged in active synthesis of
immunoglobulin.
 The ER becomes hugely distended, producing
large , homogenous eosinophilic inclusions
called Russell bodies.
Hyaline change
 The term hyaline refers to an alteration
within cells or in the extracellular space ,
which gives a homogenous, glassy, pink
appearance in routine histologic sections
stained with hematoxylin & eosin.
 Eg intracellular accumulation of protein
Pigments
 Pigments are colored substances , some of
which are normal constituents of cells (eg
melanin) whereas others are abnormal
 Pigments can be endogenous or exogenous
Exogenous pigments
 Accumulation of carbon or coal dust
blacken
lung tissue & involved lymph nodes called as
anthracosis.
 When inhaled , it is picked up by alveolar
macrophages & is transported through
lymphatic channels to the regional LNs in
tracheobronchial region.
 Aggregates of excess carbon dust (as in coal
miners) may induce a fibroblastic reaction or
emphysema & cause serious lung disease
known as coal worker’s pneumoconiosis.
 Tattooing is a form of localized exogenous
pigmentation of the skin.
 The pigments inoculated are phagocytosed
by dermal macrophages
Endogenous pigments
Lipofuscin
- It is an insoluble pigment & wear-and-tear or
A.
-
-
aging pigment
It is composed of polymers of lipids &
phospholipids complexed with protein
It is seen in cells undergoing slow, regressive
changes & is particularly prominent in liver &
heart of aging patients or patients with severe
malnutrition or cancer cachexia
In tissue sections, it appears as a yellow – brown
finely granular intracytoplasmic perinuclear
pigment
B. Melanin
 Melanin is a brownish-black pigment
produced by the melanocytes found in the
skin.
 Increased melanin pigmentation is caused by
sun tanning & certain diseases
e.g. nevus, or malignant melanoma.
 Decreased melanin pigmentation is seen in
albinism & vitiligo.
Albinism
Vitiligo
Melanoma cells with
intracytoplasmic melanin
C. Bilirubin
 Bilirubin is a yellowish pigment, mainly
produced during the degradation of
hemoglobin.
 Excess accumulation of bilirubin causes
yellowish discoloration of the sclera,
mucosa, & internal organs.
 Such a yellowish discoloration is called
jaundice.
 Jaundice is most often caused by
i. Hemolytic anemia
Hemolytic anemia is characterized by increased
destruction of red blood cells
ii.Biliary obstruction
This is obstruction of intrahepatic or
extrahepatic bile ducts. It can be caused by
gallstones.
iii. Hepatocellular disease
This is associated with failure of conjugation of
bilirubin.
D. Hemosiderin
 Hemosiderin is a hemoglobin-derived ,golden
yellow to brown, granular or crystalline
pigment in which form iron is stored in cells
& is identified by its staining reaction (blue
color) with the Prussian blue dye.
 In cells, It is stored in in form of ferritin .
When there is a local or systemic excess of
ion , ferritin forms hemosiderin granules
 Hemosiderin exists normally in small
amounts within tissue macrophages of the
bone marrow, liver, & spleen as physiologic
iron stores.
 It accumulates in tissues in excess amounts
in certain diseases.
 It can be local or systemic derangement.
- Local excesses result from gross or minute
hemorrhages eg bruise
- Systemic overload of iron can be seen

Increased absorption of dietary iron

Impaired use of iron

Hemolytic anemia

Transfusions
This excess accumulation is divided into 2
types
i. Hemosiderosis
 When accumulation of hemosiderin is
primarily within tissue macrophages & is not
associated with tissue damage, it is called
hemosiderosis.
ii. Hemochromatosis
 When there is more extensive accumulation
of hemosiderin, often within parenchymal
cells, which leads to tissue damage, scarring
& organ dysfunction, it is called
hemochromatosis.
 Primary (hereditary condition) or secondary
 Liver, pancreas and heart are commonly
affected.
 It is the abnormal tissue deposition of
calcium salts together with small amounts of
iron, magnesium and other mineral salts.
 There are two forms of pathologic
calcification
 1) Dystrophic calcification
 2) metastatic calcification
Dystrophic calcification
 It is occurs in previously damaged tissue
 It occurs in
a)
b)
c)
Areas of necrosis (Coagulative ,
Liquefactive, Caseous, Fat necrosis)
Atheroma of advanced atherosclerosis
Aging or damaged heart valves
 Typically, the serum calcium level is normal.
 Gross
 Whatever the site of deposition, it appears as
white granules or clumps, often felt as gritty
deposits.
 Microscopy
 By H & E stains it is basophilic, amorphous
granular sometimes clumped.
 Intracellular or extracellular or both
Heterotrophic bone might be formed at the
focus calcification.
 Psammoma bodies are dystrophic
calcifications with laminated configuration.

 Psammoma bodies can be seen in some
neoplastic conditions like
a)
b)
c)

Papillary thyroid carcinoma,
Serous papillary cyst adenocarcinoma of
ovary and
Meningioma.
Final common pathway of dystrophic
calcification is formation of crystalline
calcium phosphate mineral.
 The process has two steps
1)
2)


Initiation( nucleation)
Propagation
Dystrophic calcification is sure sign of
previous cell injury
It can result functional dysfunction
(narrowing heart valves and great vessels)
Metastatic calcification
 It occurs in normal tissue whenever there is
hypercalcemia.
 There are four principal causes of hypercalcemia
1) ↑secretion of parathyroid hormone(PTH) with
subsequent bone resorption (parathyroid
tumors and some lung carcinomas)
2) Destruction of bone tissue occurring with
primary tumors of bone marrow (multiple
myeloma) or diffuse skeletal metastasis(by breast
carcinoma,…)
 3) Vitamin D related disorders( Vit D
intoxication, sarcoidosis, idiopathic
hypercalcemia of infancy)
 4) Renal failure ( causing phosphate retention
resulting secondary hyperparathyroidism)
 Amyloid is a pathologic proteinaceous
substance deposited between cells in various
tissue & organs of the body in a wide variety
of clinical settings.
 Amyloidosis is not a single disease rather it is
a group of diseases having in common
deposition of similar–appearing proteins
 Clinical diagnosis depends on morphologic
identification of this distinctive
substance(Amyloid) in appropriate biopsy
specimens
 On light microscopy & standard tissue stains ,
amyloid appears as an amorphous ,
eosinophilic , hyaline, extracellular substance
with progressive accumulation, encroaches
on & produces pressure atrophy of adjacent
cells.
 To differentiate it from other proteins ,Congo
Red stain is used, it imparts a pink or red
color to tissue deposits under ordinary light
microscope.
 Under polarizing microscopy green
birefringence of the stained amyloid is seen.
Congo red stain by light
microscope
By polarizing microscopy
Physical & chemical nature of amyloid
- Amyloid material consists of mainly fibril
proteins with characteristics cross -β pleated
sheet conformation
The three most common forms of amyloid
proteins include
 AL (amyloid light chain) is derived from
plasma cells & contains immunoglobulin light
chains
 AA (amyloid-associated)
synthesized by liver
is protein
 Aβ amyloid is found in the cerebral lesions of
Alzheimer disease
Classification of Amyloidosis
1) Primary Amyloidosis
 It is usually systemic distribution & is
characterized by deposition of the AL type
 Most patients have some form of plasma cell
dyscrasia such as multiple myeloma.
2) Reactive systemic Amyloidosis
 The amyloid deposits in this pattern are
systemic in distribution & are composed of
AA protein
 It occurs secondary to an associated
inflammatory conditions like(Tuberculosis,
bronchoectasis , chronic osteomyelitis,
rheumatoid arthritis)
 Old age is a consequence of civilization
 Aging must be distinguished from mortality on the one
hand and from disease on the other.
 Death is a random event
 Even in the absence of specific diseases or vascular
abnormalities, beginning in the 4th decade of life there
is a progressive decline in many physiologic functions,
including such easily measurable parameters as
muscular strength, cardiac reserve, nerve conduction
time, pulmonary vital capacity, glomerular filtration,
and vascular elasticity.
 With age there are physiologic & structural
alteration in almost all organ systems.
 Aging in individuals is affected to great
extent by genetic factors, diet, social
conditions & occurrence of age related
diseases
 Aging –induced alterations in cells are an
important components of the aging the
organism
 Cellular aging is the result of a
a)
b)
Progressive decline in the proliferative
capacity & life span of cells
The effects of continuous exposure to
exogenous influences that result in
progressive accumulation of cellular &
molecular damage.
These include
 A number of cellular functions decline
progressively with age
 Reduction in oxidative phosphorylation &
synthesis of nucleic acids & structural &
enzymatic proteins , cell receptors &
transcription factors .
 Decreased capacity of uptake of nutrients &
repair of chromosomes
 Accumulation of Lipofuscin pigment as sign
of oxidative damage

Replicative senescence
 Cells have limited capacity for replication,this
may be due to a limited number of cellular
divisions that can take place.
 Telomeres are short repeated sequences of
DNA (TTAGGG) present at the linear ends of
chromosomes that are important for ensuring
the complete replication of chromosome ends
and protecting chromosomal termini from
fusion and degradation.
 An enzyme called telomerase, which
counteracts the tendency of the ends of
chromosomes to shorten with each cellular
division, may have decreased activity so that
the telomeric ends of chromosomes shorten,
and the ability of chromosomes to replicate is
lost.
 The process of programmed cell death
(apoptosis) may be part of a sequence of cell
maturation

Telomerase activity decreases with age
But cancer cells have maintained activity of
telomerase.
 Presence of genes that influence the aging
process
 Patients with Werner syndrome show
premature aging, and the defective gene
product is a DNA helicase — a protein
involved in DNA replication and repair
 Accumulation of metabolic & genetic damage
 Cellular life span can determined by the
balance b/n cellular damage resulting from
metabolic events occurring with in a cell &
counteracting molecular responses that can
repair the damage .
 One of these metabolic products are reactive
oxygen species whose damage increases with
age