Cellular Injury and Adaptations

CELL INJURY & CELLULAR ADAPTATIONS
Dr. Vigneshwara N
Junior Resident,
IMCH.
Introduction
• Cell injury is defined as a variety of stresses a cell encounters as a result

of changes in its internal and external environment.
• Virchow’s Cellular theory of disease (1859): diseases occur due to

abnormalities at the level of cells
• The cellular response to stress may vary and depends upon the
following:
– The type of cell and tissue involved.
– Extent and type of cell injury
Cellular Response
ETIOLOGY OF CELL INJURY
Genetic causes Acquired causes

• Developmental defects: • Hypoxia and ischaemia
Errors in morphogenesis • Physical agents
• Cytogenetic (Karyotypic) defects: • Chemical agents and drugs
chromosomal abnormalities • Microbial agents
• Single-gene defects: • Immunologic agents
Mendelian disorders • Nutritional derangements
• Multifactorial inheritance disorders • Aging
• Psychogenic diseases
• Iatrogenic factors
• Idiopathic diseases.
Acquired causes
Oxygen deprivation
HYPOXIA
Ischemia ( loss of blood supply ).
Inadequate oxygenation (cardiorespiratory

failure).
Loss of oxygen carrying capacity of the blood ( anemia or CO poisoning

).
HYPOXIC INJURY
 Loss of oxidative phosphorylation and ATP generation by mitochondria.
 Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation,

resulting in aerobic glycolysis
 Depleted glycogen.
 Reduced intracellular pH: Lactic acid and inorganic phosphate.
 Clumping of nuclear chromatin.
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PHYSICAL AGENTS
 Trauma
 Heat
 Cold
 Radiation
 Electric shock
CHEMICAL AGENTS AND DRUGS
• Endogenous products: urea
• Exogenous agents
• Therapeutic drugs: hormones
• Nontherapeutic agents: lead or alcohol
FREE RADICAL INITIATION
 Absorption of energy (UV light and x-rays)

 Oxidative metabolic reactions
 Enzymatic conversion of exogenous

.
chemicals or drugs (CCl4>CCl3 )
 Oxygen-derived radicals
 Superoxide
INFECTIOUS AGENTS
 Viruses
 Rickettsiae
 Bacteria
 Fungi
 Parasites
Abnormal immunological reactions
The immune process is normally protective but in certain circumstances

the reaction may become deranged.
– Hypersensitivity to various substances can lead to anaphylaxis or to more
localized lesions such as asthma.
– In other circumstances the immune process may act against the body cells -
autoimmunity.
Nutritional imbalances
 Protein-calorie deficiencies are the most examples of

nutrition deficiencies.
 Vitamins deficiency.
 Excess in nutrition are important causes of morbidity and

mortality.
 Excess calories and diet rich in animal fat are now strongly
implicated in the development of atherosclerosis.
 Obesity alone leads to an increased vulnerability to certain disorders,

such as atherosclerosis, coronary heart disease, diabetes mellitus
Aging
• Programmed aging whereby after a defined number of divisions the cell

undergoes terminal differentiation.
• Development of an increasing population of cells irreversibly committed
to senescence and death.
• Increased susceptibility to somatic mutation
and a build-up of errors leading to an eventual’ error catastrophe.
• Faulty DNA repair mechanisms.
CELLS REACT TO ADVERSE
INFLUENCES
 Cellular adaptation
1. Hyperplasia
2. Hypertrophy
3. Atrophy
4. Metaplasia
5. Dysplasia
 Reversible injury
1. intracellular edema,
2. fatty change,
3. hyaline change,
4. amyloidosis,
5. mucoid degeneration,
6. pathologic pigments
 Irreversible injury and dying: Necrosis, Gangrene followed by pathological

calcification
CELLULAR RESPONSE TO ADVERSE EFFECT
CELLULAR ADAPTATION
Cellular ADAPTATION
• Adaptations are reversible changes in the size, number, phenotype,

metabolic activity, or functions of cells in response to changes in their
environment
• Cells must constantly adapt, even under normal conditions, to changes
in their environment.
• These physiological adaptations usually represent responses of cells to
normal stimulation by hormones or endogenous chemical substances.
– For example, as in the enlargement of the breast and induction of lactation
by pregnancy.
Types of Adaptation
• Pathologic adaptations may share the same

underlying mechanisms, but they provide the cells
with the ability to survive in their environment and
perhaps escape injury.
• Cellular adaptation is a state that lies intermediate

between the normal, unstressed cell and the
injured, overstressed cell.
Cellular Adaptation
• Cell can adapt themselves by undergoing 5 different conditions

1. Hyperplasia
2. Hypertrophy
3. Atrophy
4. Metaplasia
5. Dysplasia
Hyperplasia
An increase in the number of
cells in an organ or tissue,
which may then have
increased volume.
Types of Hyperplasia : Physiological
a. Hormonal : influence of hormonal stimulation

• hyperplasia of the female breast epithelium at puberty or in pregnancy.
• pregnant uterus
• normal endometrium after a normal menstrual cycle.
• Prostatic hyperplasia in old age
b. Compensatory: hyperplasia occurring following removal of part of an organ or a

contralateral organ in paired organ
• Regeneration of the liver following partial hepatectomy
• Regeneration of epidermis after skin abrasion
• Following nephrectomy on one side, there is hyperplasia of nephrons of the other
kidney.
Types of Hyperplasia : Pathological
• Excessive stimulation of hormones or growth

factors
– Endometrial hyperplasia
– wound healing - of granulation tissue due to
proliferation of fibroblasts and endothelial cells.
– skin warts from hyperplasia of epidermis due to human
papilloma virus.
– Pseudocarcinomatous hyperplasia of the skin
Hypertrophy
Definition
An increase in the size of cells, and with such change, an increase in
the size of the organ.
Types
• Physiologic: Physiologic growth of the uterus during pregnancy involves
both hypertrophy and hyperplasia
.
• Pathologic causes: increased workload,
hormonal stimulation and growth factors stimulation.
(hypertrophy of heart the most common stimulus is chronic hemodynamic
overload)
Hypertrophied heart
（ From ROBBINS BASIC PATHOLOGY ， 2003 ）
Normal uterus gravid uterus
Physiologic hypertrophy of the uterus during pregnancy.A, gross appearance of a

normal uterus (right) and a gravid uterus (left) that was removed for postpartum
bleeding,
（ From ROBBINS BASIC

PATHOLOGY ， 2003 ）
The relationship between
hyperplasia and hypertrophy:
Although hypertrophy and hyperplasia are two distinct processes,

frequently both occur together, and they well be triggered by the
same mechanism.
Atrophy
Definition:
Acquired loss of size due to reduction of cell size or number of
parenchymal cells in an organ.
Types: Physiologic or Pathological
Left Normal facebook.com/notesdental

Right Atrophy
Physiologic atrophy
• A normal process of aging in

some tissues, which could be
due to loss of endocrine
stimulation or arteriosclerosis.
– Atrophy of lymphoid tissue in
lymph nodes, appendix and
thymus.
– Atrophy of gonads after
menopause.
– Atrophy of brain with
aging.
Pathologic atrophy.
• Starvation atrophy.
• Ischaemic atrophy
• Disuse atrophy.
• Neuropathic atrophy.
• Endocrine atrophy
• Pressure atrophy.
• Idiopathic atrophy
Metaplasia
Definition
Metaplasia is a reversible change in which one adult cell
type is replaced by another adult cell type.
Causes
• Changes in environment
• Irritation or inflammation
• Nutritional
Types of Metaplasia
• There are basically 2 types of metaplasia
• EPITHELIAL METAPLASIA
– Squamous metaplasia: changes in bronchus, uterine endocervix,
gallbladder, prostate, renal pelvis and urinary bladder
• vitamin A deficiency: squamous metaplasia in the nose, bronchi, urinary tract,
lacrimal and salivary glands
– Columnar metaplasia: Intestinal metaplasia in healed chronic gastric
ulcer and Barrett’s oesophagus
• MESENCHYMAL METAPLASIA
– Osseous metaplasia.
– Cartilaginous metaplasia.
Squamous metaplasia in bronchitis
Schematic diagram of columnar to squamous metaplasia
（ From ROBBINS BASIC PATHOLOGY ， 2003 ）
DYSPLASIA
• disordered cellular development.
• also referred to as atypical hyperplasia
• Epithelial dysplasia is characterised by cellular proliferation and cytologic changes
– Increased number of layers of epithelial cells
– Disorderly arrangement of cells from basal layer to the surface layer
– Loss of basal polarity i.e. nuclei lying away from basement membrane
– Cellular and nuclear pleomorphism
– Increased nucleocytoplasmic ratio
– Nuclear hyperchromatism
– Increased mitotic activity.
• The two most common examples of dysplastic changes are the uterine cervix and
respiratory tract
Differences between Metaplasia and Dysplasia
Reversible Injury
• Intracellular edema,
• Fatty change,
• Hyaline change,
• Amyloidosis,
• Mucoid Degeneration,
• Pathologic Pigments
Intracellular edema
• Also known as cloudy swelling.
• Accumulation of watery fluid in cells.
• Commonest and earliest form of cell injury
• Caused by bacterial toxins, chemicals, poisons, burns, high fever, intravenous
administration of hypertonic glucose or saline.
• Impaired regulation of sodium and potassium at the level of cell
membrane.
• Morphologic change
• Gross features: cloudy swelling
• M/S Changes: Parenchymal cells swollen.
Left Granularity change in kidney Right Hydropic change
Fatty change
Definition
There is the accumulation of fat in non-fatty cells.
Also known as steatosis
Morphologic change
Gross features:
The organ enlarges and becomes yellow, soft, and greasy.
M/S:
An Fatty change appears as clear vacuoles within
parenchymal cells.
Fatty change: Liver
• Since this organ plays a central role in fat

metabolism,
• The accumulation of fat in toxic conditions can
be very dangerous.
• Depending upon the cause and amount of
accumulation, fatty change may be
• mild and reversible,
• or severe producing irreversible cell injury and
cell death
Etiology
• Conditions with excess fat
– Obesity
– Diabetes mellitus
– Congenital hyperlipidaemia
• Liver cell damage:
– Alcoholic liver disease (most common)
– Starvation
– Protein calorie malnutrition
– Chronic illnesses (e.g. tuberculosis)
– Acute fatty liver in late pregnancy
– Hypoxia (e.g. anaemia, cardiac failure)
– Hepatotoxins (e.g. carbon tetrachloride, chloroform, ether, aflatoxins and other poisons)
– Drug-induced liver cell injury (e.g. administration of methotrexate, steroids, CCl4, halothane
anaesthetic, tetracycline etc)
– Reye’s syndrome
MORPHOLOGIC FEATURES
• Grossly
– the liver in fatty change is enlarged with a
tense, glistening capsule and rounded
margins.
– The cut surface bulges slightly and is pale-
yellow to yellow and is greasy to touch
• Microscopically
– characteristic feature is the presence of
numerous lipid vacuoles in the
cytoplasm of hepatocytes.
Fatty change: Heart
• It occurs in two patterns,
• Prolonged moderate hypoxia causes intracellular

deposits of fat,
• grossly apparent bands of yellowed myocardium alterations with bands
of darker, red-brown, uninvolved myocardium (tigered effect).
• Profound hypoxia or diphtheritic myocarditis, the

myocardial cells are uniformly affected.
tigered effect
Prof. （ From CIBA PHARMAafCecEbUooTc.IkoCmAn/LtoPseRedOtnDlaUCTS, INC. 1948 ） Orr
Fatty change: Kidney
• In most cases fatty change is confined to the epithelium of the convoluted tubules,
• but in severe poisoning it may affect all structures including the glomerule.
Causes:
 Poisons. e. g. carbon tetrachloride, phosphorus (liver)
 Chronic alcoholism (liver)
 Infections
 Congestive cardiac failure
 Severe anaemia
 Ischaemia
 Diabetes mellitus
 Malnutrition and wasting disease.
Hyaline change
• Not a distinct chemical
entity.
• Various histological or
cytological alterations
characterized by
homogeneous, glasslike
appearance in
hematoxylin and eosin-
stained sections.
Hyalinization Arteriolar Sclerosis
• It may be intracellular or
extracellular.
INTRACELLULAR HYALINE
• Its mainly seen in epithelial cells.
• Hyaline droplets in the proximal tubular epithelial cells: excessive reabsorption of

plasma proteins.
• Hyaline degeneration of rectus abdominalis muscle called

Zenker’s degeneration, occurring in typhoid fever.
• Mallory’s hyaline represents aggregates of intermediate filaments in the

hepatocytes in alcoholic liver cell injury.
• Nuclear or cytoplasmic hyaline inclusions seen in some viral infections.
• Russell’s bodies representing excessive immunoglobulins in the rough endoplasmic

reticulum of the plasma cells
INTRACELLULAR HYALINE
Intracellular hyaline as
Russell’s bodies in the
plasma cells. The cytoplasm
shows pink homogeneous
globular material due to
accumulated
immunoglobulins.
EXTRACELLULAR HYALINE
• Extracellular hyaline is seen in connective tissues.

• A few examples of extracellular hyaline change are as under:
– Hyaline degeneration in leiomyomas of the uterus
– Hyalinised old scar of fibro-collagenous tissues.
– Hyaline arteriolosclerosis in renal vessels in hypertension and diabetes mellitus.

– Hyalinised glomeruli in chronic glomerulonephritis.
– Corpora amylacea are rounded masses of concentric hyaline laminae seen in the
prostate in the elderly, in the brain and in the spinal cord in old age, and in old
infarcts of the lung.
Extracellular Hyaline
Extracellular hyaline deposit in leiomyoma uterus.

The centres of whorls of smooth muscle and
connective tissue show pink homogeneous
hyaline material (connective tissue hyaline)
EPITHELIAL MUCIN
• Following are some examples of functional excess of epithelial mucin:

• Catarrhal inflammation of mucous membrane (e.g. of respiratory
tract, alimentary tract, uterus).
• Obstruction of duct leading to mucocele in the oral cavity and
gallbladder.
• Cystic fibrosis of the pancreas.
• Mucin-secreting tumours (e.g. of ovary, stomach, large bowel etc)
Epithelial mucin
Mucinous cystadenoma of the

ovary showing intracytoplasmic
mucinous material in the epithelial
cells lining the cyst
CONNECTIVE TISSUE MUCIN
• A few examples of disturbances of connective tissue mucin are as

under
– Mucoid or myxoid degeneration in some tumours e.g. myxomas,
neurofibromas, fibroadenoma, soft tissue sarcomas etc
– Dissecting aneurysm of the aorta due to Erdheim’s medial degeneration

and Marfan’s syndrome.
– Myxomatous change in the dermis in myxoedema.
– Myxoid change in the synovium in ganglion on the

wris
Connective tissue mucin
Myxoid change in
neurofibroma
Amyloid degeneration
• Extracellular deposition of fibrillar

proteinaceous substance called
amyloid
– a ‘waxy substance’ composed essentially of
an abnormal protein
– Particularly around the supporting
fibres of blood vessels and basement
membranes.
• Associated with a number of inherited

Primary Amyloidosis of kidneys
and inflammatory disorders
Structure of Amyloid
Electron micrograph of 7.5-10 nm Congo red staining shows an apple-green

amyloid fibrils. birefringence under polarized light, a
diagnostic feature of amyloid.
Types of Amyloid
• Based on the biochemical analysis, its composed of 2 main
types of complex proteins.
• Fibril proteins: comprise about 95% of amyloid.
– AL (amyloid light chain) protein
– AA (amyloid associated) protein
– Other proteins (Transthyretin (TTR), Aβ2-microglobulin
(Aβ2M), β-amyloid protein (Aβ), Immunoglobulin heavy chain
amyloid (AH))
• Non-fibrillar components: which include P-component
predominantly; constitute the remaining 5% of amyloid
– Amyloid P (AP)-component
– Apolipoprotein-E (apoE)
– α-1 anti-chymotrypsin.
– Protein X.
PATHOGENESIS OF AMYLOIDOSIS
• Result of immunologic mechanisms.
• Multifactorial and that different
mechanisms are involved in different
types of amyloid.
• Fundamentally a disorder of protein
misfolding.
• More than 20 (at last count, 23) different
proteins can aggregate and form fibrils
with the appearance of amyloid
• The dye Congo red binds to these fibrils
and produces a red-green dichroism
(birefringence)
– commonly used to identify amyloid
desposits in tissues
PATHOGENESIS OF AMYLOIDOSIS
CLASSIFICATION OF AMYLOIDOSIS
• Based on cause
– Primary : with unknown cause and the deposition is in the
disease itself
– Secondary: as a complication of some underlying known
disease
• Based on extent of amyloid deposition
– Systemic (generalised) involving multiple organs
– Localised amyloidosis involving one or two organs or sites
• Based on histological basis
– Pericollagenous: corresponding in distribution to primary
amyloidosis
– Perireticulin: corresponding in distribution to secondary
amyloidosis
• Based on clinical location,
– Pattern I: involving tongue, heart, bowel, skeletal and
smooth muscle, skin and nerves),
– Pattern II: principally involving liver, spleen, kidney and
adrenals
– Mixed pattern : involving sites of both pattern I and II
• Based on tissues in which amyloid is deposited,
– Mesenchymal : organs derived from mesoderm
– Parenchymal: organs derived from ectoderm and
endoderm
• Based on precursor biochemical proteins, into specific
type of serum amyloid proteins.
(AL= Amyloid light chain; AA= Amyloid-associated protein; Aβ2M= Amyloid β2-
microglobulin; ATTR= Amyloid transthyretin; APrP=Amyloid of prion proteins, Aβ= β-
amyloid protein).
STAINING CHARACTERISTICS OF
AMYLOID
• STAIN ON GROSS
– Virchow
– frozen/paraffin section
– Lugol’s iodine imparts
mahogany brown colour to
the amyloid
– on addition of dilute sulfuric
acid turns
blue.
• H&E
– extracellular, homogeneous,
structureless
– Eosinophilic hyaline
material, especially in
relation to blood vessels
DIAGNOSIS OF AMYLOIDOSIS
• BIOPSY EXAMINATION: commonest and
confirmatory method for diagnosis in a
suspected case of amyloidosis.
• IN VIVO CONGO RED TEST: confirmatory
• OTHER TESTS
– supportive of amyloid disease
– electrophoresis, immunoelectrophoresis of urine
and serum, and bone marrow aspiration
Pathological effects of
Amyloidosis
AMYLOID DEPOSITION
Pressure on adjacent cells Blood vessels
Atrophy Narrowing Increased permeability
Transudation of
protein out of vessels
MORPHOLOGIC FEATURES OF
AMYLOIDOSIS OF ORGANS
• Different organs shows variation in morphologic pattern,
some features are applicable in general to most of the
involved organs
• Most commonly amyloid deposits appear at the contacts
between the vascular spaces and parenchymal cells
• Grossly
– affected organ is usually enlarged, pale and rubbery
– Cut surface shows firm, waxy and translucent parenchyma
– positive staining with the iodine test.
• Microscopically
– the deposits of amyloid are found in the extracellular locations,
initially in the walls of small blood vessels producing microscopic
changes and effects,
– the deposits are in large amounts causing macroscopic changes
and effects of pressure atrophy.
Amyloidosis of kidney
The kidney is small and

pale in colour.
Sectioned surface
shows loss of cortico-
medullary distinction
(arrow) and pale, waxy
translucency.
Amyloidosis of kidney
The amyloid deposits are seen mainly in the glomerular capillary tuft. The
deposits are also present in peritubular connective tissue producing atrophic
tubules and amyloid casts in the tubular lumina, and in the arterial wall
producing luminal narrowing.
Amyloidosis of the spleen
Lardaceous amyloidosis of the spleen
The sectioned surface shows

presence of plae waxy
translucency in a map-like
pattern
Amyloidosis spleen
A, The pink acellular amyloid material is seen in the red pulp causing
atrophy of while pulp.
B, Congo red staining shows Congophilia as seen by red-pink colour.
C, When viewed under polarising microscopy the corresponding area
shows apple-green birefringence.
Amyloidosis of the liver
A, The deposition is extensive in the

space of Disse causing compression
and pressure atrophy of hepatocytes.
B, Congo red staining shows
congophilia which under polarising
microscopy.
C, shows apple-green birefringence.
Pathologic Pigments
• Pigments are coloured
substances present in
most living beings
including humans.
• There are 2 broad
categories of
pigments:
endogenous and
exogenous.
Endogenous Pigmentation
• Melanin Melanin-like pigment
– •Generalised – Alkaptonuria
hyperpigmentation: Addison’s – Dubin-Johnson syndrome
disease, Chloasma, chronic
arsenical poisoning • Haemoprotein-derived
– Focal hyperpigmentation: pigments
Cäfe-au-lait spots, Peutz- – Haemosiderin
Jeghers syndrome, Melanosis – Acid haematin (Haemozoin)
coli, Melanotic tumours, – Bilirubin
Lentigo , Dermatopathic
lymphadenitis – Porphyrins
– Generalised • Lipofuscin (Wear and tear
hypopigmentation: Albinism pigment)
– Localised hypopigmentation:
Leucoderma, Vitiligo , Acquired
focal hypopigmentation,
leprosy, healing of wounds,
DLE, radiation dermatitis
Brown atrophy of the heart. The lipofuscin pigment granules are seen in the
cytoplasm of the myocardial fibres, especially around the nuclei.
Compound naevus showing clusters of benign naevus cells in the dermis as well as in
lower epidermis. These cells contain coarse, granular, brown-black melanin pigment
EXOGENOUS PIGMENTS
• Inhaled pigments
– Atmospheric pollutants and of smokers
– Pneumoconiosis: occupational lung diseases
– Anthracosis: deposition of coal
• Ingested pigments
– Argyria : silver compounds - brownish pigmentation in the skin, bowel,
and kidney.
– Burtonian Lines: Chronic lead poisoning - blue lines on teeth at the
gumline.
– Melanosis coli : cathartics (stimulates evacuation of the bowels)
– Carotenaemia: yellowish-red colouration of the skin - ingestion of
carrots which contain carotene.
• Injected pigments (Tattooing): India ink, cinnabar and carbon
deposited in dermis
EXOGENOUS PIGMENTS
Anthracosis lung: There is presence of abundant coarse black carbon pigment in

the septal walls and around the bronchiole
Irreversible Injury
Irreversible Injury
• Cell death is a state of irreversible injury,
• It may occur in the living body as a local or focal
change: autolysis, necrosis and apoptosis
• The changes that follow it: gangrene and
pathologic calcification
NECROSI
• S area of death of tissue
Defined as a localised
followed by degradation of tissue by hydrolytic
enzymes liberated from dead cells.
• It is invariably accompanied by inflammatory
reaction.
• Various agents such as hypoxia, chemical and
physical agents, microbial agents, immunological
injury, etc
• Two essential changes characterise irreversible
cell injury in necrosis of all types
– Cell digestion by lytic enzymes
– Denaturation of proteins
Types of Necrosis
Morphologically, there are five types of
necrosis
• Cogulative
• Liquefaction
• Caseous
• Fat
• Fibrinoid
COAGULATIVE NECROSIS
• It’s a form of tissue necrosis in which the
component cells are dead but the basic tissue
architecture is preserved for at least several days.
• The affected tissues take on a firm texture
• Presumably the injury denatures not only
structural proteins but also enzymes and so
blocks the proteolysis of the dead cells
– as a result, eosinophilic, anucleate cells may persist
for days or weeks
– Ultimately, the necrotic cells are removed by
phagocytosis of the cellular debris.
• Most common type of
necrosis
• Mostly from sudden
cessation of blood flow
(ischaemia)
• Less often from bacterial and
chemical agents.
• It’s characteristic of infarcts
(areas of ischemic necrosis)
in all solid organs except the Coagulative necrosis of the left
brain. ventricular wall
• The organs commonly
affected are the
heart, kidney, and
spleen
Morphology
• Gross
– foci of coagulative necrosis in the early stage are pale, firm, and
slightly swollen.
– With progression, they become more yellowish,
softer, and shrunken.
• Microscopically
– the hallmark of coagulative necrosis - the conversion of normal
cells into their ‘tombstones’
• outlines of the cells are retained so that the cell type but their
cytoplasmic and nuclear details are lost.
– The necrosed cells are swollen and appear more eosinophilic
than the normal, along with nuclear changes described above.
– But cell digestion and liquefaction fail to occur
– Eventually, the necrosed focus is infiltrated by inflammatory
cells
– And the dead cells are phagocytosed leaving granular debris and
fragments of cells
Infarct Kidney
The affected area on right shows cells with intensely eosinophilic cytoplasm of
tubular cells but the outlines of tubules are still maintained.
The nuclei show granular debris.
The interface between viable and non-viable area shows nonspecific chronic
inflammation and proliferating vessels
LIQUEFACTION (COLLIQUATIVE)
NECROSIS
• Due to ischaemic injury and bacterial or fungal
infections
• degradation of tissue by the action of powerful
hydrolytic enzyme.
• The common examples are infarct brain
and abscess cavity.
• Whatever the pathogenesis, liquefaction completely
digests the dead cells, resulting in transformation of
the tissue into a liquid viscous mass.
• If the process was initiated by acute inflammation, the
material is frequently creamy yellow and is called pus
LIQUEFACTION NECROSIS
Morphology
• Gross
– The affected area is soft with liquefied centre
containing necrotic debris.
– Later, a cyst wall is formed.
• Microscopically,
– the cystic space contains necrotic cell debris and
macrophages filled with phagocytosed material.
– The cyst wall is formed by proliferating capillaries,
inflammatory cells, and gliosis (proliferating glial cells)
in the case of brain
– proliferating fibroblasts in the case of abscess cavity
LIQUEFACTION NECROSIS
Liquefactive necrosis brain

The necrosed area on right side of the field shows a
cystic space containing cell debris, while the surrounding
zone shows granulation tissue and gliosis.
CASEOUS NECROSIS
• found in the centre of foci
of tuberculous infections.
• It combines features of
both coagulative and
liquefactive necrosis.
• term "caseous" (cheese-
like) is derived from the
friable yellow-white
appearance of the area of
necrosis
CASEOUS NECROSIS
Morphology
• Grossly
– foci of caseous necrosis,
– as the name implies, resemble dry cheese and are soft,
granular and yellowish.
– This appearance is partly attributed to the histotoxic effects of
lipopolysaccharides present in the capsule of the tubercle
bacilli, Mycobacterium tuberculosis.
• Microscopically
– the necrosed foci are structureless, eosinophilic, and contain
granular debris
– The surrounding tissue shows characteristic granulomatous
inflammatory reaction
• Consisting of epithelioid cells with interspersed giant cells of Langhans’
or foreign body type
• And peripheral mantle of lymphocytes.
CASEOUS NECROSIS
Caseous necrosis lymph node

There is eosinophilic, amorphous, granular material, while the periphery shows
granulomatous inflammation.
FAT NECROSIS
• Refers to focal areas of fat destruction
– Acute pancreatic necrosis,
– traumatic fat necrosis commonly in breasts
• Pancreatic enzymes that have leaked out of
acinar cells and ducts
– liquefy the membranes of fat cells in the
peritoneum.
– lipases split the triglyceride esters contained within fat
cells to fatty acid.
– These combines calcium to produce grossly visible
chalky white areas (fat saponification)
FAT NECROSIS
Fat necrosis in acute pancreatitis.

The areas of white chalky deposits represent foci of fat necrosis with
calcium soap formation (saponification) at sites of lipid breakdown in the
mesentery.
Morphology
• Grossly
– fat necrosis appears as
yellowish-white and firm
deposits.
– Formation of calcium
soaps imparts the
necrosed foci firmer and
chalky white appearance.
• Microscopically
– the necrosed fat cells Formation of calcium soaps
have cloudy appearance is identified in the tissue
– surrounded by an sections as amorphous,
inflammatory reaction. granular and basophilic
material
FIBRINOID NECROSIS
• Characterised by deposition of fibrin-like
material which has the staining properties of
fibrin.
• It is encountered in various examples of
immunologic tissue injury
– immune complex vasculitis,
– autoimmune diseases,
– Arthus reaction
• Arterioles in hypertension, peptic ulcer
FIBRINOID NECROSIS
Fibrinoid necrosis in an artery in a patient with polyarteritis nodosa.

The wall of the artery shows a circumferential bright pink area of necrosis with protein
deposition and inflammation (dark nuclei of neutrophils).
Morphology
• Microscopically
– identified by brightly
eosinophilic, hyaline-like
deposition in the vessel
wall.
– Necrotic focus is
surrounded by nuclear
debris of neutrophils
(leucocytoclasis)
– Local haemorrhage may Fibrinoid necrosis in autoimmune vasculitis.
occur due to rupture of The vessel wall shows brightly pink
the blood vessel. amorphous material and nuclear fragments
of necrosed neutrophils
Gangrene
• A form of necrosis of tissue with superadded
putrefaction.
• All types of gangrene, necrosis undergoes liquefaction
by the action of putrefactive bacteria.
• It may be caused either ischemic or inflammatory
• Coagulative Necrosis due to ischaemia
– gangrene of the bowel,
– gangrene of limb
• Gangrenous or necrotising inflammation: primarily
inflammation provoked by virulent bacteria resulting in
massive tissue necrosis.
– Gangrenous appendicitis,
– Gangrenous stomatitis (noma, cancrum oris)
Types of Gangrene
• 2 main forms of
gangrene
• Dry gangrene
• Wet Gangrene
– Gas gangrene: a
kind of wet
gangrene
Dry Gangrene
• begins in the distal part of a limb due to ischaemia.
• The gangrene spreads slowly upwards until it reaches a
point where the blood supply is adequate to keep the
tissue viable.
• A line of separation is formed at this point between
the gangrenous part and the viable part.
– Toes and feet of an old patient due to arteriosclerosis.
– Thromboangiitis obliterans (Buerger’s disease),
– Raynaud’s disease,
– Trauma
– Ergot poisoning
Dry
Gangrene
Dry gangrene
• Grossly
– the affected part is dry, shrunken
Morphology and dark black, resembling the
foot of a mummy.
– It is black due to liberation of
haemoglobin from haemolysed
red blood cells which is acted
upon by
hydrogen disulfide (H2S) produced
by bacteria resulting
in formation of black iron sulfide.
– The line of separation usually
brings about complete separation
with eventual falling off of the
gangrenous tissue if it is not
removed surgically
• Histologically
– Necrosis with smudging of the
tissue.
– The line of separation consists of
inflammatory granulation tissue
Wet Gangrene
• Naturally moist tissues and organs such as the
mouth, bowel, lung, cervix, vulva.
• develops rapidly due to blockage of venous, and
less commonly, arterial blood flow from
thrombosis or embolism.
• The affected part is stuffed with blood which
favours the rapid growth of putrefactive bacteria.
• The toxic products formed by bacteria are
absorbed causing profound systemic
manifestations of septicaemia, and finally death.
Wet Gangrene
• Diabetic foot
– high sugar content in
the necrosed tissue
which favours growth
of bacteria.
• Bed sores
– bed-ridden patient
due to pressure on
sites like the sacrum,
buttocks and heels
Wet
gangren
e
Intestine
• Grossly,
– the affected part is soft, swollen, putrid, rotten and dark.
– The classic example is gangrene of bowel, commonly due to
strangulated hernia, volvulus or intussusception.
– The part is stained dark due to the same mechanism as in dry
gangrene
• Histologically,
– coagulative necrosis with stuffing of affected part with blood.
– There is ulceration of the mucosa and intense inflammatory
infiltration.
– Lumen of the bowel contains mucus and blood.
– The line of demarcation between gangrenous segment and
viable bowel is generally not clear-cut
Wet gangrene of the small bowel
Coagulative necrosis of the affected bowel wall and thrombosed vessels while the
junction with normal intestine is indistinct and shows an inflammatory infiltrate
Contrasting Features of Dry and Wet
Gangrene
GAS GANGRENE
• Special form of wet gangrene caused by gas-forming
clostridia (gram-positive anaerobic bacteria).
• gain entry into the tissues through open contaminated
wounds,
• especially in the muscles, or as a complication of
operation on colon which normally contains clostridia.
• It produce various toxins which produce necrosis and
oedema locally
• Also absorbed producing profound systemic
manifestations.
GAS GANGRENE
• Grossly
– the affected area is swollen, oedematous, painful and
crepitant due to accumulation of gas bubbles within the
tissues.
– Subsequently, the affected tissue becomes dark black and
foul smelling.
• Microscopically
– the muscle fibres undergo coagulative necrosis with
liquefaction
– Large number of gram-positive bacilli can be
identified.
– At the periphery, a zone of leucocytic infiltration, oedema
and congestion are found.
– Capillary and venous thrombi are common.
GAS GANGRENE
Pathologic calcification
Definition: Abnormal deposits of calcium salts
occur in any tissues except bones and teeth.
• Two distinct types of pathologic calcification:
– Dystrophic calcification: characterised by deposition
of calcium salts in dead or degenerated tissues with
normal calcium metabolism and normal serum
calcium levels.
– Metastatic calcification: apparently normal tissues
and is associated with deranged calcium metabolism
and hypercalcaemia.
Morphological Features
• Etiology and pathogenesis of the two are different.
• But morphologically the deposits in both resemble normal minerals of
the bone.
• H and E stained sections,
– Calcium salts appear as deeply basophilic, irregular and granular
clumps.
– The deposits may be intracellular, extracellular, or at both
locations.
– Occasionally, heterotopic bone formation (ossification) may
occur.
– Calcium deposits can be confirmed by special stains
• Silver impregnation method of von-Kossa producing black
colour,
• Alizarin red S that produces red staining.
Dystrophic calcification
• Encountered in areas of
necrosis of any type
• Although dystrophic
calcification may be an
incidental finding indicating
insignificant past cell
injury, it may also be a
cause of organ dysfunction
• May occur due to 2 types of
causes:
– Dead tissue
Calcification of the aortic valve
– Degenerated tissue.
Dystrophic Calcification: Dead Tissue
• Caseous necrosis in tuberculosis is the most common site
• Liquefaction necrosis in chronic abscesses may get calcified.
• Fat necrosis following acute pancreatitis or traumatic fat necrosis in
the breast results in deposition of calcium soaps.
• Gamna-Gandy bodies in chronic venous congestion (CVC) of the
spleen is characterised by calcific deposits admixed with haemosiderin
on fibrous tissue.
• Infarcts may sometimes undergo dystrophic calcification.
• Thrombi, especially in the veins, may produce phleboliths.
• Haematomas in the vicinity of bones may undergo dystrophic
calcification.
• Dead parasites like in hydatid cyst, Schistosoma eggs, and
cysticercosis.
• Calcification in breast cancer detected by mammography.
• Congenital toxoplasmosis involving the central nervous system
visualised by calcification in the infant brain.
Dystrophic calcification: Degenerated
Tissues
• Dense old scars may undergo hyaline degeneration and subsequent calcification.
• Atheromas in the aorta and coronaries frequently undergo calcification.
• Mönckeberg’s sclerosis shows calcification in the tunica media of muscular arteries
in elderly people
• Stroma of tumours such as uterine fibroids, breast cancer, thyroid adenoma, goitre
etc show calcification.
• Psammoma bodies or calcospherites: characteristic spherules of calcification such as
in meningioma, papillary serous cystadenocarcinoma of the ovary and papillary
carcinoma of the thyroid.
• Cysts which have been present for a long time e.g. epidermal and pilar cysts.
• Calcinosis cutis is a condition of unknown cause in which there are irregular nodular
deposits of calcium salts in the skin and subcutaneous tissue.
• Senile degenerative changes may be accompanied by dystrophic calcification such as
in costal cartilages, tracheal or bronchial cartilages, and pineal gland in the brain etc.
Fibrosis and dystrophic

calcifications of the
pancreatic parenchyma.
Mitral Stenosis:
Gross natural
color opened
valve with
commissure fusion
dystrophic
calcification
Degenerated tunica media of muscular Caseous necrosis in tuberculous lymph

artery of uterine myometrium in node. In H & E, the deposits are basophilic
Mönckeberg’s arteriosclerosis granular while the periphery shows healed
granulomas.
Dystrophic calcification: Pathogenesis
• Denatured proteins in necrotic or degenerated tissue
bind phosphate ions, which react with calcium ions to
form precipitates of calcium phosphate.
• It involves 2 steps
• Initiation (or nucleation)
– phase in which precipitates of calcium phosphate begin to
accumulate intracellularly in the mitochondria,
– or extracellularly in membrane-bound vesicles: matrix
vesicles
• Propagation
– phase in which minerals deposited in the initiation phase are
propagated to form mineral crystals
Metastatic calcification
• Calcification in normal
tissue whenever
there is
hypercalcemia.
• These may be due to
– Excessive mobilisation
of calcium from the
bone
– Excessive absorption of
calcium from the gut
Excessive mobilisation of calcium
from the bone
• Hyperparathyroidism
– Primary : parathyroid adenoma,
– Secondary: parathyroid hyperplasia, chronic renal
failure
• Bony destructive lesions
– Multiple myeloma
– Metastatic carcinoma
– leukemia
• Prolonged immobilisation
– Disuse atrophy of the bones and hypercalcaemia.
Excessive absorption of calcium from
the gut
• Hypervitaminosis D
• Milk-alkali syndrome
– Excessive oral intake of calcium in the form of milk
– And administration of calcium carbonate in the
treatment of peptic ulcer.
• Hypercalcaemia of infancy
• Sarcoidosis: macrophages activate a vitamin D
precursor
Sites of Metastatic calcification
• May occur in any normal tissue of the
body but affects the
following organs more commonly:
• Kidneys, especially at the basement
membrane of tubular
epithelium and in the tubular lumina
causing nephrocalcinosis
• Lungs, especially in the alveolar
walls.
• Stomach, on the acid-secreting fundal
glands.
• Blood vessels, especially on the internal
elastic lamina.
Tubular basement membrane in
• metastatic calcification.
Cornea: another site affected by
nephrocalcinosis due to
• Synovium of the joint causing pain and
hypercalcaemia
dysfunction.
Metastatic calcification
Lung:
Metastatic
Calcification
Differences between Dystrophic and
Metastatic Calcification
CELL DEATH
APOPTOSIS
• a form of ‘coordinated and internally
programmed cell death’
• pathway of cell death that is induced by a tightly
regulated suicide program in which cells destined
to die activate enzymes capable of degrading the
cells' own nuclear DNA and nuclear and
cytoplasmic proteins
• Apoptosis is responsible for mediating cell death
in a wide variety of physiologic and pathologic
processes
APOPTOSIS
APOPTOSIS
• The plasma membrane of the apoptotic cell
remains intact, but the membrane is altered in
such a way that the cell and its fragments
become avid targets for phagocytes.
• The dead cell is rapidly cleared before its contents
have leaked out, and therefore cell death by this
pathway does not elicit an inflammatory reaction
in the host
• Thus, apoptosis differs from necrosis
• However, apoptosis and necrosis sometimes
coexist, and apoptosis induced by some
pathologic stimuli may progress to necrosis
Apoptosis V/S Necrosis
Physiologic Processes
• Organised cell destruction in sculpting of tissues
during development of embryo.
• Physiologic involution of cells in hormone-
dependent tissues
– Endometrial shedding during mensuration
– Regression of lactating breast after withdrawal of
breast-feeding.
• Normal cell destruction followed by replacement
proliferation such as in intestinal epithelium.
• Involution of the thymus in early age.
Pathologic Processes
• Cell death in tumours exposed to chemotherapeutic agents.
• Cell death by cytotoxic T cells in immune mechanisms such
as in graft-versus-host disease and rejection reactions.
• Progressive depletion of CD4+T cells in the pathogenesis of
AIDS.
• Cell death in viral infections e.g. viral hepatitis.
• Pathologic atrophy of organs and tissues on withdrawal of
stimuli e.g. prostatic atrophy after orchiectomy, atrophy of
kidney or salivary gland on obstruction of ureter or ducts,
respectively.
• Cell death in response to injurious agents involved in
causation of necrosis e.g. radiation, hypoxia and mild
thermal injury.
• In degenerative diseases of CNS e.g. in Alzheimer’s disease,
Parkinson’s disease, and chronic infective dementias
A,Apoptosis in the skin in an immune-mediated reaction
B,High power of apoptotic cell in live in immune-mediated hepatic cell injury.
Recognition of Cell death
Ultrastructural changes
• Margination or progressive loss of nuclear chromatin
• Focal rupture of the nuclear membrane
• Breakdown of the plasmalemma.
• Development of flocculent densities in mitochondria.
Changes in the nucleus
• Pyknosis: condensation of chromatin of chromatin and
shrinkage of the nucleus.
• Karyorrhexis: fragmentation of the nucleus.
• Karyolysis: dissolution of the nucleus.
Normal Pyknosis Karyorrhexis Karyolysis
Changes in cytoplasm staining
• Positive staining with vital dyes such as Trepan blue which reflects
abnormal membrane permeability.
• Opacification: denaturation of proteins lead to aggregation
with resultant opacification of the cytoplasm.
• Eosinophilia: exposure of basic amino groups results in
increased affinity for acidic dyes such as eosin.
Biochemical changes
• Release of K+ by dead cells.
• Release of enzymes into the blood. e. g. increased plasma levels of
creatine kinases, lactic dehydrogenase and aspartate
aminotransferase.
• Release of protein or protein breakdown products into the blood.
Postmortem change
• Tissues in dead body can be distinguished
from necrosis by being diffuse and not
associated with inflammatory response.
Autolysis
• Digestion of cell by enzymes released
from lysosome; occurs after cell dies.
References
• Robbinson's basic pathology 8 ed
• Harsh Mohan - Textbook of Pathology 6th Ed.
• Color atlas of pathology
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Cellular Injury and Adaptations

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CELL INJURY & CELLULAR ADAPTATIONS

• Cell injury is defined as a variety of stresses a cell encounters as a result

• Virchow’s Cellular theory of disease (1859): diseases occur due to

Genetic causes Acquired causes

Inadequate oxygenation (cardiorespiratory

Loss of oxygen carrying capacity of the blood ( anemia or CO poisoning

 Loss of oxidative phosphorylation and ATP generation by mitochondria.

 Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation,

 Reduced intracellular pH: Lactic acid and inorganic phosphate.

 Clumping of nuclear chromatin.

• Endogenous products: urea

 Absorption of energy (UV light and x-rays)

 Enzymatic conversion of exogenous

The immune process is normally protective but in certain circumstances

 Protein-calorie deficiencies are the most examples of

 Excess in nutrition are important causes of morbidity and

 Obesity alone leads to an increased vulnerability to certain disorders,

• Programmed aging whereby after a defined number of divisions the cell

 Irreversible injury and dying: Necrosis, Gangrene followed by pathological

• Adaptations are reversible changes in the size, number, phenotype,

• Pathologic adaptations may share the same

• Cellular adaptation is a state that lies intermediate

• Cell can adapt themselves by undergoing 5 different conditions

a. Hormonal : influence of hormonal stimulation

b. Compensatory: hyperplasia occurring following removal of part of an organ or a

• Excessive stimulation of hormones or growth

Physiologic hypertrophy of the uterus during pregnancy.A, gross appearance of a

（ From ROBBINS BASIC

Although hypertrophy and hyperplasia are two distinct processes,

Types: Physiologic or Pathological

Left Normal facebook.com/notesdental

• A normal process of aging in

（ From ROBBINS BASIC PATHOLOGY ， 2003 ）

• Since this organ plays a central role in fat

• It occurs in two patterns,

• Prolonged moderate hypoxia causes intracellular

• Profound hypoxia or diphtheritic myocarditis, the

• Hyaline droplets in the proximal tubular epithelial cells: excessive reabsorption of

• Hyaline degeneration of rectus abdominalis muscle called

• Mallory’s hyaline represents aggregates of intermediate filaments in the

• Nuclear or cytoplasmic hyaline inclusions seen in some viral infections.

• Russell’s bodies representing excessive immunoglobulins in the rough endoplasmic

• Extracellular hyaline is seen in connective tissues.

– Hyalinised old scar of fibro-collagenous tissues.

– Hyaline arteriolosclerosis in renal vessels in hypertension and diabetes mellitus.

Extracellular hyaline deposit in leiomyoma uterus.

• Following are some examples of functional excess of epithelial mucin:

Mucinous cystadenoma of the

• A few examples of disturbances of connective tissue mucin are as

– Dissecting aneurysm of the aorta due to Erdheim’s medial degeneration

– Myxomatous change in the dermis in myxoedema.

– Myxoid change in the synovium in ganglion on the

• Extracellular deposition of fibrillar

• Associated with a number of inherited

Electron micrograph of 7.5-10 nm Congo red staining shows an apple-green

Pressure on adjacent cells Blood vessels

Atrophy Narrowing Increased permeability

The kidney is small and

The sectioned surface shows

A, The deposition is extensive in the

Anthracosis lung: There is presence of abundant coarse black carbon pigment in

Liquefactive necrosis brain

Caseous necrosis lymph node

Fat necrosis in acute pancreatitis.