Introduction to

Pathology
Lecture Session
By

Dr Raghu Nataraj
Assistant Professor
Division of Molecular Biology
School of Lifesciences, Mysore
JSS AHER, Mysore-15
Karnataka, INDIA
Learning Objectives
• Upon completing this introduction you be:
1. Define pathology
2. Discuss the core aspects of disease in
pathology
3. Know the diagnostic techniques used in
pathology
4. Know the various categories of the causes of
diseases
5. Know the course, outcome, consequences of
diseases
I. Definition
• Pathology is the study of disease by scientific
methods.

• The word pathology came from the Latin words

“patho” & “logy”.
• ‘Patho’ means disease and ‘logy’ means study,
therefore pathology is a scientific study of
disease.
• It describes the effects, progress and
consequences of the disease and attempts to
determine the cause (etiology) and underlying
mechanisms (pathogenesis).

• It forms a bridge between basic science and

clinical practice and has traditionally had the
same role in linking pre-clinical and clinical study.
• The manifestations of the disease are the sum of
the damage done by the precipitating cause and
the body’s response (which may be helpful or
unhelpful or both).
• The variations in these components account for
the great diversity of disease, which can then be
classified into four main groups:

• DEVELOPMENTAL-INFLAMMATORY-NEOPLASTIC-
DEGENERATIVE
• Different diseases affect different age groups.
• Developmental disorders and degenerative
diseases affect the opposite extremes of life
while tumors, in general, affect an ageing
population.

• Physiological ageing itself implies a gradual loss

of cellular and body vitality usually associated
with atrophy of tissues and organs.
• This process is aggravated and mimicked by the
degenerative diseases of old age so that the
physiological and pathological states tend to
merge.

• One should attempt to identify the distinctions

between ageing and disease.
• Additionally, in old age multiple diseases often
coexist and interact with one another, and drug
induced disorders are also common in this age
group.
II. Basic Principles in Human
Pathology

• Pathology gives explanations for the components

of a disease by understanding four aspects:
1. Aetiology
2. Pathogenesis
3. Morphologic changes
4. Functional derangements and clinical
significance.
1. Aetiology
• Aetiology of a disease means the cause of the
disease. If the cause of a disease is known it is
called primary etiology.

• If the cause of the disease is unknown it is called

Idiopathic.
• Knowledge or discovery of the primary cause
remains the backbone on which a diagnosis can
be made, a disease understood, & a treatment
developed.
• There are two major classes of etiologic factors:
Genetic
Acquired (infectious, nutritional, chemical,
physical, etc).
2. Pathogenesis

• Pathogenesis means the mechanism through

which the cause operates to produce the
pathological and clinical manifestations.
• The pathogenetic mechanisms could take place in
the latent or incubation period.

• Pathogenesis leads to morphologic changes.

3. Morphologic changes
• The morphologic changes refer to the structural
alterations in cells or tissues that occur following
the pathogenetic mechanisms.
• The structural changes in the organ can be seen
with the naked eye or they may only be seen under
the microscope.

• Those changes that can be seen with the naked eye

are called gross morphologic changes & those that
are seen under the microscope are called
microscopic changes.
• Both the gross & the microscopic morphologic
changes may only be seen in that disease, i.e.
they may be specific to that disease.
• Therefore, such morphologic changes can be used
by the pathologist to identify (i.e. to diagnose)
the disease.

• In addition, the morphologic changes will lead to

functional alteration & to the clinical signs &
symptoms of the disease.
4. Functional derangements and
clinical significance
• The morphologic changes in the organ influence
the normal function of the organ.

• By doing so, they determine the clinical features

(symptoms and signs), course, and prognosis of
the disease.
• Understanding all the 4 core aspects of disease
(i.e. understanding pathology) will help one to
understand how the clinical features of different
diseases occur & how their treatments work.

• This understanding will, in turn, enable health

care workers (Clinicians, paramedicals,
Biomedical researchers, pre-clinical researchers)
to handle the disease/disorder in a patient in a
better & scientific way.
• It is for these reasons that the health science
student should study pathology.
• In addition, the pathologist can use the
morphologic changes seen in diseases to
diagnose different diseases.

• There are different diagnostic modalities used in

pathology.
• Most of these diagnostic techniques are based on
morphologic changes.
III. Diagnostic techniques used
in pathology
• The pathologist uses the following techniques to
the diagnose diseases:
a. Histopathology
b. Cytopathology
c. Hematopathology
d. Immunohistochemistry…
e. Microbiological examination
f. Biochemical examination
g. Cytogenetics
h. Molecular techniques
i. Autopsy
A. Histopathological techniques
• Histopathological examination studies tissues
under the microscope. During this study, the
pathologist looks for abnormal structures in the
tissue.
• Tissues for histopathological examination are
obtained by biopsy.

• Biopsy is a tissue sample from a living person to

identify the disease.
• Biopsy can be either incisional or excisional.
• Once the tissue is removed from the patient, it
has to be immediately fixed by putting it into
adequate amount of 10% Formaldehyde (10%
formalin) before sending it to the pathologist.

• The purpose of fixation is:

1. To prevent autolysis and bacterial
decomposition and putrefaction
2. To coagulate the tissue to prevent loss of
easily diffusible substances
• 3. To fortify the tissue against the deleterious
effects of the various stages in the preparation of
sections and tissue processing.
• 4. To leave the tissues in a condition which
facilitates differential staining with dyes and other
reagents.

• Once the tissue arrives at the pathology

department, the pathologist will exam it
macroscopically (i.e. naked-eye examination of
tissues).
• Then the tissue is processed to make it ready for
microscopic examination.
• The whole purpose of the tissue processing is to
prepare a very thin tissue (i.e. five to seven μm
or one cell thick tissue) which can be clearly seen
under the microscope.

• The tissue is processed by putting it into different

chemicals.
• It is then impregnated (embedded) in paraffin,
sectioned (cut) into thin slices, & is finally
stained.
• The stains can be Hematoxylin/Eosin stain or
special stains such as PAS or
Immunohistochemistry.

• The Hematoxylin/Eosin stain is usually

abbreviated as H&E stain.
• The H&E stain is routinely used.
• It gives the nucleus a blue color & the cytoplasm
& the extracellular matrix a pinkish color.

• Then the pathologist will look for abnormal

structures in the tissue.
• And based on this abnormal morphology he/she
will make the diagnosis.
• Histopathology is generally the gold standard for
pathologic diagnosis.
B. Cytopathologic techniques
• Cytopathology is the study of cells from various
body sites to determine the cause or nature of
disease.

• Applications of cytopathology:
• The main applications of cytology are:
• 1. Screening for the early detection of
asymptomatic cancer for example, the
examination of scrapings from cervix for early
detection and prevention of cervical cancer.
• 2. Diagnosis of symptomatic cancer
• Cytopathology may be used alone or in
conjunction with other modalities to diagnose
tumors revealed by physical or radiological
examinations.

• It can be used in the diagnosis of cysts,

inflammatory conditions and infections of various
organs.
• 3. Surveillance of patients treated for cancer

• For some types of cancers, cytology is the most

feasible method of surveillance to detect
recurrence.
• The best example is periodic urine cytology to
monitor the recurrence of cancer of the urinary
tract.
• Advantages of cytological examination
• Compared to histopathologic technique it is
cheap, takes less time and needs no anesthesia
to take specimens.

• Therefore, it is appropriate for developing

countries with limited resources.
• In addition, it is complementary to
histopathological examination.
• Cytopathologic methods
• There are different cytopathologic methods
including:
1. Fine-needle aspiration cytology (FNAC)
• In FNAC, cells are obtained by aspirating the
diseased organ using a very thin needle under
negative pressure.

• Virtually any organ or tissue can be sampled by

fine-needle aspiration.
• The aspirated cells are then stained & are studied
under the microscope.
• Superficial organs (e.g. thyroid, breast, lymph
nodes, skin and soft tissues) can be easily
aspirated.)
• Deep organs, such as the lung, mediastinum,
liver, pancreas, kidney, adrenal gland, and
retroperitoneum are aspirated with guidance by
fluoroscopy, ultrasound or CT scan.

• FNAC is cheap, fast, & accurate in diagnosing

many diseases.
• 2. Exfoliative cytology
• Refers to the examination of cells that are shed
spontaneously into body fluids or secretions.

• Examples include sputum, cerebrospinal fluid,

urine, effusions in body cavities (pleura,
pericardium, peritoneum), nipple discharge and
vaginal discharge.
• 3. Abrasive cytology
• Refers to methods by which cells are dislodged by
various tools from body surfaces (skin, mucous
membranes, and serous membranes).
• E.g. preparation of cervical smears with a spatula or a
small brush to detect cancer of the uterine cervix at
early stages.

• Such cervical smears, also called Pap smears, can

significantly reduce the mortality from cervical
cancer.
• C. Hematological examination
• This is a method by which abnormalities of the
cells of the blood and their precursors in the bone
marrow are investigated to diagnose the different
kinds of anemia & leukemia.

• D. Immunohistochemistry
• This is a method is used to detect a specific
antigen in the tissue in order to identify the type
of disease.
• E. Microbiological examination
• This is a method by which body fluids, excised
tissue, etc. are examined by microscopically,
cultural and serological techniques to identify
micro-organisms responsible for many diseases.
• F. Biochemical examination
• This is a method by which the metabolic disturbances
of disease are investigated by assay of various normal
and abnormal compounds in the blood, urine, etc.

• G. Clinical genetics (cytogenetics),

• This is a method in which inherited chromosomal
abnormalities in the germ cells or acquired
chromosomal abnormalities in somatic cells are
investigated using the techniques of molecular
biology.
• H. Molecular techniques
• Different molecular techniques such as
fluorescent in situ hybridization, Southern blot,
etc... can be used to detect genetic diseases.

• I. Autopsy
• Autopsy is examination of the dead body to
identify the cause of death.
• This can be for forensic or clinical purposes.
• The relative importance of each of the above
disciplines to our understanding of disease varies
for different types of diseases.

• For example, in diabetes mellitus, biochemical

investigation provides the best means of
diagnosis and is of greatest value in the control
of the disease.
• Whereas in the diagnosis of tumors, FNAC &
histopathology contribute much.

• However, for most diseases, diagnosis is based on

a combination of pathological investigations.
IV. General pathology–cell injury
causes
• Diseases can be caused by either environmental factors,
genetic factors or a combination of the two.
• A. Environmental factors
• Environmental causes of disease are many and are
classified into:
1. Physical agents
2. Chemicals
3. Nutritional deficiencies & excesses
4. Infections & infestations
5. Immunological factors
6. Psychogenic factors
• 1. Physical agents
• These include trauma, radiation, extremes of
temperature, and electric power.
• These agents apply excess physical energy, in
any form, to the body.
• 2. Chemicals
• With the use of an ever-increasing number of chemical
agents such as drugs, in industrial processes, and at
home, chemically induced injury has become very
common.

• Their effects vary:

• Some act in a general manner, for example cyanide is
toxic to all cells.
• Others act locally at the site of application, for
example strong acids and caustics.
• Paraquat affects the lungs and organic solvents
damage especially the kidneys and liver.
• Others, for example strong acids and alkalis, act
locally.

• iatrogenic diseases are an increasingly important

subgroup as powerful drugs often have
undesirable side effects, either predictably in a
dose-dependent fashion or in an unpredictable
idiosyncratic manner.
• Another group exhibit a predilection for certain
organs, for example – the effect of paracetamol
and alcohol on liver.

• Many toxic chemicals are metabolized in liver and

excreted in kidney, as a result, these organs are
susceptible to chemical injury.
• 3. Nutritional deficiencies and excesses
• Nutritional deficiencies may arise as a result of poor
supply, interference with absorption, inefficient
transport within the body, or defective utilization.

• It may take the form of deficiency either of major

classes of food, usually protein and energy, or
vitamins or elements essential for specific
metabolic processes, e.g. iron for haemoglobin
production.
• Often, the deficiencies are multiple and complex.
• On the other hand, dietary excess plays an
important role in diseases in Western countries.

• Obesity has become increasingly common, with

its attendant dangers of type 2 diabetes, high
blood pressure and heart disease.
• 4. Infections and infestations
• Viruses, bacteria, fungi, protozoa, and metazoa
all cause diseases.
• They may do so by causing cell destruction
directly as in virus infections (for example
poliomyelitis) or protozoal infections (for example
malaria).
• However, in others the damage is done by toxins
elaborated by the infecting agent as in diphtheria
and tetanus.

• Like chemicals, they may have a general effect or

they may show a predilection for certain tissues.
• 5. Immunological factors
• The immune process is essential for protection
against micro-organisms and parasites.

• However, the immune system can be abnormal

which can lead to diseases.
• The abnormalities of the immune system include:
• A. Hypersensitivity reaction
• This is exaggerated immune response to an
antigen.
• For example, bronchial asthma can occur due to
exaggerated immune response to the harmless
pollen.

• B. Immunodeficiency
• This is due to deficiency of a component of the
immune system which leads to increased
susceptibility to different diseases.
• An example is AIDS.
• C. Autoimmunity
• This is an abnormal (exaggerated) immune
reaction against the self antigens of the host.
• Therefore, autoimmunity is a hypersensitivity
reaction against the self antigens.

• For example, type 1 diabetes mellitus is caused

by autoimmune destruction of the beta cells of
the islets of Langerhans of the pancreas.
• D. Infections and infestations
• Viruses, bacteria, fungi, protozoa and metazoa all
cause disease.

• They may do so by destroying cells directly, for

example in malaria. Infection with HIV destroys T
cells resulting in severe immunodeficiency which
renders the individual susceptible to many other
infections, often due to organisms of low
virulence (opportunistic infections).
• 6. Psychogenic factors
• The mental stresses imposed by conditions of
life, particularly in technologically advanced
communities, are probably contributory factors in
some groups of diseases.

• These cause and influence disease processes in

several ways.
• They alter the individual’s symptoms and
response to somatic diseases.
• They are important components of diseases
caused by addiction such as alcohol, tobacco and
drugs.

• Finally, it is thought that psychological factors

may be causally related to diseases such as
hypertension, coronary thrombosis and, perhaps
because of its effects on the immune system, to
ulcerative colitis.
• B. Genetic Factors
• These are hereditary factors that are inherited
genetically from parents.
• They are the results of actions of single genes or
groups of genes.
V. Course of disease
• The course of a disease in the absence of any
intervention is called the natural history of the
• disease.
• The different stages in the natural history of
disease include:
a) Exposure to various risk factors (causative
agents)
b) Latency, period between exposure and
biological onset of disease
• e) The clinical onset of the disease, when the
signs and symptoms of the disease become
apparent.

• The expression of the disease may be variable in

severity or in terms of range of manifestations.
• f) The onset of permanent damage
• g) Death
• Natural recovery, i.e. recovery without any
intervention, can occur at any stage in the
progression of the disease.
VI. Outcome and consequences
of disease
• Following clinical onset, disease may follow any
of the following trends:
• a) Resolution can occur leaving no sequelae,
• b) The disease can settle down, but sequelae are
left, or
• c) It may result in death.
VII. Clinical & biologic death
• Clinical death
• Clinical death is the reversible transmission
between life and biologic death.
• Clinical death is defined as the period of
respiratory, circulatory and brain arrest during
which initiation of resuscitation can lead to
recovery.
• Clinical death begins with either the last agonal
inhalation or the last cardiac contraction.
• Signs indicating clinical death are
• The patient is without pulse or blood
pressure and is completely unresponsive to the
most painful stimulus.
• The pupils are widely dilated
• Some reflex reactions to external stimulation are
preserved.
• For example, during intubations, respiration may
be restored in response to stimulation of the
receptors of the superior laryngeal nerve, the
nucleus of which is located in the medulla
oblongata near the respiratory center.

• • Recovery can occur with resuscitation.

Biological Death
• Biological death (sure sign of death), which sets in
after clinical death, is an irreversible state of
cellular destruction.
• It manifests with irreversible cessation of
circulatory and respiratory functions, or irreversible
cessation of all functions of the entire brain,
including brain stem.

• However, one should notice that there are

internationally accepted criteria to diagnose
biological death.
Cell injury
• Cells are the basic units of tissues, which form
organs and systems in the human body.
• Traditionally, body cells are divided in to two
main types: epithelial and mesenchymal cells.

• In health, the cells remain in accord with each

other.
Dr Raghu Nataraj
• In 1859, Virchow first published cellular theory of
disease, bringing in the concept that diseases
occur due to abnormalities at the level of cells.

• Thus, most forms of diseases begin with cell

injury followed by consequent loss of cellular
function.
Cell injury is defined as a variety of stresses a cell
encounters as a result of changes in its internal
and external environment.
• The cellular response to stress/injury may vary
and depends upon the following variables:
i) The type of cell and tissue involved.
ii) Extent and type of cell injury.
Different forms of cellular responses to cell injury:

1. When there is increased functional demand, the

cell may adapt to the changes which are expressed
morphologically and then revert back to normal
after the stress is removed
2. When the stress is mild to moderate, the injured
cell may recover (reversible cell injury), while
when the injury is persistent cell death may occur
(irreversible cell injury).

3. The residual effects of reversible cell injury may

persist in the cell as evidence of cell injury at
subcellular level (subcellular changes), or
metabolites may accumulate within the cell
(intracellular accumulations).
• In order to learn the fundamentals of disease
processes at cellular level, it is essential to have
an understanding of the causes and mechanisms
of cell injury and cellular adaptations, which can
be best understood in the context of basic
knowledge of normal structure and functions of a
cell.
• The cells may be broadly injured by two major
ways:
A. By genetic causes
B. By acquired causes

• The genetic & acquired causes of diseases have

been discussed.
• Cell injury underlies all diseases.

• In-order to understand diseases one, has to start

by knowing what cell injury is!
• When a cell is exposed to an injurious agent, the
possible outcomes are:
1. The cell may adapt to the situation or
2. They cell may acquire a reversible injury or
3. The cell may obtain an irreversible injury &
may die.

The cell may die via one of two ways: either by

necrosis or by apoptosis
• Which of the outcomes occur depends on both
the injurious agent & on cellular factors.

• In other words, the result depends on the type,

severity, & duration of the injury & on the type of
the cell.
PATHOGENESIS OF CELL INJURY
• Injury to the normal cell by one or more of the
above listed etiologic agents may result in a state
of reversible or irreversible cell injury.

• The underlying alterations in biochemical

systems of cells for reversible and irreversible
cell injury by various agents is complex and
varied.
• However, in general, the following principles
apply in pathogenesis of most forms of cell injury
by various agents:
1. Type, duration and severity of
injurious agent
• The extent of cellular injury depends upon type,
duration and severity of the stimulus e.g. small
dose of chemical toxin or short duration of
ischaemia cause reversible cell injury while large
dose of the same chemical agent or persistent
ischaemia cause cell death.
2. Type, status and adaptability
of target cell
• The type of cell as regards its susceptibility to
injury, its nutritional and metabolic status, and
adaptation of the cell to hostile environment
determine the extent of cell injury e.g. skeletal
muscle can withstand hypoxic injury for long-time
while cardiac muscle suffers irreversible cell
injury after 20-30 minutes of persistent
ischaemia.
3. Underlying intracellular
phenomena
• Irrespective of other factors, following essential
biochemical phenomena underlie all forms of cell
injury:
i) Mitochondrial damage causing ATP
depletion.
ii) Cell membrane damage disturbing the
metabolic and trans-membrane exchanges.
iii). Release of toxic free radicals.
4. Morphologic consequences
• All forms of biochemical changes underlying cell
injury are expressed in terms of morphologic
changes.

• The ultrastructural changes become apparent

earlier than the light microscopic alterations.
• The morphologic changes of reversible cell injury
(e.g. hydropic swelling) appear earlier than
morphologic alterations in cell death (e.g. in
myocardial infarction).
• All forms of biochemical changes underlying cell
injury are expressed in terms of morphologic
changes.
• The ultrastructural changes become apparent
earlier than the light microscopic alterations.

• The morphologic changes of reversible cell injury

(e.g. hydropic swelling) appear earlier than
morphologic alterations in cell death (e.g. in
myocardial infarction).
REVERSIBLE CELL
INJURY
REVERSIBLE CELL INJURY
• Retrogressive changes or simply reversible cell
injury are nothing but non-lethal cell injury.

• Morphologic forms of reversible cell injury are:

1. Hydropic change (cloudy swelling, or
vacuolar degeneration)
2. Fatty change
3. Hyaline change
4. Mucoid change
Hydropic Change
• Hydropic change means accumulation of water
within the cytoplasm of the cell.

• Other synonyms used are cloudy swelling (for

gross appearance of the affected organ) and
vacuolar degeneration (due to cytoplasmic
vacuolation).
• PATHOGENESIS. Cloudy swelling results from
impaired regulation of sodium and potassium at
the level of cell membrane.

• This results in intracellular accumulation of

sodium and escape of potassium.
• This, in turn, leads to rapid flow of water into the
cell to maintain iso-osmotic conditions and hence
cellular swelling occurs.
• In addition, influx of calcium too occurs.

• Hydropic swelling is an entirely reversible change

upon removal of the injurious agent.
ETIOLOGY
• This is the commonest and earliest form of cell
injury from almost all causes.

• The common causes include acute and subacute

cell injury from various etiologic agents such as
bacterial toxins, chemicals, poisons, burns, high
fever, intravenous administration of hypertonic
glucose or saline etc.
MORPHOLOGIC FEATURES
• Grossly, the affected organ such as kidney,
liver, pancreas, or heart muscle is enlarged due to
swelling.

• The cut surface bulges outwards and is slightly

opaque.
Microscopically
it is characterised by the following features:
• i) The cells are swollen and the microvasculature
compressed.
• ii) Small clear vacuoles are seen in the cells and
hence the term vacuolar degeneration.
These vacuoles represent distended cisternae of
the endoplasmic reticulum.
• iii) Small cytoplasmic blebs may be seen.
• iv) The nucleus may appear pale.
Hyaline Change
• The word ‘hyaline’ means glassy (hyalos = glass).

• Hyaline is a descriptive histologic term for glassy,

homogeneous, eosinophilic appearance of
material in haematoxylin and eosin-stained
sections and does not refer to any specific
substance.
• Hyaline change is associated with heterogeneous
pathologic conditions.

• It may be intracellular or extracellular.

INTRACELLULAR HYALINE
Intracellular hyaline is mainly seen in epithelial
cells.
• A few examples are as follows:
1. Hyaline droplets in the proximal tubular
epithelial cells in
cases of excessive reabsorption of plasma
proteins.
• 2. Hyaline degeneration of rectus abdominalis
muscle called Zenker’s degeneration, occurring in
typhoid fever.

• The muscle loses its fibrillar staining and

becomes glassy and hyaline.
• 3. Mallory’s hyaline represents aggregates of
intermediate filaments in the hepatocytes in
alcoholic liver cell injury.

• 4. Nuclear or cytoplasmic hyaline inclusions seen

in some viral infections.
• 5. Russell’s bodies representing excessive
immunoglobulins in the rough endoplasmic
reticulum of the plasma cells
EXTRACELLULAR HYALINE
Extracellular hyaline is seen in connective tissues.
A few examples of extracellular hyaline change are
as under:
• 1. Hyaline degeneration in leiomyomas of the
uterus.
• 2. Hyalinised old scar of fibrocollagenous tissues.
• 3. Hyaline arteriolosclerosis in renal vessels in
hypertension and diabetes mellitus.
• 4. Hyalinised glomeruli in chronic
glomerulonephritis.

• 5. 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.
Mucoid Change
• Mucus secreted by mucous glands is a
combination of proteins complexed with
mucopolysaccharides.
• Mucin, a glycoprotein, is its chief constituent.
• Mucin is normally produced by epithelial cells of
mucous membranes and mucous glands, as well as by
some connective tissues like in the umbilical cord.
• By convention, connective tissue mucin is termed
myxoid (mucus like).

• Both types of mucin are stained by alcian blue.

• However, epithelial mucin stains positively with
periodic acid-Schiff (PAS), while connective tissue
mucin is PAS negative but is stained positively with
colloidal iron.
EPITHELIAL MUCIN
Following are some examples of functional excess of
epithelial mucin:
• 1. Catarrhal inflammation of mucous membrane (e.g. of
respiratory tract, alimentary tract, uterus).
• 2. Obstruction of duct leading to mucocele in the oral
cavity and gallbladder.

• 3. Cystic fibrosis of the pancreas.

• 4. Mucin-secreting tumours (e.g. of ovary, stomach,
large
• bowel etc)
CONNECTIVE TISSUE MUCIN
A few examples of disturbances of connective tissue
mucin are as under:
• 1. Mucoid or myxoid degeneration in some tumours e.g.
myxomas, neurofibromas, fibroadenoma, soft tissue
sarcomas etc.
• 2. Dissecting aneurysm of the aorta due to Erdheim’s
medial degeneration and Marfan’s syndrome.

• 3. Myxomatous change in the dermis in myxoedema.

• 4. Myxoid change in the synovium in ganglion on the
wrist.
FATTY CHANGE (STEATOSIS)
• Fatty change, steatosis or fatty metamorphosis is
the intracellular accumulation of neutral fat
within parenchymal cells.

• It includes the older, now abandoned, terms of

fatty degeneration and fatty infiltration because
fatty change neither necessarily involves
degeneration nor infiltration.
• The deposit is in the cytosol and represents an
absolute increase in the intracellular lipids.

• It is especially common in the liver but may occur

in other non-fatty tissues like the heart, skeletal
muscle, kidneys (lipoid nephrosis or minimum
change disease) and other organs.
Fatty Liver
• Liver is the commonest site for accumulation of
fat because it plays central role in fat
metabolism.

• 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.
Fatty change in the liver may result from one of
the two types of causes:
• 1. Conditions with excess fat (hyperlipidameia),
exceeding the capacity of the liver to metabolise
it.
• 2. Liver cell damage, when fat cannot be
metabolised in it.
These causes are listed below:
1. Conditions with excess fat:
i) Obesity
ii) Diabetes mellitus
iii) Congenital hyperlipidaemia
• 2. Liver cell damage:
i) Alcoholic liver disease (most common)
ii) Starvation
iii) Protein calorie malnutrition
iv) Chronic illnesses (e.g. tuberculosis)
v) Acute fatty liver in late pregnancy
vi) Hypoxia (e.g. anaemia, cardiac failure)
 vii) Hepatotoxins (e.g. carbon tetrachloride,
chloroform, ether, aflatoxins and other poisons)
viii) Drug-induced liver cell injury (e.g.
administration of methotrexate, steroids, CCl4,
halothane anaesthetic, tetracycline etc)
ix) Reye’s syndrome
PATHOGENESIS.
Mechanism of fatty liver depends upon the stage
at which the etiologic agent acts in the normal fat
transport and metabolism.

• Hence, pathogenesis of fatty liver is best

understood in the light of normal fat metabolism
in the liver
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.
• Fat in H & E stained section prepared by paraffinembedding
technique appear non-staining vauloes because it is dissolved
in alcohol.
• i) The vacuoles are initially small and are present around the
nucleus (microvesicular).
• ii) But with progression of the process, the vacuoles become
larger pushing the nucleus to the periphery of the cells
(macrovesicular).
• iii) At times, the hepatocytes laden with large lipid vacuoles
may rupture and lipid vacuoles coalesce to form fatty cysts.
PATHOGENESIS OF ISCHAEMIC
AND HYPOXIC INJURY-
REVERSIBLE INJURY
• Ischaemia and hypoxia are the most common
forms of cell injury.

• Although underlying intracellular mechanisms

and ultrastructural changes involved in reversible
and irreversible cell injury by hypoxia and
ischaemia depending upon extent of hypoxia and
type of cells are involved are a continuation of
the process
• If the ischaemia or hypoxia is of short duration,
the effects may be reversible on rapid restoration
of circulation e.g. in coronary artery occlusion,
myocardial contractility, metabolism and
ultrastructure are reversed if the circulation is
quickly restored.

• The sequential biochemical and ultrastructural

changes in reversible cell injury are:
1. Decreased generation of
cellular ATP
• Damage by ischaemia versus Hypoxia from other
causes.

• All living cells require continuous supply of

oxygen to produce ATP which is essentially
required for a variety of cellular functions (e.g.
membrane transport, protein synthesis, lipid
synthesis and phospholipid metabolism).
• ATP in human cell is derived from 2 sources:

• Firstly, by aerobic respiration or oxidative

phosphorylation (which requires oxygen) in the
mitochondria.
• Secondly, cells may switch over to anaerobic
glycolytic oxidation to maintain constant supply
of ATP (in which ATP is generated from
glucose/glycogen in the absence of oxygen).
• Ischaemia due to interruption in blood supply as
well as hypoxia from other causes limit the
supply of oxygen to the cells, thus causing
decreased ATP generation from ADP:

• In ischaemia, aerobic respiration as well as

glucose availability are both compromised
resulting in more severe and faster effects of cell
injury.
• Ischaemic cell injury also causes accumulation of
metabolic waste products in the cells.
• On the other hand, in hypoxia from other causes
(RBC disorders, heart disease, lung disease),
anaerobic glycolytic ATP generation continues,
and thus cell injury is less severe.
2. Intracellular lactic acidosis:
Nuclear clumping
• Due t low oxygen supply to the cell, aerobic
respiration by mitochondria fails first.
• This is followed by switch to anaerobic glycolytic
pathway for the requirement of energy (i.e. ATP).

• This results in rapid depletion of glycogen and

accumulation of lactic acid lowering the
intracellular pH.
• Early fall in intracellular pH (i.e. intracellular
lactic acidosis) results in clumping of nuclear
chromatin.
3. Damage to plasma membrane
pumps: Hydropic
swelling and other membrane
changes.
• Lack of ATP interferes in generation of
phospholipids from the cellular fatty acids which
are required for continuous repair of membranes.

• This results in damage to membrane pumps

operating for regulation of sodium and calcium
as:
i) Failure of sodium-potassium
pump.
• Normally, the energy (ATP)-dependent sodium
pump (Na+-K+ ATPase) operating at the plasma
membrane allows active transport of sodium out
of the cell and diffusion of potassium into the
cell.

• Lowered ATP in the cell and consequent increased

ATPase activity interfere with this membrane-
regulated process.
• This results in intracellular accumulation of
sodium and diffusion of potassium out of cell.

• The accumulation of sodium in the cell leads to

increase in intracellular water to maintain
isosmotic conditions
ii) Failure of calcium pump.
• Membrane damage causes disturbance in the
calcium ion exchange across the cell membrane.

• Excess of calcium moves into the cell (i.e. calcium

influx), particularly in the mitochondria, causing
its swelling and deposition of phospholipid-rich
amorphous densities.
• Ultrastructural evidence of reversible cell
membrane damage is seen in the form of loss of
microvilli, intramembranous particles and focal
projections of the cytoplasm (blebs).

• Myelin figures may be seen lying in the cytoplasm

or present outside the cell, these are derived
from membranes (plasma or organellar) enclosing
water and dissociated lipoproteins between the
lamellae of injured membranes.
4. Reduced protein synthesis:
Dispersed ribosomes.
• As a result of continued hypoxia, membranes of
endoplasmic reticulum and Golgi apparatus swell
up.

• Ribosomes are detached from granular

endoplasmic reticulum and polysomes are
degraded to monosomes, thus dispersing
ribosomes in the cytoplasm and inactivating their
function.
• Similar reduced protein synthesis occurs in Golgi
apparatus.
Ischaemia-Reperfusion Injury
and
Free Radical-Mediated Cell
Injury
• Depending upon the duration of
ischaemia/hypoxia, restoration of blood flow may
result in the following 3 different consequences:
1. From ischaemia to reversible injury.
2. From ischaemia to reperfusion injury.
3. From ischaemia to irreversible injury.
1. From ischaemia to reversible injury.
When the period of ischaemia is of short duration,
reperfusion with resupply of oxygen restores the
structural and functional state of the injured cell
i.e. reversible cell injury.
2. From ischaemia to reperfusion injury.
When ischaemia is for longer duration, then rather
than restoration of structure and function of the
cell, reperfusion paradoxically deteriorates the
already injured cell.
This is termed ischaemia-reperfusion injury.
3. From ischaemia to irreversible injury. Much
longer period of ischaemia may produce
irreversible cell injury during ischaemia itself when
so much time has elapsed that neither blood flow
restoration is helpful nor reperfusion injury can
develop.
• Cell death in such cases is not attributed to
formation of activated oxygen species.
• But instead, on reperfusion there is further
marked intracellular excess of sodium and
calcium ions due to persistent cell membrane
damage.

• The underlying mechanism of reperfusion injury

and free radical mediated injury is complex but
following three main components are involved in
it:
• 1. Calcium overload.

• 2. Generation of reactive oxygen radicals

(superoxide, H2O2, hydroxyl radicals).

• 3. Subsequent inflammatory reaction.

1. CALCIUM OVERLOAD. Upon restoration of blood
supply, the ischaemic cell is further bathed by
the blood fluid that has more calcium ions at a
time when the ATP stores of the cell are low.

This results in further calcium overload on the

already injured cells, triggering lipid peroxidation
of the membrane causing further membrane
damage.
• 2. GENERATION OF REACTIVE OXYGEN RADICALS.
• Although oxygen is the lifeline of all cells and
tissues, its molecular forms as reactive oxygen
radicals or reactive oxygen species can be most
devastating for the cells.
Mechanism of oxygen free
radical generation
• Normally, metabolism of the cell involves
generation of ATP By oxidative process in which
biradical oxygen (O2) combines with hydrogen
atom (H) and in the process forms water (H2O).

• This reaction of O2 to H2O involves ‘four electron

donation’ in four steps involving transfer of one
electron at each step.
• Oxygen free radicals are the intermediate
chemical species having an unpaired oxygen in
their outer orbit.

• These are generated within mitochondrial inner

membrane where cytochrome oxidase catalyses
the O2 to H2O reaction.
• Three intermediate molecules of partially reduced
species of oxygen are generated depending upon
the number of electrons transferred:

• Superoxide oxygen (O’2): one electron

• Hydrogen peroxide (H2O2): two electrons
• Hydroxyl radical (OH–): three electrons
• These are generated from enzymatic and non-
enzymatic reaction as under:
1. Superoxide (O’2):
Superoxide anion O’2 may be generated by
direct auto-oxidation of O2 during mitochondrial
electron transport reaction.

Alternatively, O2 is produced enzymatically by

xanthine oxidase and cytochrome P450 in the
mitochondria or cytosol. O2 so formed is
catabolised to produce H2O2 by superoxide
dismutase (SOD).
2. Hydrogen peroxide (H2O2):
H2O2 is reduced to water enzymatically by
catalase (in the peroxisomes) and glutathione
peroxidase GSH (both in the cytosol and
mitochondria).
3. Hydroxyl radical (OH–):
OH– radical is formed by 2 ways in biologic
processes—by radiolysis of water and by reaction
of H2O2 with ferrous (Fe++) ions; the latter
process is termed as Fenton reaction.
Cytotoxicity of oxygen free
radicals
• Free radicals are formed in physiologic as well as
pathologic processes.
• Basically, oxygen radicals are unstable and are
destroyed spontaneously.
• The rate of spontaneous destruction is determined by
catalytic action of certain enzymes such as superoxide
dismutase (SOD), catalase and glutathione peroxidase.

• The net effect of free radical injury in physiologic and

disease states, therefore, depends upon the rate of
free radical formation and rate of their elimination.
• However, if not degraded, then free radicals are
highly destructive to the cell since they have
electron-free residue and thus bind to all
molecules of the cell; this is termed oxidative
stress.
• Out of various free radicals, hydroxyl radical is
the most reactive species.

• Free radicals may produce membrane damage by

the said mechanisms:
i) Lipid peroxidation.
Polyunsaturated fatty acids (PUFA) of membrane
are attacked repeatedly and severely by
oxygenderived free radicals to yield highly
destructive PUFA radicals—lipid hydroperoxy
radicals and lipid hypoperoxides.
This reaction is termed lipid peroxidation.
The lipid peroxides are decomposed by transition
metals such as iron.

Lipid peroxidation is propagated to other sites

causing widespread membrane damage and
destruction of organelles.
ii) Oxidation of proteins.
Oxygen-derived free radicals cause cell injury by
oxidation of protein macromolecules of the cells,
crosslinkages of labile amino acids as well as by
fragmentation of polypeptides directly.

The end-result is degradation of cytosolic neutral

proteases and cell destruction.
iii) DNA damage.
Free radicals cause breaks in the single strands of
the nuclear and mitochondrial DNA.

This results in cell injury; it may also cause

malignant transformation of cells.
iv) Cytoskeletal damage.
Reactive oxygen species are also known to interact
with cytoskeletal elements and interfere in
mitochondrial aerobic phosphorylation and thus
cause ATP depletion.
Conditions with free radical
injury
• Currently, oxygenderived free radicals have been
known to play an important role in many forms of
cell injury:
i) Ischaemic reperfusion injury
ii) Ionising radiation by causing radiolysis of
water
iii) Chemical toxicity…
iv) Chemical carcinogenesis
v) Hyperoxia (toxicity due to oxygen therapy)
vi) Cellular aging
vii) Killing of microbial agents
viii) Inflammatory damage
ix) Destruction of tumour cells
x) Atherosclerosis.
3. SUBSEQUENTI NFLAMMATORY
EACTION.
• Ischaemia-reperfusion event is followed by
inflammatory reaction.
• Incoming activated neutrophils utilise oxygen
quickly (oxygen burst) and release a lot of oxygen
free radicals.

• Ischaemia is also associated with accumulation of

precursors of ATP, namely ADP and pyruvate,
which further build-up generation of free radicals.
Pathogenesis of Chemical Injury
• Chemicals induce cell injury by one of the two
mechanisms: by direct cytotoxicity, or by
conversion of chemical into reactive metabolites.

• DIRECT CYTOTOXIC EFFECTS.

• Some chemicals combine with
components of the cell and produce direct
cytotoxicity without requiring metabolic
activation.
• The cytotoxic damage is usually greatest to cells
which are involved in the metabolism of such
chemicals e.g. in mercuric chloride poisoning, the
greatest damage occurs to cells of the alimentary
tract where it is absorbed and kidney where it is
excreted.
• Cyanide kills the cell by poisoning mitochondrial
cytochrome oxidase thus blocking oxidative
phosphorylation.
• Other examples of directly cytotoxic chemicals
include chemotherapeutic agents used in
treatment of cancer, toxic heavy metals such as
mercury, lead and iron.
CONVERSION TO REACTIVE
TOXIC METABOLITES.
• This mechanism involves metabolic activation to
yield ultimate toxin that interacts with the target
cells.
• The target cells in this group of chemicals may
not be the same cell that metabolised the toxin.

• Example of cell injury by conversion of reactive

metabolites is toxic liver necrosis caused by
carbon tetrachloride (CCl4), acetaminophen
(commonly used analgesic and antipyretic) and
bromobenzene.
• Cell injury by CCl4 is classic example of an
industrial toxin (earlier used in drycleaning
industry) that produces cell injury by conversion
to a highly toxic free radical, CCl3, in the body’s
drug-metabolizing P450 enzyme system in the
liver cells.
• Thus, it produces profound liver cell injury by free
radical generation.

• Other mechanism of cell injury includes direct

toxic effect on cell membrane and nucleus.
Pathogenesis of Physical Injury
• Injuries caused by mechanical force are of
medicolegal significance. But they may lead to a
state of shock.
• Injuries by changes in atmospheric pressure (e.g.
decompression sickness).

• Radiation injury to human by accidental or

therapeutic exposure is of importance in
treatment of persons with malignant tumours as
well as may have carcinogenic influences
• Killing of cells by ionising radiation is the result
of direct formation of hydroxyl radicals from
radiolysis of water.

• These hydroxyl radicals damage the cell

membrane as well as may interact with DNA of
the target cell.
• In proliferating cells, there is inhibition of DNA
replication and eventual cell death by apoptosis
(e.g. epithelial cells).

• In non-proliferating cells there is no effect of

inhibition of DNA synthesis and in these cells
there is cell membrane damage followed by cell
death by necrosis (e.g. neurons).
IRREVERSIBLE CELL
INJURY
IRREVERSIBLE CELL INJURY
(CELL DEATH)
• Cell death is a state of irreversible injury. It may
occur in the living body as a local or focal change
(i.e. autolysis, necrosis and apoptosis) and the
changes that follow it (i.e. gangrene and
pathologic calcification), or result in end of the
life (somatic death).

• These pathologic processes involved in cell death

are:
AUTOLYSIS
• Autolysis (i.e. self-digestion) is disintegration of
the cell by its own hydrolytic enzymes liberated
from lysosomes.

• Autolysis can occur in the living body when it is

surrounded by inflammatory reaction (vital
reaction), but the term is generally used for
postmortem change in which there is complete
absence of surrounding inflammatory response.
• Autolysis is rapid in some tissues rich in
hydrolytic enzymes such as in the pancreas, and
gastric mucosa; intermediate in tissues like the
heart, liver and kidney; and slow in fibrous tissue.

• Morphologically, autolysis is identified by

homogeneous and eosinophilic cytoplasm with
loss of cellular details and remains of cell as
debris.
NECROSIS
• Necrosis is defined as a localised area of death of
tissue followed by degradation of tissue by hydrolytic
enzymes liberated from dead cells.
• It is invariably accompanied by inflammatory
reaction.

• Necrosis can be caused by various agents such as

hypoxia, chemical and physical agents, microbial
agents, immunological injury, etc.
• Two essential changes characterize irreversible cell
injury in necrosis of all types:
i) Cell digestion by lytic enzymes.
Morphologically this change is identified as
homogeneous and intensely eosinophilic
cytoplasm.

Occasionally, it may show cytoplasmic vacuolation

or dystrophic calcification.
ii) Denaturation of proteins.
This process is morphologically seen as
characteristic nuclear changes in necrotic cell.

• These nuclear changes may include: condensation

of nuclear chromatin (pyknosis) which may either
undergo dissolution (karyolysis) or fragmentation
into many granular clumps (karyorrhexis).
Types of Necrosis
• Morphologically, there are five types of necrosis:
• Coagulative necrosis
• liquefaction (colliquative) necrosis
• Caseous necrosis
• Fat necrosis
• fibrinoid necrosis
1. COAGULATIVE NECROSIS
• This is the most common type of necrosis caused
by irreversible focal injury, mostly from sudden
cessation of blood flow (ischaemia), and less
often from bacterial and chemical agents.

• The organs commonly affected are the heart,

kidney, and spleen.
• Grossly, 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 ithe conversion of normal cells into their
‘tombstones’ i.e. outlines of the cells are retained so
that the cell type can still be recognised 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
(c.f. liquefaction necrosis).

• Eventually, the necrosed focus is infiltrated by

inflammatory cells and the dead cells are
phagocytosed leaving granular debris and
fragments of cells
2. LIQUEFACTION
(COLLIQUATIVE) NECROSIS.
• Liquefaction or colliquative necrosis occurs
commonly due to ischaemic injury and bacterial
or fungal infections.

• It occurs due to degradation of tissue by the

action of powerful hydrolytic enzymes.
• The common examples are infarct brain and
abscess cavity.
• Grossly, 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 and
proliferating fibroblasts in the case of abscess
cavity
3. CASEOUS NECROSIS.
• Caseous necrosis is found in the centre of foci of
tuberculous infections.

• It combines features of both coagulative and

liquefactive necrosis.
• 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.
4. FAT NECROSIS
• Fat necrosis is a special form of cell death occurring at two
anatomically different locations but morphologically similar lesions.
• These are:
• Acute pancreatic necrosis, and traumatic fat necrosis commonly in
breasts.
• In the case of pancreas, there is liberation of
pancreatic lipases from injured or inflamed tissue
that results in necrosis of the pancreas as well as
of the fat depots throughout the peritoneal
cavity, and sometimes, even affecting the
extraabdominal adipose tissue.
• Fat necrosis hydrolyses neutral fat present in
adipose cells into glycerol and free fatty acids.
• The damaged adipose cells assume cloudy
appearance.

• The leaked out free fatty acids complex with

calcium to form calcium soaps (saponification)
discussed later under dystrophic calcification.
• 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
have cloudy appearance and are surrounded by
an inflammatory reaction.
• Formation of calcium soaps is identified in the
tissue sections as amorphous, granular and
basophilic material.
5. FIBRINOID NECROSIS
• Fibrinoid necrosis is characterised by deposition
of fibrin-like material which has the staining
properties of fibrin.
• It is encountered in various examples of
immunologic tissue injury (e.g. in immune
complex vasculitis, autoimmune diseases, Arthus
reaction etc), arterioles in hypertension, peptic
ulcer etc.
• Microscopically, fibrinoid necrosis is identified by
brightly eosinophilic, hyaline-like deposition in
the vessel wall.

• Necrotic focus is surrounded by nuclear debris of

neutrophils (leucocytoclasis).
• Local haemorrhage may occur due to rupture of
the blood vessel.
APOPTOSIS
• Apoptosis is a form of ‘coordinated and internally
programmed cell death’ having significance in a
variety of physiologic and pathologic conditions
(apoptosis is a Greek word meaning ‘falling off’ o
‘dropping off’).
Dr Raghu Nataraj
• The term was first introduced in 1972 as distinct
from necrosis by being a form of cell death which
is controlled and regulated by the rate of cell
division; when the cell is not needed, pathway of
cell death is activated (‘cell suicide’) and is
unaccompanied by any inflammation and
collateral tissue damage.

• Apoptosis is responsible for mediating cell death

in a wide variety o physiologic and pathologic
processes as under:
Physiologic Processes:
• 1. Organised cell destruction in sculpting of
tissues during development of embryo.
• 2. Physiologic involution of cells in hormone-
dependent tissues e.g. endometrial shedding,
regression of lactating breast after withdrawal of
breast-feeding.

• 3. Normal cell destruction followed by

replacement proliferation such as in intestinal
epithelium.
• 4. Involution of the thymus in early age.
Pathologic Processes
• 1. Cell death in tumours exposed to
chemotherapeutic agents.
• 2. Cell death by cytotoxic T cells in immune
mechanisms such as in graft-versus-host disease
and rejection reactions.

• 3. Progressive depletion of CD4+T cells in the

pathogenesis of AIDS.
• 4. Cell death in viral infections e.g. formation of
Councilman bodies in viral hepatitis.
• 5. 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.

• 6. Cell death in response to injurious agents

involved in causation of necrosis e.g. radiation,
hypoxia and mild thermal injury.
• 7. In degenerative diseases of CNS e.g. in
Alzheimer’s disease, Parkinson’s disease, and
chronic infective dementias.

• 8. Heart diseases e.g. heart failure, acute

myocardial infarction (20% necrosis and 80%
apoptosis).
MORPHOLOGIC FEATURES
The characteristic morphologic changes in
apoptosis seen in histologic and electron
microscopic examination are as under:
• 1. Involvement of single cells or small clusters of
cells in the background of viable cells.
• 2. The apoptotic cells are round to oval shrunken
masses of intensely eosinophilic cytoplasm
(mummified cell) containing shrunken or almost-
normal organelles
• 3. The nuclear chromatin is condensed or
fragmented (pyknosis or karyorrehexis).

• 4. The cell membrane may show convolutions or

projections on the surface.
• 5. There may be formation of membrane-bound
nearspherical bodies on or around the cell called
apoptotic bodies containing compacted
organelles.

• 6. Characteristically, unlike necrosis, there is no

acute inflammatory reaction around apoptosis.
• 7. Phagocytosis of apoptotic bodies by
macrophages takes place at varying speed.

• There may be swift phagocytosis, or loosely

floating apoptotic cells after losing contact, with
each other and basement membrane as single
cells, or may result in major cell loss in the tissue
without significant change in the overall tissue
structure.
Techniques to identify and
count apoptotic cells.
• In addition to routine H & E stain, apoptotic cells
can be identified and counted by following
methods:
• 1. Staining of chromatin condensation
(haematoxylin, Feulgen, acridine orange).
• 2. Flow cytometry to visualise rapid cell
shrinkage.
• 3. DNA changes detected by in situ techniques or
by gel electrophoresis.
• 4. Annexin V as marker for apoptotic cell
membrane having phosphatidylserine on the cell
exterior.
BIOCHEMICAL CHANGES
Biochemical processes underlying the morphologic
changes are as under:
• 1. Proteolysis of cytoskeletal proteins.
• 2. Protein-protein cross linking.
• 3. Fragmentation of nuclear chromatin by
activation of nuclease.
• 4. Appearance of phosphatidylserine on the outer
surface of cell membrane.
• 5. In some forms of apoptosis, appearance of an
adhesive glycoprotein thrombospondin on the
outer surface of apoptotic bodies.

• 6. Appearance of phosphatidylserine and

thrombospondin on the outer surface of apoptotic
cell facilitates early recognition by macrophages
for phagocytosis prior to appearance of
inflammatory cells.
MOLECULAR MECHANISMS OF
APOPTOSIS
1. Initiators of apoptosis.
Triggers for signalling programmed cell death act
at the cell membrane, either intracellularly or
extracellularly. These include the following:

• i) Withdrawal of signals required for normal cell

survival (e.g. absence of certain hormones,
growth factors, cytokines).
• ii) Extracellular signals triggering of programmed
cell death (e.g. activation of FAS receptor
belonging to TNF-R family).

• iii) Intracellular stimuli e.g. heat, radiation,

hypoxia etc.
2. Process of programmed cell
death.
• After the cell has been initiated into self-destruct
mode, the programme inbuilt in the cell gets
activated as under:

• i) Activation of caspases. Caspases are a series of

proteolytic or protein-splitting enzymes which act
on nuclear proteins and organelles containing
protein components.
• The term ‘caspase’ is derived from: c for cystein
protease; asp for aspartic acid; and ase is used
for naming an enzyme.

• Caspases get activated either by coming in

contact with some etiologic agent of cell injury
agent or by unknown mechanism.
• ii) Activation of death receptors. Activated
caspases set in activation of FAS receptor (CD
95), a cell surface receptor present on cytotoxic
(CD 8+) T cells, belonging to the family of tumour
necrosis factor receptors (TNF-R).

• FAS receptor is appropriately called a death

receptor because on coming in contact with the
specific binding site on the target cell, it
activates specific growth controlling genes, BCL-2
and p53.
iii) Activation of growth controlling genes (BCL-2
and p53).
• BCL- 2 gene is a human counterpart of CED-9 (cell
death) gene found in programmed cell death of
nematode worm Caenorabditis elegans.

• BCL-2 gene family is located in the outer

mitochondrial membrane and includes both
activators and inhibitors of apoptosis.
• Thus, it may regulate the apoptotic process by
binding to some related proteins (e.g. to BAX and
BAD) for promoting apoptosis, or to BCL-XL for
inhibiting apoptosis.

• The net effect on the mitochondrial membrane is

thus based on the pro-apoptotic and anti-
apoptotic actions of BCL-2 gene family.
• Besides BCL-2, the apoptotic pathway is partly
also governed by p53 molecule which promotes
apoptosis.
iv) Cell death.
The above mechanisms lead to proteolytic actions
on nucleus, chromatin clumping, cytoskeletal
damage, disruption of endoplasmic reticulum,
mitochondrial damage, and disturbed cell
membrane.
3. Phagocytosis
• The dead apoptotic cells develop membrane
changes which promote their phagocytosis.
• Phosphatidylserine and thrombospondin
molecules which are normally present on the
inside of the cell membrane, appear on the outer
surface of the cells in apoptosis, which facilitate
their identification by adjacent phagocytes and
promotes phagocytosis.
• The phagocytosis is unaccompanied by any other
inflammatory cells.
GANGRENE
• Gangrene is a form of necrosis of tissue with
superadded putrefaction.

• The type of necrosis is usually coagulative due to

ischaemia (e.g. in gangrene of the bowel,
gangrene of limb).

• On the other hand, gangrenous or necrotising

inflammation is characterised by primarily
inflammation provoked by virulent bacteria
resulting in massive tissue necrosis.
• Thus, the end-result of necrotising inflammation
and gangrene is the same but the way the two
are produced, is different.

• The examples of necrotising inflammation are:

• gangrenous appendicitis
• gangrenous stomatitis (noma, cancrum oris).
• There are 2 main forms of gangrene
• dry gangrene
• Wet gangrene &
• A variant form of wet gangrene called gas
gangrene.

• In all types of gangrene, necrosis undergoes

liquefaction by the action of putrefactive
bacteria.
Dry Gangrene
• This form of gangrene begins in the distal part of
a limb due to ischaemia.
• The typical example is the dry gangrene in the
toes and feet of an old patient due to
arteriosclerosis.

• Other causes of dry gangrene foot include

thromboangiitis obliterans (Buerger’s disease),
Raynaud’s disease, trauma, ergot poisoning.
• It is usually initiated in one of the toes which is
farthest from the blood supply, containing so
little blood that even the invading bacteria find it
hard to grow in the necrosed tissue.
• 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.
MORPHOLOGIC FEATURES
• Grossly, the affected part is dry, shrunken 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, there is necrosis with smudging of

the tissue. The line of separation consists of
inflammatory granulation tissue
Wet Gangrene
• Wet gangrene occurs in naturally moist tissues
and organs such as the mouth, bowel, lung,
cervix, vulva etc.

• Diabetic foot is another example of wet gangrene

due to high sugar content in the necrosed tissue
which favours growth of bacteria.
• Bed sores occurring in a bed-ridden patient due
to pressure on sites like the sacrum, buttocks and
heels are the other important clinical conditions
included in wet gangrene.

• Wet gangrene usually 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.

• The spreading wet gangrene generally lacks

clear-cut line of demarcation and may spread to
peritoneal cavity causing peritonitis.
MORPHOLOGIC FEATURES
• 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, there is 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.
GAS GANGRENE
• It is a special form of wet gangrene caused by
gas-forming clostridia (gram-positive anaerobic
bacteria) which 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.

• Clostridia produce various toxins which produce

necrosis and oedema locally and are also
absorbed producing profound systemic
manifestations
MORPHOLOGIC FEATURES
• 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.

PATHOLOGIC CALCIFICATION
• Deposition of calcium salts in tissues other than
osteoid or enamel is called pathologic or
heterotopic calcification.

• Two distinct types of pathologic calcification are

recognised:
Dystrophic calcification
• Characterised by deposition of calcium salts in
dead or degenerated tissues with normal calcium
metabolism and normal serum calcium levels.
Metastatic calcification
• Occurs in apparently normal tissues and is
associated with deranged calcium metabolism
and hypercalcaemia.
• Etiology and pathogenesis of the two are
different but morphologically the deposits in both
resemble normal minerals of the bone.
Histologically
• In routine 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 like silver impregnation method of von-
Kossa producing black colour, and alizarin red S
that produces red staining.

• Pathologic calcification is often accompanied by

diffuse or granular deposits of iron giving positive
Prussian blue reaction in Perl’s stain
Etiopathogenesis
• The two types of pathologic calcification result
from distinctly different etiologies and
mechanisms.
• As apparent from definition, dystrophic
calcification may occur due to 2 types of causes:
• Calcification in dead tissue
• Calcification of degenerated tissue.
Calcification in dead tissue
• 1. Caseous necrosis in tuberculosis is the most
common site for dystrophic calcification. Living
bacilli may be present even in calcified
tuberculous lesions, lymph nodes, lungs, etc.

• 2. Liquefaction necrosis in chronic abscesses may

get calcified.
• 3. Fat necrosis following acute pancreatitis or
traumatic fat necrosis in the breast results in
deposition of calcium soaps.
• 4. Gamna-Gandy bodies in chronic venous
congestion (CVC) of the spleen is characterised
by calcific deposits admixed with haemosiderin
on fibrous tissue.

• 5. Infarcts may sometimes undergo dystrophic

calcification.
• 6. Thrombi, especially in the veins, may produce
phleboliths.

• 7. Haematomas in the vicinity of bones may

undergo dystrophic calcification.
• 8. Dead parasites like in hydatid cyst,
Schistosoma eggs, and cysticercosis are some of
the examples showing dystrophic calcification.
• 9. Calcification in breast cancer detected by
mammography.

• 10. Congenital toxoplasmosis involving the

central nervous system visualised by calcification
in the infant brain.
Calcification in degenerated
tissues
• 1. Dense old scars may undergo hyaline
degeneration and subsequent calcification.
• 2. Atheromas in the aorta and coronaries
frequently undergo calcification.
Calcification in degenerated
tissues
• 3. Mönckeberg’s sclerosis shows calcification in
the tunica media of muscular arteries in elderly
people.
• 4. Stroma of tumours such as uterine fibroids,
breast cancer, thyroid adenoma, goitre etc show
calcification.
Calcification in degenerated
tissues
• 5. Some tumours show characteristic spherules of
calcification called psammoma bodies or
calcospherites such as in meningioma, papillary
serous cystadenocarcinoma of the ovary and
papillary carcinoma of the thyroid.
• 6. Cysts which have been present for a long time
may show calcification of their walls e.g.
epidermal and pilar cysts.
Calcification in degenerated
tissues
• 7. Calcinosis cutis is a condition of unknown
cause in which there are irregular nodular
deposits of calcium salts in the skin and
subcutaneous tissue.
• 8. 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.
Pathogenesis of dystrophic
calcification.
• It is not quite clear as to how dystrophic
calcification takes place.
• Since serum calcium levels are within normal
limits, the denatured proteins in necrotic or
degenerated tissue bind phosphate ions, which
react with calcium ions to form precipitates of
calcium phosphate.
• The process of dystrophic calcification has been
likened to the formation of normal hydroxyapatite
in the bone involving 2 phases:

• initiation
• propagation.
• Initiation is the phase in which precipitates of
calcium phosphate begin to accumulate
intracellularly in the mitochondria, or
extracellularly in membrane-bound vesicles.
• Propagation is the phase in which minerals
deposited in the initiation phase are propagated
to form mineral crystals
METASTATIC CALCIFICATION
• Since metastatic calcification occurs in normal
tissues due to hypercalcaemia, its causes would
include one of the following two conditions:
• Excessive mobilisation of calcium from the bone.
• Excessive absorption of calcium from the gut.
• Excessive mobilisation of calcium from the bone.
• These causes are more common and include the
following:
• 1. Hyperparathyroidism which may be primary
such as due to parathyroid adenoma, or
secondary such as from parathyroid hyperplasia,
chronic renal failure etc.
• 2. Bony destructive lesions such as multiple
myeloma, metastatic carcinoma.
• 3. Prolonged immobilisation of a patient results
in disuse atrophy of the bones and
hypercalcaemia.
• Excessive absorption of calcium from the gut.
Less often, excess calcium may be absorbed from
the gut causing hypercalcaemia and metastatic
calcification.
• These causes are as under:
• 1. Hypervitaminosis D results in increased
calcium absorption
• 2. Milk-alkali syndrome caused by excessive oral
intake of calcium in the form of milk and
administration of calcium carbonate in the
treatment of peptic ulcer.
• 3. Hypercalcaemia of infancy is another condition
in which metastatic calcification may occur
Sites of metastatic calcification
• Metastatic calcification may occur in any normal
tissue of the body but affects the following
organs more commonly:
• 1. Kidneys, especially at the basement membrane
of tubular epithelium and in the tubular lumina
causing nephrocalcinosis.
• 2. Lungs, especially in the alveolar walls.
• 3. Stomach, on the acid-secreting fundal glands.
• 4. Blood vessels, especially on the internal elastic
lamina.
• 5. Cornea is another site affected by metastatic
calcification.
• 6. Synovium of the joint causing pain and
dysfunction.
Pathogenesis of metastatic
calcification
• Metasatic calcification at the above-mentioned
sites occurs due to excessive binding of inorganic
phosphate ions with calcium ions, which are
elevated due to underlying metabolic
derangement.
• This leads to formation of precipitates of calcium
phosphate at the preferential sites.

• Metastatic calcification is reversible upon

correction of underlying metabolic disorder.
ATROPHY
• Reduction of the number and size of parenchymal
cells of an organ or its parts which was once
normal is called atrophy (compared from
hypoplasia which is the term used for
developmentally small size, and aplasia for
extreme failure of development so that only
rudimentary tissue is present).

• CAUSES. Atrophy may occur from physiologic or

pathologic causes:
A. Physiologic Atrophy
• Atrophy is a normal process of aging in some
tissues, which could be due to loss of endocrine
stimulation or arteriosclerosis.
• For example:
• i) Atrophy of lymphoid tissue in lymph nodes,
appendix and thymus. ii) Atrophy of gonads after
menopause.
• iii) Atrophy of brain with aging.
B. Pathologic atrophy
• The causes are as under:
• 1. Starvation atrophy.
In starvation, there is first depletion of
carbohydrate and fat stores followed by protein
catabolism. There is general weakness, emaciation
and anaemia referred to as cachexia seen in
cancer and severely ill patients
• 2. Ischaemic atrophy.
• Gradual diminution of blood supply due to
atherosclerosis may result in shrinkage of the affected
organ e.g.
• i) Small atrophic kidney in atherosclerosis of renal
artery.
• ii) Atrophy of brain in cerebral atherosclerosis.
• 3. Disuse atrophy.
• Prolonged diminished functional activity is associated
with disuse atrophy of the organ e.g. i) Wasting of
muscles of limb immobilised in cast.
ii) Atrophy of the pancreas in obstruction of pancreatic
duct
• 4. Neuropathic atrophy.
• Interruption in nerve supply leads to wasting of
muscles e.g.
• i) Poliomyelitis
• ii) Motor neuron disease
• iii) Nerve section.
• 5. Endocrine atrophy.
• Loss of endocrine regulatory mechanism results in
reduced metabolic activity of tissues and hence
atrophy e.g.
• i) Hypopituitarism may lead to atrophy of thyroid,
adrenal and gonads.
• ii) Hypothyroidism may cause atrophy of the skin and
its adnexal structures.
• 6. Pressure atrophy.
• Prolonged pressure from benign tumours or cyst or
aneurysm may cause compression and atrophy of the
tissues e.g.
• i) Erosion of spine by tumour in nerve root.
• ii) Erosion of skull by meningioma arising from
piaarachnoid.
• iii) Erosion of sternum by aneurysm of arch of aorta.
• 7. Idiopathic atrophy.
• There are some examples of atrophy where no obvious
cause is present e.g.
i) Myopathies.
ii) Testicular atrophy
MORPHOLOGIC FEATURES
• Irrespective of the underlying cause for atrophy,
the pathologic changes are similar.
• The organ is small, often shrunken.

• The cells become smaller in size but are not dead

cells. Shrinkage in cell size is due to reduction in
cell organelles, chiefly mitochondria,
myofilaments and endoplasmic reticulum.
MORPHOLOGIC FEATURES
• There is often increase in the number of
autophagic vacuoles containing cell debris.

• These autophagic vacuoles may persist to form

‘residual bodies’ in the cell cytoplasm e.g.
lipofuscin pigment granules in brown atrophy.
HYPERTROPHY

• Hypertrophy is an increase in the size of

parenchymal cells resulting in enlargement of the
organ or tissue, without any change in the
number of cells.
• CAUSES.
• Hypertrophy may be physiologic or pathologic.
• In both cases, it is caused either by increased
functional demand or by hormonal stimulation.
• Hypertrophy without accompanying hyperplasia
affects mainly muscles.

• In nondividing cells too, only hypertrophy occurs.

• A. Physiologic hypertrophy.

• Enlarged size of the uterus in pregnancy is an

excellent example of physiologic hypertrophy as
well as hyperplasia.
• B. Pathologic hypertrophy.
• Examples of certain diseases associated with
hypertrophy are as under:
• 1. Hypertrophy of cardiac muscle may occur in a
number of cardiovascular diseases.
• A few conditions producing left ventricular
hypertrophy are as under:
• i) Systemic hypertension
• ii) Aortic valve disease (stenosis and
insufficiency)
• iii) Mitral insufficiency
• 2. Hypertrophy of smooth muscle
• e.g.
• i) Cardiac achalasia (in oesophagus)
• ii) Pyloric stenosis (in stomach)
• iii) Intestinal strictures
• iv) Muscular arteries in hypertension.
• 3. Hypertrophy of skeletal muscle
• e.g. hypertrophied muscles in athletes and
manual labourers.
• 4. Compensatory hypertrophy may occur in an
organ when the contralateral organ is removed
• e.g.
• i) Following nephrectomy on one side in a young
patient, there is compensatory hypertrophy as well as
hyperplasia of the nephrons of the other kidney.
• ii) Adrenal hyperplasia following removal of one
adrenal gland
MORPHOLOGIC FEATURES
• The affected organ is enlarged and heavy.
• For example, a hypertrophied heart of a patient
with systemic hypertension may weigh 700-800 g
as compared to average normal adult weight of
350 g.

• There is enlargement of muscle fibres as well as

of nuclei.
• At ultrastructural level, there is increased
synthesis of DNA and RNA, increased protein
synthesis and increased number of organelles like
mitochondria, endoplasmic reticulum and
myofibrils.
HYPERPLASIA
• Hyperplasia is an increase in the number of
parenchymal cells resulting in enlargement of the
organ or tissue.
• Quite often, both hyperplasia and hypertrophy
occur together.
• Hyperplasia occurs due to increased recruitment
of cells from G0 (resting) phase of the cell cycle
to undergo mitosis, when stimulated.

• All body cells do not possess hyperplastic growth

potential.
• Labile cells (e.g. epithelial cells of the skin and
mucous membranes, cells of the bone marrow
and lymph nodes) and stable cells (e.g.
parenchymal cells of the liver, pancreas, kidney,
adrenal, and thyroid) can undergo hyperplasia,
while permanent cells (e.g. neurons, cardiac and
skeletal muscle) have little or no capacity for
regenerative hyperplastic growth.
• Neoplasia differs from hyperplasia in having
hyperplastic growth with loss of growth-
regulatory mechanism due to change in genetic
composition of the cell.

• Hyperplasia, on the other hand, persists so long

as stimulus is present.
• CAUSES. As with other non-neoplastic adaptive
disorders of growth, hyperplasia has also been
divided into physiologic and pathologic.
A. Physiologic hyperplasia
• The two most common types are as follows:
• 1. Hormonal hyperplasia i.e. hyperplasia
occurring under the influence of hormonal
stimulation e.g.
• i) Hyperplasia of female breast at puberty, during
pregnancy and lactation.
• ii) Hyperplasia of pregnant uterus.
• iii) Proliferative activity of normal endometrium after a
normal menstrual cycle.
• iv) Prostatic hyperplasia in old age.
• 2. Compensatory hyperplasia i.e. hyperplasia
occurring following removal of part of an organ or
a contralateral organ in paired organ e.g.
• i) Regeneration of the liver following partial
hepatectomy
• ii) Regeneration of epidermis after skin abrasion
• iii) Following nephrectomy on one side, there is
hyperplasia of nephrons of the other kidney
B. Pathologic hyperplasia
• Most examples of pathologic hyperplasia are due
to excessive stimulation of hormones or growth
factors e.g.
• i) Endometrial hyperplasia following oestrogen
excess.
ii) In wound healing, there is formation of
granulation tissue due to proliferation of
fibroblasts and endothelial cells.
• iii) Formation of skin warts from hyperplasia of
epidermis due to human papilloma virus.
• iv) Pseudocarcinomatous hyperplasia of the skin.

• v) Intraductal epithelial hyperplasia in the breast

in fibrocystic breast disease.
• PATHOLOGIC FEATURES.
• There is enlargement of the affected organ or tissue
and increase in the number of cells.
• This is due to increased rate of DNA synthesis and
hence increased mitoses of the cells.
METAPLASIA
• Metaplasia is defined as a reversible change of
one type of epithelial or mesenchymal adult cells
to another type of adult epithelial or
mesenchymal cells, usually in response to
abnormal stimuli, and often reverts back to
normal on removal of stimulus.

• However, if the stimulus persists for a long time,

epithelial metaplasia may transform into cancer.
• Metaplasia is broadly divided into 2 types:
• Epithelial
• Mesenchymal.
A. EPITHELIAL METAPLASIA
• This is the more common type.
• The metaplastic change may be patchy or diffuse
and usually results in replacement by stronger
but less wellspecialised epithelium.
• However, the metaplastic epithelium being less
well-specialised such as squamous type, results
in deprivation of protective mucus secretion and
hence more prone to infection.

• Depending upon the type epithelium

transformed, two types of epithelial metaplasia
are seen squamous and columnar
1. Squamous metaplasia
• This is more common.
• Various types of specialised epithelium are
capable of undergoing squamous metaplastic
change due to chronic irritation that may be
mechanical, chemical or infective in origin.

• Some common examples of squamous metaplasia

are seen at following sites:
• i) In bronchus (normally lined by pseudostratified
columnar ciliated epithelium) in chronic smokers.
• ii) In uterine endocervix (normally lined by simple
columnar epithelium) in prolapse of the uterus
and in old age.
• iii) In gallbladder (normally lined by simple
columnar epithelium) in chronic cholecystitis with
cholelithiasis.
• iv) In prostate (ducts normally lined by simple
columnar epithelium) in chronic prostatitis and
oestrogen therapy.
• v) In renal pelvis and urinary bladder (normally
lined by transitional epithelium) in chronic
infection and stones.
• vi) In vitamin A deficiency, apart from
xerophthalmia, there is squamous metaplasia in
the nose, bronchi, urinary tract, lacrimal and
salivary glands.
2. Columnar Metaplasia
• There are some conditions in which there is
transformation to columnar epithelium.
• For example:
• i) Intestinal metaplasia in healed chronic gastric
ulcer.
• ii) Columnar metaplasia in Barrett’s oesophagus,
in which there is change of normal squamous
epithelium to columnar epithelium.
• iii) Conversion of pseudostratified ciliated
columnar epithelium in chronic bronchitis and
bronchiectasis to columnar type.

• iv) In cervical erosion (congenital and adult type),

there is variable area of endocervical glandular
mucosa everted into the vagina.
B. MESENCHYMAL METAPLASIA
• A. Less often, there is transformation of one adult
type of mesenchymal tissue to another. The
examples are as under:
• 1. Osseous metaplasia. Osseous metaplasia is
formation of bone in fibrous tissue, cartilage and
myxoid tissue.
• Examples of osseous metaplasia are as under:
• i) In arterial wall in old age (Mönckeberg’s medial
calcific sclerosis)
• ii) In soft tissues in myositis ossificans
• iii) In cartilage of larynx and bronchi in elderly
people
• iv) In scar of chronic inflammation of prolonged
duration
• v) In the fibrous stroma of tumour.
• 2. Cartilaginous metaplasia.
• In healing of fractures, cartilaginous metaplasia
may occur where there is undue mobility.
DYSPLASIA
• Dysplasia means ‘disordered cellular
development’, often accompanied with
metaplasia and hyperplasia;
• It is therefore also referred to as atypical
hyperplasia.

• Dysplasia occurs most often in epithelial cells.

• Epithelial dysplasia is characterised by cellular
proliferation and cytologic changes.
• These changes include:
• 1. Increased number of layers of epithelial cells
• 2. Disorderly arrangement of cells from basal
layer to the surface layer
• 3. Loss of basal polarity i.e. nuclei lying away
from basement membrane
• 4. Cellular and nuclear pleomorphism
• 5. Increased nucleocytoplasmic ratio.
• 6. Nuclear hyperchromatism
• 7. Increased mitotic activity.

• The two most common examples of dysplastic

changes are the uterine cervix and respiratory
tract.
• Dysplastic changes often occur due to chronic
irritation or prolonged inflammation.
• On removal of the inciting stimulus, the changes
may disappear.

• In a proportion of cases, however, dysplasia

progresses into carcinoma in situ (cancer
confined to layers superficial to basement
membrane) or invasive cancer.
CELLULAR AGING
• Old age is a concept of longevity in human
beings.
• The consequences of aging appear after
reproductive age.

• However, aging is distinct from mortality and

disease although aged individuals are more
vulnerable to disease.
• The average age of death of primitive man was
barely 20-25 years compared to life-expectancy
now which is approaching 80 years, survival
being longer in women than men (3:2).
• In general, the life expectancy of an individual
depends upon the following factors:
• 1. Intrinsic genetic process i.e. the genes
controlling response to endogenous and
exogenous factors initiating apoptosis in senility.
• 2. Environmental factors e.g. consumption and
inhalation of harmful substances, diet, role of
antioxidants etc.
• 3. Lifestyle of the individual such as diseases due
to alcoholism (e.g. cirrhosis, hepatocellular
carcinoma), smoking (e.g. bronchogenic
carcinoma and other respiratory diseases), drug
addiction.
• 4. Age-related diseases e.g. atherosclerosis and
ischaemic heart disease, diabetes mellitus,
hypertension, osteoporosis, Alzheimer’s disease,
Parkinson’s disease etc.
• The following hypotheses based on investigations
explain the cellular basis of aging:
• 1. Experimental cellular senescence.
• By in vitro studies of tissue culture, it has been
observed that cultured human fibroblasts
replicate for up to 50 population doublings and
then the culture dies out.
• It means that in vitro there is reduced functional
capacity to proliferate with age.
• Studies have shown that there is either loss of
chromosome 1 or deletion of its long arm (1q).
• Alternatively it has been observed that with
every cell division there is progressive shortening
of telomere present at the tips of chromosomes,
which in normal cell is repaired by the presence
of RNA enzyme, telomerase.

• However, due to aging, because of inadequate

presence of telomerase enzyme, lost telomere is
not repaired resulting in interference in viability
of cell.
• 2. Genetic control in invertebrates.
• Clock (clk) genes responsible for controlling the
rate and time of aging have been identified in
lower invertebrates e.g. clk-1 gene mutation in
the metazoa, Caenorhabditis elegans, results in
prolonging the lifespan of the worm and slowing
of some metabolic functions.
• 3. Diseases of accelerated aging.
• Aging under genetic control in human beings is
supported by the observation of high
concordance in lifespan of identical twins.
• A heritable condition associated with signs of
accelerated aging process is termed progeria and
is characterised by baldness, cataracts, and
coronary artery disease.
• Another example is Werner’s syndrome, a rare
autosomal recessive disease, characterised by
similar features of premature aging,
atherosclerosis and risk for development of
various cancers.
• 4. Oxidative stress hypothesis (free radical-
mediated injury).
• Currently, it is believed that aging is partly
caused by progressive and reversible molecular
oxidative damage due to persistent oxidative
stress on the human cells.

• In normal cells, very small amount (3%) of total

oxygen consumption by the cell is converted into
reactive oxygen species.
• The rate of generation of reactive oxygen species
is directly correlated with metabolic rate of the
organisms.

• With aging, there is low metabolic rate with

generation of toxic oxygen radicals, which fail to
get eliminated causing their accumulation and
hence cell damage.
• The underlying mechanism appears to be
oxidative damage to mitochondria.

• The role of antioxidant in retarding the oxidant

damage has been reported in some studies.
ORGAN CHANGES IN AGING
• Although all organs start showing deterioration
with aging, following organs show evident
morphologic and functional changes:
• 1. Cardiovascular system: Atherosclerosis,
arteriosclerosis with calcification, Mönckeberg’s
medial calcification, brown atrophy of heart, loss
of elastic tissue from aorta and major arterial
trunks causing their dilatation.
• 2. Nervous system: Atrophy of gyri and sulci,
Alzheimer’s disease, Parkinson’s disease.

• 3. Musculoskeletal system: Degenerative bone

diseases, frequent fractures due to loss of bone
density, age related muscular degeneration.
• 4. Eyes: Deterioration of vision due to cataract
and vascular changes in retina.

• 5. Hearing: Disability in hearing due to senility is

related to otosclerosis.
• 6. Immune system: Reduced IgG response to
antigens, frequent and severe infections.
• 7. Skin: Laxity of skin due to loss of elastic tissue.

• 8. Cancers: 80% of cancers occur in the age range

of 50 and 80 years.
******