INTRODUCTION TO

THE DISCIPLINE OF
PATHOLOGY

April 2023, HUCHS

REFERENCE
GOAL
 The principal goal of the second year pathology
course in medical schools is to foster
understanding of the mechanisms of
disease(pathogenesis) as a foundation for
dealing with a vast amount of clinical
information the student will encounter in later
clinical years

3
THE PRINCIPAL OBJECTIVES
 To use pathology to facilitate medical education
 understanding mechanisms is more a function of
logic than of a memory
 To leave students with a lasting knowledge of
pathology
 To use pathology as the scientific basis of the”
art” of medicine

4
WHAT IS PATHOLOGY
 Pathology literally is the study (logos) of
suffering (pathos)
 Pathology is the scientific study of disease
 Pathology is the foundation of medical science
& practice
 Pathology is a bridging discipline devoted to the
study of the structure & functional changes in
cells, tissues & organs that underlie diseases

5
 Pathology attempts to explore the “ whys” and “
wherefores” of the signs and symptoms of
diseases
 Pathology much of it has a visible expressions _
Radiographs
_ CT-scans
_ MRI (magnetic resonance
imaging)
_ Ultrasound
_ Clear drawings
MOLECULAR abnormalities

6
HISTORY OF PATHOLOGY
 Era of Medical Antiquity
the early dominance of animism
PLATO & PYTHOGORAS

 Era of Morbid Anatomy

Autopsies performed scientifically from about
1500A.D,19th century in Germany
ROKITANSKY&ASCHOFF

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 The application of MICROSCOPY
revolutionized medicine
Pasteur’s demonstration

Rudolf Virchow (1821-1902)

CELLULAR PATHOLOGY

The impact of pathology in the realm of

molecular changes
Cancer,Congenital diseases

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Rudolph Virchow
1821-1902
The Father of
Modern Pathology
THE SCOPE OF PATHOLOGY
 Scientific knowledge about human diseases is
derived from observations on patients or , by
analogy, from experimental studies on animals
& cell cultures.
 Clinical medicine is based on a longitudinal
approach to a patient’s illness
 Clinical pathology is more concerned with a
cross-sectional analysis at the level of the
disease itself, studied in depth- the cause &
mechanisms of the disease, & the effects of
the disease upon the various organs&systems 10
SUBDIVISIONS OF PATHOLOGY
 Histopathology: the investigation & diagnosis of
disease from the examination of tissues
 Cytopathology:the investigation & the diagnosis
of disease from the examination of isolated
cells
 Haematology:the study of the disorders of the
cellular & coagulable components of blood

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 Toxicology: the study of the effects of known
or suspected poisons
 Forensic pathology: the application of pathology
to legal purposes( e.g. investigation of death in
suspicious circumstances)
 Chemical pathology : the study & diagnosis of
disease from the chemical changes in tissues &
fluids

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TECHNIQUES OF PATHOLOGY
 Light Microscopy- the structure of tissues &
cells in health & disease
 Histochemistry- is the study of the chemistry
of tissues
 Immunohistochemistry- employ
antibodies( immunoglobulins with antigen
specificity) to visualize substances in tissues
sections or cell preparations

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 Electron Microscopy- study of disorders at an
organelle level, & to the demonstration of viruses
in tissue samples
 Biochemical techniques-fluid & electrolyte
homeostasis, serum enzyme assays e.g.raised
levels of cardiac enzymes in the blood
 Haematological techniques- in the diagnosis &
study of blood disorders

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 Molecular Pathology-many advances come from
the relatively new science of molecular
pathology
defects in the chemical structure of
molecules arising from errors in the genome,
using IN SITU HYBRIDISATION e.g.Hg
molecule,collagen molecule, alterations in the
genome governing the controlof cell & tissue
growth

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GENERAL & SYSTEMATIC
PATHOLOGY
 General Pathology: is our current understanding
of the causation mechanisms ,and
characteristics of the major categories of
disease( e.g. congenital versus acquired
diseases,inflammation,tumors,degenerations)
 General Pathology is the foundation of
knowledge that has to be laid down

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 Systematic Pathology is our current knowledge
of specific diseases as they affect individual
organs or systems( e.g.appendicitis, lung cancer,
atheroma).
 “Systematic” should not be confused with
“Systemic”

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LEARNING PATHOLOGY
 There are two apparent difficulties that face
the new student of pathology:
LANGUAGE&PROCESS
 The student must not confuse the learning of
the language with the learning of the
mechanisms of disease and their effects on
individual organs and patients e.g. the term
hyperplasia

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 Pathology is learnt through a variety of
media -text book
-relatively didactic lectures
-tutorials
-demonstrations( gross &
microscopic examination of diseased
tissues)
-post – mortem teaching
-problem- solving orientated
practical classes
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 Disease Mechanisms constitute general
pathology
 A logical & orderly way of thinking about
diseases& their characteristics must be
cultivated -incidence
-etiology
-pathogenesis
-pathological and clinical
features -complications and sequelae
-prognosis

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PATHOGENESIS
 Refers to the sequence of events in the
response of the cells or tissues to the
etiologic agent, from the initial stimulus
to the ultimate expression of the
disease.
 The mechanism through which the
etilogy( cause) operates to produce the
pathological and clinical manifestations.
 Examples include:
inflammation,degeneration ,
carcinogenesis,immune reactions 21
MAKING DIAGNOSES
 Diagnosis is the act of naming a disease in an
individual patient
 The process of making diagnoses involves: taking
a clinical history to document
symptoms,examining the patient for clinical
signs& if necessary, performing investigations
guided by the provisional diagnosis based on
signs & symptoms

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DIAGNOSTIC PATHOLOGY
 In living patients we investigate & diagnose their
illness by applying pathological methods to the
examination of TISSUE BIOPSIES& BODY
FLUIDS
 Biopsies are samples of tissue removed from a
patient for diagnostic purposes.
 Resections specimens are the whole or part of an
organ removed for a previously diagnosed
condition.

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 Biopsies can be obtained by a variety of
methods: needle biopsy, endoscopic biopsy
and incisional biopsy
 Cytology involves the examination and
interpretation of dispersed cells rather
than solid tissues,usually for the diagnosis
of cancer & pre-cancerous lesions.
 These cells can be obtained by a variety
of methods according to the organ being
investigated

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 Exfoliative cytology: cells shed from, or
scraped or brushed off ,an epithelial
surface
 Fluid cytology :cells withdrawn with the
fluid in which they are suspended
 Washings: cells flushed out of an organ
using an irrigating fluid
 Fine –needle aspiration cytology: cells
sucked out of a solid tissue using a thin
needle attached to a syringe.
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AUTOPSIES
 Autopsy( necropsy and post- mortem examination
are synonymous)
 Autopsy means to ‘see for oneself’
 Autopsies are used for:

-determining the cause of death

-audit of the accuracy of clinical
diagnosis
-education of undergraduates &
postgraduates

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 Research into the causes and mechanisms of
disease
 Gathering accurate statistics about disease
incidence
 There has been a regrettable decline in the
autopsy rate during the latter half of the 20th
century

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CELLULAR ADAPTATIONS, CELL
INJURY AND CELL
DEATH
- The normal cell is confined to a fairly normal
range of function & structure. It is nevertheless
able to handle normal physiologic demands,
maintaining steady state called homeostasis.
- More severe physiologic stresses & some
pathologic stimuli may bring about a number of
physiologic & morphologic cellular adaptation.
 If the limits of adaptive response to a stimulus
are exceeded, or the cell is exposed to an
injurious agent or stress , a sequence of events
follows that is termed Cell injury.
STAGES OF THE CELLULAR
RESPONSE TO STRESS AND
INJURIOUS STIMULI.
 Acute reversible changes
Cellular swelling (hydropic change or vacuolar degeneration)
 Chronic reversible changes
Cellular adaptation of growth and differentiation :
 hypertrophy and hyperplasia
 atrophy and involution
 metaplasia
Intracellular accumulation of lipids :
 fatty change (steatosis)
 cholesterolosis
Intra cellular Pigment accumulation :
 lipofuscin
 melanin
 hemosiderin
 bilirubin
Extracellular accumulation of proteins
Hyalinosis
Amyloidosis
Pathological calcification (metastatic and
dystrophic)
 Irreversible cell changes (cell death)

Apoptosis
Necrosis
THE RELATIONSHIP BETWEEN NORMAL,
ADAPTED, REVERSIBLY INJURED, AND DEAD
MYOCARDIAL CELLS
Cellular adaptation
- It is a new but altered steady state which
preserves the viability of the cell & modulates
its function as it responds to a stimuli.
HYPERPLASIA
- It is an increase in number of cells in an organ or
tissue , usually resulting in increased volume of the
organ or tissue.

- Hyperplasia takes place if the cellular population is

capable of synthesizing DNA or able to undergo
mitotic division.

- Usually,it occurs together with hypertrophy.

- It can be physiologic or pathologic.
PHYSIOLOGIC HYPERPLASIA

1. Hormonal hyperplasia which increases the

functional capacity of a tissue when needed.
eg. Proliferation of glandular epithelium of
female breast during pregnancy & puberty or
physiologic hyperplasia that occurs in pregnant
uterus.
2. Compensatory hyperplasia, which increases
tissue mass after damage or partial resection.
Eg.
- Liver regeneration after partial resection.
- After unilateral nephrectomy , when the
remaining kidney undergoes compensatory
hyperplasia.
 PATHOLOGIC HYPERPLASIA

- Most are caused by excessive hormonal stimulation or

growth factors acting on target cells eg. Endometrial
hyperplasia (due to estrogen), benign prostatic
hyperplasia (due to androgen).

- Its response to normal regulatory mechanisms

distinguishes benign pathologic hyperplasia from cancer.

- However, Pathologic hyperplasia constitutes a fertile soil

in which cancerous proliferation may eventually arise.
ENDOMETRIAL HYPERPLASIA,
GROSS
 Usually results with
conditions of
prolonged estrogen
excess and can lead to
metrorrhagia (uterine
bleeding at irregular
intervals),
menorrhagia
(excessive bleeding
with menstrual
periods), or
menometrorrhagia.
ENDOMETRIAL HYPERPLASIA,
MICROSCOPY
THYROID HYPERPLASIA
MICROSCOPY: THYROID
HYPERPLASIA
BENIGN PROSTATIC
HYPERPLASIA
 The normal adult male
prostate is about 3 to 4
cm in diameter. The
number of prostatic
glands, as well as the
stroma, has increased in
this enlarged prostate
seen in cross section. The
pattern of increase here is
not uniform, but nodular.
This increase is in
response to hormonal
manipulation, but in this
case is not a normal
physiologic process.
PROSTATIC HYPERPLASIA,
MICROSCOPY
 HYPERTROPHY
- It refers to an increase in the size of cells , resulting in an
increase in the size of the organ.

- The increase in size is due to synthesis of more structural

components.

- It can be physiologic or pathologic & is caused by increased

functional demand or by specific hormonal stimulation.

- Example:

the enlargement of the left ventricle in

hypertensive heart disease & the increase in
skeletal muscle during strenuous exercise.
SKELETAL MUSCLE HYPERTROPHY
IN BODYBUILDERS
PHYSIOLOGIC HYPERTROPHY OF
THE UTERUS DURING PREGNANCY
 Gross appearance of a normal uterus (right) and a gravid
uterus (removed for postpartum bleeding) (left). B, Small
spindle-shaped uterine smooth muscle cells from a normal
uterus, compared with C, large plump cells from the gravid
uterus, at the same magnification

gravid smooth muscle

normal

normal uterus gravid uterus

LEFT VENTRICULAR
HYPERTROPHY
wall thickness over 2 cm (normal, 1-1.5 cm).
 In untreated severe
hypertension
MYOCARDIAL CELL
HYPERTROPHY
 Cells have higher DNA content (92
chromosomes)
 ATROPHY
- Shrinkage in the size of the cell by loss of cell substance

- Atrophy can be physiologic or pathologic.

- Physiologicatrophy is common during early development.

- Early embryonic structures such as thyroglossal duct
undergo atrophy during fetal development.
- Uterus decreases in size shortly after parturition.
PATHOLOGIC ATROPHY…
 can be local or generalized

 The common causes of atrophy are the following

 Decreased work load (Atrophy of disuse)

 Loss of innervation (denervation atrophy)
 Diminished blood supply
 Inadequate nutrition
 Loss of endocrine stimulation
 Aging

 Pressure
BRAIN ATROPHY: LOSS OF BRAIN SUBSTANCE
NARROWS THE GYRI AND WIDENS THE SULCI
 A: Normal brain B: Atrophy of the
brain
BRAIN ATROPHY: ALZHEIMER’S
DISEASE
 notewide sulci caused by narrowed [lost
tissue] gyri
TESTES
Normal Atrophic
KIDNEY
 Ureteric obstruction=> pressure atrophy of renal
cortex & hydronephrosis
SEVERE ADVANCED CARPAL
TUNNEL SYNDROME
 Thenar muscle atrophy (arrow)
NEUROGENIC SKELETAL
MUSCLE ATROPHY
 trichrome stain
METAPLASIA
- It is a reversible change in which one adult cell
type (epithelial or mesenchymal) is replaced by
another adult cell type.

- It may represent an adaptive substitution of

cells that are sensitive to stress by cell types
better able to withstand the adverse
environment.
METAPLASIA….
- The most common metaplasia is columnar to
squamous. The normal ciliated columnar
epithelial cells of the trachea & bronchi are
often replaced focally or widely by stratified
squamous epithelial cells in cigarette smokers.

 The influences that predispose to metaplasia , if

persistent, may induce malignant transformation
in metaplastic epithelium.
METAPLASIA OF COLUMNAR TO
SQUAMOUS EPITHELIUM
 A, Schematic
diagram.
 B, Metaplasia of
columnar epithelium
(left) to squamous
epithelium (right) in a
bronchus
BRONCHUS: SQUAMOUS
METAPLASIA
ENDOCERVIX, SQUAMOUS
METAPLASIA
ENDOCERVIX: SQUAMOUS
METAPLASIA
METAPLASIA….
 Metaplasia from squamous to columnar type
(Barret esophagus) may also occur. Esophageal
squamous epithelium is replaced by intestinal –
like columnar under the influence of refluxed
gastric acid.
 Cancers may arise that are typically glandular
carcinoma (adenocarcinoma).
BARRETT’S ESOPHAGUS
METAPLASIA….
 Connective tissue metaplasia is the formation of
cartilage , bone or adipose tissue (mesenchymal
tissue) in tissues that normally do not contain
these elements. Myositis ossificans – bone
formation in muscle after bone fracture.
MYOSITIS OSSIFICANS

 X-ray  Microscopy
MYOSITIS OSSIFICANS, MICROSCOPY
CELL INJURY
 Cell injury results when cells are stressed so severely
that they no longer able to adapt or the cells are
exposed to inherently damaging agents . These
alterations may be divided into the following stages

 Reversible cell injury – is manifested as functional &

morphologic changes that are reversible if the
damaging stimulus is removed.

 Irreversible injury or cell death – with continuing

damage , the injury becomes irreversible .
 CAUSES OF CELL INJURY

 Oxygen deprivation
- Hypoxia is a deficiency of oxygen , which causes cell injury by reducing aerobic
oxidative respiration. It should be distinguished from ischemia , which is loss of
blood supply from impeded arterial flow or reduced venous drainage in tissue.
- Causes of hypoxia include cardiorespiratory failure, anemia, carbon monoxide
poisoning.

 Physical agents – mechanical trauma, extremes of temperature, sudden changes

in atmospheric pressure.

 Chemical agents & Drugs

 Infectious agents

 Immunologic reactions

 Genetic derangements

 Nutritional imbalance
SEQUENTIAL DEVELOPMENT OF BIOCHEMICAL AND
MORPHOLOGIC CHANGES IN CELL INJURY.
MECHANISMS OF CELL INJURY
- Principles that are relevant to most forms of cell
injury.

 The cellular response to injurious stimuli

depends on the type of injury, its duration & its
severity.

 The consequences of cell injury depend on the

type, state, & adaptability of the injured cell.
 Cell injury results from functional & biochemical
abnormalities in one or more of several essential
cellular components. The most important targets
of injurious stimuli are;
 Aerobic respiration involving mitochondrial
oxidative phosphorylation & production of ATP
 The integrity of cell membranes
 Protein synthesis
 The cytoskeleton
 The integrity of the genetic apparatus of the
cell
 Biochemical mechanisms that are responsible for
cell injury induced by different stimuli
- Depletion of ATP
- Mitochondrial damage

- Influx of intracellular calcium & loss of

calcium homeostasis
- Accumulation of oxygen –derived free radicals
(oxidative stress)
- Defects in membrane permeability
MORPHOLOGY OF CELL INJURY &
NECROSIS
Reversible injury
Two patterns of reversible cell injury can be
recognized under the light microscope
 Cell swelling

- The first manifestation of injury

- It appears whenever the cells are incapable of

maintaining ionic & fluid homeostasis & is result
of loss of function of plasma membrane energy-
dependent ion pumps.
 Fatty change
- It is manifested by the appearance of small &
large lipid vacuoles in the cytoplasm & occurs in
hypoxic & various toxic injury.
- It is principally seen in cells involved in &
dependent on fat metabolism such as
hepatocytes & myocardial cells.
 Cell death
- Necrosis
- Apoptosis
Necrosis
- It refers to a spectrum of morphologic changes that
follow cell death in a living tissue resulting from the
progressive degradative action of enzymes in lethally
injured cells.
- Necrosis is cell death occurring in the setting of
irreversible exogenous injury.
- Necrotic cells aren’t able to maintain membrane
integrity & their content leak out & elicit inflammation
in the surrounding tissue.
Morphology
- The morphologic features of necrosis is the
result of denaturation of intracellular proteins &
enzymatic digestion of the cell.
- These processes require hrs to develop so there
would be no detectable change immediately.
- Necrotic cells show increased eosinophilia due to loss
the normal basophilia impartd by RNA in the
cytoplasm
Nuclear changes
- Karyolysis – The basophilia of the nucleus fades

- Pyknosis- Nuclear shrinkage & increased basophilia

- Karyorrhexis – Nuclear fragmentation

 B

 A, Normal myocardium. B, Myocardium with

coagulation necrosis having inflammatory response

88
Morphologic patterns of necrosis
Coagulative necrosis
- Most often results from sudden interruption of
blood supply to an organ.
- It is, in early stages, characterized by general
preservation of tissue architecture when
denaturation is the primary pattern.
RENAL INFARCTION - COAGULATIVE

90
Liquefactive necrosis
- It is characterized by digestion of tissue. It
shows softening & liquefaction of tissue. It
characteristically results from ischemic injury
to the CNS. It also occurs in suppurative
infections characterized by formation of pus.
LIVER ABSCESS: LIQUIFACTIVE
NECROSIS

95
 A B

 Coagulative and liquefactive necrosis. A, Kidney

infarct;
 B, A focus of liquefactive necrosis in the kidney
caused by fungal infection.
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 Gangrenous necrosis
- It is due to vascular occlusion & most affects
the lower extremities & the bowel.
- It Is called wet gangrene if it is complicated by
bacterial infection which leads to superimposed
liquefactive necrosis. Dry gangrene if there is
only coagulative necrosis without liquefactive
necrosis.
GANGRENE - AMPUTATED DIABETIC
FOOT
GANGRENOUS BOWEL INFARCTION
Caseous necrosis
- It is type of necrosis most often seen in foci of
tuberculous infection
- The term caseous is derived from the cheesy
white gross appearance of the area of necrosis
- On microscopic examination, the necrotic focus
appears as amorphous granular debris enclosed
within a distinctive inflammatory border known
as a granulomatous reaction
MICROSCOPY OF CASEOUS
NECROSIS
Fat necrosis
- Focal areas of fat destruction, typically
occurring as a result of release of activated
pancreatic lipases into the substance of the
pancreas & the peritoneal cavity. This occurs in
acute pancreatitis.
- The activated enzymes liquefy fat cell
membranes &The lipases split the triglyceride
contained with in fat cells. The released fatty
acids combine with calcium to produce grossly
visible chalky white areas (fat saponification)
FAT NECROSIS AND
SAPONIFICATION
On histological examination , foci of shadowy
outlines of necrotic fat cells with basophilic
calcium deposits & surrounded by an
inflammatory reaction
 Necrosis can be followed by release of
intracellular enzymes into the blood ( creatinine
kinase or troponin in myocardial infarction ) ,
inflammation or dystrophic calcification ( if
necrotic cells are not phagocytosed , they tend
to attract calcium salts )
Fibrinoid necrosis is a special form of necrosis
usually seen in immune reactions involving blood
vessels.
 This pattern of necrosis typically occurs when
complexes of antigens and antibodies are
deposited in the walls of arteries.
 Deposits of these “immune complexes,” together
with fibrin that has leaked out of vessels, result
in a bright pink and amorphous appearance in
H&E stains, called “fibrinoid” (fibrin-like).
FIBRINOID NECROSIS IN AN
ARTERY.
Apoptosis
- It is a pathway of cell death that is induced by
tightly regulated intracellular program in which
cells destined to die activate enzymes that
degrade the cells’ own nuclear DNA & nuclear &
cytoplasmic proteins
Apoptosis in physiologic situations
 Programmed destruction of cells during embryogenesis


 Hormone –dependent involution in the adult such as endometrial

cell breakdown during menstrual cycle , the regression of the
lactating breast after weaning

 Cell deletion in proliferating cell populations

 Death of host cells that have served their useful purpose such as
neutrophils in acute inflammatory response

 Elimination of potentially harmful self reactive lymphocytes

 Cell death induced by cytotoxicT cells that serves eliminate virus
infected & tumor cells
Apoptosis in Pathologic conditions
 Cell death produced by a variety of injurious stimuli
such as radiation & cytotoxic anticancer drugs

 Cell injury in certain viral diseases such as viral

hepatitis

 Pathologic atrophy in parenchymal organs after duct

obstruction

 Cell death in tumors

MORPHOLOGY

The following morphologic features characterize cells

undergoing apoptosis
- Cell shrinkage

- Chromatin condensation

- Formation of cytoplasmic blebs & apoptotic bodies.

The apoptotic cell undergoes fragmentation into
membrane bound apoptotic bodies

- Phagocytosisof apoptotic cells or cell bodies usually

by macrophages
- On histologic examination , apoptosis involves
single cells or small cluster of cells . The
apoptotic cells appear as a round or oval mass of
intensely eosinophilic cytoplasm with dense
nuclear chromatin fragments
 A, EPIDERMAL APOPTOSIS IN IMMUNE REACTIO

B, APOPTOSIS OF LIVER CELL IN IMMUNE REACTION(MAGNIFIED )

118
FEATURES OF NECROSIS AND APOPTOSIS
Feature Necrosis Apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis - Fragmentation into
karyorrhexis – nucleosome size
karyolysis fragments
Plasma membrane Disrupted Intact; altered
structure, especially
orientation of lipids
Cellular contents Enzymatic digestion; Intact; may be
may leak out of cell released in apoptotic
bodies
Adjacent Frequent No
inflammation
Physiologic or Invariably pathologic Often physiologic,
pathologic role (culmination of means of eliminating
irreversible cell unwanted cells; may
injury) be pathologic
Subcellular Responses to Injury
- Certain conditions are associated with
distinctive alteration in cell organelles or the
cytoskeleton.
Lysosomal catabolism
- Primary lysosomes are membrane bound intracellular
organelles that contain d/t enzymes . They fuse
with membrane bound vacuoles that contain
material to be digested forming secondary
lysosomes.
 Heterophagy
- It is the process of lysosomal digestion of materials
ingested from the extracellular environment.
- Extracellular materials are taken up through general
process of endocytosis. Uptake of particulate material
is known as phagocytosis; uptake of soluble smaller
macromolecules is called pinocytosis
- It is common in professional phagocytes such as
neutrophils & macrophages
 Autophagy
- It refers to lysosomal digestion of the cells’
own components
- Some lipids may remain undigested by lysosomal
enzymes & persist in cells as residual bodies eg.
Lipofuscin pigment – It represents undigested
material derived from intracellular perioxidation.
LIPOFUSCIN GRANULES
 Liver Heart
Induction (Hypertrophy) of smooth endoplasmic
reticulum
- The smooth ER is involved in the metabolism of
various chemicals & cells exposed to these
chemicals show hypertrophy of the ER as an
adaptive response that may have functional
consequences. Eg protracted use of barbiturates
leads to a state of tolerance , with decrease in
the effects the drug & the need to use
increasing doses . This is due to hypertrophy of
smooth ER of hepatocytes that metabolize the
drug
Cytoskeletal abnormalities
- It consists of microtubules, thin actin filaments ,
thick myosin filaments & various classes of
intermediate filaments
 Thin filaments
They are important for leukocyte movement .
Some drugs & toxins can affect these processes.
 Microtubules
- Defect in microtubules can inhibit sperm motility causing
male sterility & can immobilize the cilia of respiratory
epithelium causing interference with the ability to clear
inhaled bacteria, leading to bronchiectasis (kartagener’s
syndrome – immotile cilia syndrome )

- Microtubules are also important for leukocyte migration &

phagocytosis. Drugs such as colchicine bind to tubulin &
prevent the assembly of microtubules . It is used in acute
attacks of gout.

- Microtubules are also important component of the mitotic

spindle . Drugs (eg vinca alkaloids) can be antiproliferative
& so act as antitumor agents
 Intermediate filaments
- These components provide a flexible intracellular
scaffold that organizes the cytoplasm & resist forces
applied to the cell.
- Intemediate filaments are divided into five classes

1. Keratin filaments (characteristics of epithelial cells)

2. Neurofilaments (neurons)

3. Desmin filaments (muscle cells)

4. Vimentin filaments (connective tissue cells)

5. Glial filaments (astrocytes)

- Mallory body (alcoholic hyaline) is eosinophilic

intracytoplasmic inclusion in liver cells that is
characteristic of alcoholic liver disease it is composed
of keratin filaments.
Intracellular Accumulations
- One of the manifestations of metabolic derangements
in cells is the intracellular accumulation of abnormal
amounts of various substances
- They fall into three categories

 A normal cellular constituent accumulated in excess

such as lipids

 An abnormal substance , either exogenous such as

mineral or product of infectious agents or endogenous
such as product of abnormal synthesis or metabolism

 Pigment
Lipids
Fatty change (Steatosis)
- It implies abnormal accumulation of triglycerides
within parenchymal cells
- It is caused by an imbalance between the
uptake, utilization, & secretion of fat
- It is often seen in liver because it is the major
organ involved in fat metabolism. It also occurs
in heart, muscle & kidney.
- The causes of steatosis include alcohol abuse,
toxins, protein malnutrition, diabetes mellitus,
obesity, & anoxia
FATTY LIVER

135
Morphology
- Fatty change is most often seen in the liver &
heart
- It appears as clear vacuoles within parenchymal
cells. Intracellular accumulation of water or
polysaccharides (glycogen) may also produce
clear vacuoles . To distinguish b/n them, special
stains are used…
 Fat – Sudan IV or oil Red-O both impart orange –
red color to the contained lipids

 Glycogen – periodic acid –Schiff (PAS)

 Water – when neither glycogen or fat can be

demonstrated , it is presumed to contain water
Cholesterol
- Atherosclerosis – Cholesterol & cholesterol esters fill
smooth muscle cells & macrophages within the intimal
layer of the aorta & large arteries

- Xanthoma – intracellular accumulation of cholesterol

within macrophages in the subepithelial connective
tissue of the skin & in tendons

- Cholesterolosis
– focal accumulation of cholesterol
laden macrophages in the lamina propria of the
gallbladder
Proteins
- Intracellular accumulation of proteins usually
appear as rounded, eosinophilic droplets,
vacuoles or aggregates in the cytoplasm
- Excess protein accumulation has various causes
 Reabsorption droplets in proximal renal tubules
are seen in renal diseases associated with
protein loss in the urine (proteinuria)
 Synthesis of excessive amounts of normal
secretory protein such as plasma cells engaged in
active synthesis of immunoglobulins. The ER
becomes hugely distended, producing large ,
homogenous eosinophilic inclusions called Russel
bodies
 Defects in protein folding may underlie some of
depositions.
Hyaline change
- The term hyaline refers to an alteration within
cells or in the extracellular space , which gives a
homogenous, glassy, pink appearance in routine
histologic sections stained with hematoxylin &
eosin. Eg intracellular accumulation of protein
Pigments
- Pigments are colored substances , some of which
are normal constituents of cells (eg melanin)
whereas others are abnormal
- Pigments can be endogenous or exogenous
Exogenous pigments
- Accumulation of carbon or coal dust blacken lung
tissue & involved lymph nodes – anthracosis . When
inhaled , it is picked up by alveolar macrophages & is
transported through lymphatic channels to the
regional LNs in tracheobronchial region.

- Aggregates of excess carbon dust (as in coal miners)

may induce a fibroblastic reaction or emphysema &
cause serious lung disease known as coal worker’s
pneumoconiosis
- Tattooing is a form of localized exogenous
pigmentation of the skin. The pigments
inoculated are phagocytosed by dermal
macrophages
Endogenous pigments
A. Lipofuscin
- It is an insoluble pigment & wear-and-tear or
aging pigment
- It is composed of polymers of lipids &
phospholipids complexed with protein
- It is seen in cells undergoing slow, regressive
changes & is particularly prominent in liver &
heart of aging patients or patients with severe
malnutrition or cancer cachexia
- In tissue sections, it appears as a yellow – brown
finely granular intracytoplasmic perinuclear
pigment
B. Melanin
Melanin is a brownish-black pigment produced by
the melanocytes found in the skin. Increased
melanin pigmentation is caused by suntanning &
certain diseases e.g. nevus, or malignant
melanoma. Decreased melanin pigmentation is
seen in albinism & vitiligo.
B. Bilirubin
Bilirubin is a yellowish pigment, mainly produced
during the degradation of hemoglobin. Excess
accumulation of bilirubin causes yellowish
discoloration of the sclera, mucosa, & internal
organs. Such a yellowish discoloration is called
jaundice.
 Jaundice is most often caused by
i. Hemolytic anemia
Hemolytic anemia is characterized by
increased destruction of red blood cells
ii. Biliary obstruction
This is obstruction of intrahepatic or
extrahepatic bile ducts. It can be caused by
gallstones.
iii. Hepatocellular disease
This is associated with failure of conjugation of
bilirubin.
C. Hemosiderin
- Hemosiderin is a hemoglobin-derived ,golden yellow to
brown, granular or crystalline pigment in which form
iron is stored in cells & is identified by its staining
reaction (blue color) with the Prussian blue dye.
- In cells, It is stored in in form of ferritin . When
there is a local or systemic excess of iron , ferritin
forms hemosiderin granules
- Hemosiderin exists normally in small amounts within
tissue macrophages of the bone marrow, liver, & spleen
as physiologic iron stores.
- It can be local or systemic derangement.
- It accumulates in tissues in excess amounts in certain
diseases.
- Local excesses result from gross or minute
hemorrhages eg bruise
- Systemic overload of iron can be seen

 Increased absorption of dietary iron

 Impaired use of iron
 Hemolytic anemia
 Transfusions
This excess accumulation is divided into 2 types
i. Hemosiderosis
When accumulation of hemosiderin is primarily
within tissue macrophages & is not associated with
tissue damage, it is called hemosiderosis.
ii. Hemochromatosis
When there is more extensive accumulation of
hemosiderin, often within parenchymal cells, which
leads to tissue damage, scarring & organ
dysfunction, it is called hemochromatosis
Pathologic calcification
- It is the abnormal tissue deposition of calcium
salts
- There are two forms of pathologic calcification
Dystrophic calcification
- It is occurs in previously damaged tissue
- It occurs in areas of necrosis (coagulative ,
liquefactive, caseous, enzymatic necrosis of
fat) , atheroma, in aging or damaged heart valves
- Typically, the serum calcium level is normal.
Metastatic calcification
- It occurs in normal tissue whenever there is hypercalcemia.
- There are four principal causes of hypercalcemia

 Increased secretion of parathyroid hormone with

subsequent bone resorption

 Destruction of bone tissue occurring with primary tumors

of bone marrow (multiple myeloma) or diffuse skeletal
metastasis

 Vitamin D – related disorders

 Renal failure
Amyloidosis
- Amyloid is a pathologic proteinaceous
substance deposited between cells in various
tissue & organs of the body in a wide variety of
clinical settings.

- Amyloidosis is not a single disease rather it is a

group of diseases having in common deposition of
similar –appearing proteins
- Clinical diagnosis depends on morphologic
identification of this distinctive substance in
appropriate biopsy specimens

- On light microscopy & standard tissue stains ,

amyloid appears as an amorphous , eosinophilic ,
hyaline, extracellular substance with progressive
accumulation, encroaches on & produces pressure
atrophy of adjacent cells
- To differentiate it from other proteins , congo
red stain is used, it imparts a pink or red color to
tissue deposits under ordinary light. Under
polarizing microscopy green birefringence of
the stained amyloid is seen.
Physical & chemical nature of amyloid
- Amyloid material consists of mainly fibril
proteins with characteristics cross -β pleated
sheet conformation
The three most common forms of amyloid proteins
include
 AL (amyloid light chain) is derived from plasma
cells & contains immunoglobulin light chains

 AA (amyloid-associated) is protein synthesized

by liver

 Aβ amyloid is found in the cerebral lesions of

Alzheimer disease
Classification of amyloidosis
Primary amyloidosis
- Itis usually systemic distribution & is
characterized by deposition of the AL type
- Most patients have some form of plasma cell
dyscrasia such as multiple myeloma
Reactive systemic amyloidosis
- The amyloid deposits in this pattern are
systemic in distribution & are composed of AA
protein
- It occurs secondary to an associated
inflammatory condition - Tuberculosis,
bronchoectasis , chronic osteomyelitis,
rheumatoid arthritis
Cellular Aging
- With age there are physiologic & structural
alteration in almost all organ systems.
- Aging in individuals is affected to great extent
by genetic factors, diet, social conditions &
occurrence of age related diseases
- Aging –induced alterations in cells are an
important components of the aging the organism
- Cellular aging is the result of a progressive
decline in the proliferative capacity & life span
of cells & the effects of continuous exposure to
exogenous influences that result in progressive
accumulation of cellular & molecular damage
These include
 A number of cellular functions decline
progressively with age
- a reduction in oxidative phosphorylation &
synthesis of nucleic acids & structural &
enzymatic proteins , cell receptors &
transcription factors .
- Decreased capacity of uptake of nutrients &
repair of chromosomes
- Accumulation of lipofuscin pigment as sign of
oxidative damage
 Replicative senescence
- Cells have limited capacity for replication This
may be due to a limited number of cellular
divisions that can take place.
- An enzyme called telomerase, which counteracts
the tendency of the ends of chromosomes to
shorten with each cellular division, may have
decreased activity so that the telomeric ends of
chromosomes shorten, and the ability of
chromosomes to replicate is lost. The process of
programmed cell death (apoptosis) may be part
of a sequence of cell maturation
 Presence of genes that influence the aging
process
 Accumulation of metabolic & genetic damage
Cellular life span can be determined by the
balance b/n cellular damage resulting from
metabolic events occurring with in a cell &
counteracting molecular responses that can
repair the damage . One of these metabolic
products are reactive oxygen species whose
damage increases with age