HISTOPATH Reed-Sternberg cells

 Large, abnormal lymphocytes that may contain more than

PATHOLOGY one nucleus.
Definition  These cell are found in Hodgkin lymphoma.
 Latin words: “Patho” and “logy” (Disease and Study)
 Scientific study of disease 2. Cytology
 Disease  The cells from cysts, body cavities or scraped from
 Abnormal variation in structure or function of any body surfaces as aspirated by fine needle from solid
part of the body lesions can also be studied under light microscope.
This study of cells is known as cytology and used
ASPECTS OF DISEASE widely especially in diagnosis and screening of
cancer.
1. Etiology
 Cause of disease 3. Histochemistry (special stains)
 Primary etiology: cause of disease is known  The study of the chemistry of tissues, where tissue /
 Idiopathic etiology: cause of the disease is cells are treated with specific reagent so that the
unknown features of individual cells / structure can be
 Two major classes of etiology factors: visualized.
 Genetic
 Acquired 4. Immunohistochemistry & immunofluorescence
o Infections, nutritional, chemicals,  Utilize antibodies (immunoglobulins with antigen
physical, etc. specificity) to visualize substances in tissue sections
or cell preparations
2. Pathogenesis  Former uses monoclonal antibodies linked chemically
 Mechanisms through which the cause operates to to enzymes and later fluorescent dyes.
produce the pathological and clinical manifestations
 The pathogenetic mechanisms could take place in  Electron Microscopy (EM)
the latent or incubation period.  Useful to the study changes at ultra structural level
 Latent period: etiological agents takes some  The demonstration of viruses in tissue samples in certain
time to manifest the disease diseases
 Incubation period: time between exposure  Most common diagnostic use of EM: interpretation of
and the development of disease biopsy specimen from kidney.
 Pathogenesis leads to morphologic changes

3. Morphologic changes FUNCTIONAL DERANGEMENTS AND CLINICAL SIGNIFICANCE

 The structural alterations in cells or tissues that
1) Functional derangements
occur following the pathogenic mechanisms
 The effects of genetic, biochemical and structural
 Gross morphologic changes: changes that can be
changes in cells and tissues are functional
seen with the naked eye
abnormalities.
 Cirrhosis of liver is characterized by total
 For example, excessive secretion of cell product
replacement of liver by regenerating nodules
(e.g. nasal mucus in the common cold); insufficient
 Microscopic changes: changes that are seen under
secretion of a cell product (e.g. insulin lack in
the microscope
diabetes mellitus).
MICROSCOPY
2) Clinical manifestations
 Light Microscopy
 The functional derangements produce, clinical
1. Histopathology
manifestations of disease, namely symptoms and
 Sections are routinely cut from tissues and
signs.
processed by paraffin-embedding. The sections
 Disease characterized by multiple abnormalities
are cut from the tissue by a special instrument
(symptoms complex) are called syndromes.
called microtome and examined under light
microscope. In certain situations (e.g.
3) Prognosis
histochemistry, rapid diagnosis) sections are cut
 The prognosis forecasts (predicts) the known or
from tissue that has been hardened rapidly by
freezing (frozen section). The sections are stained likely course (outcome) of the disease and,
routinely by hematoxylin and eosin. (H and E). therefore, the fate of the patient.

 Pathognomonic abnormalities 4) Complication

o Structural changes are characteristic of  It is a negative pathologic process or event
occurring during the disease which is not as
a single disease / disease category.
essential part of the disease. It usually aggravates
o The diagnosis should not be made
the illness.
without them.
 For example, perforation and hemorrhage are
 Aschoff bodies: rheumatic heart
complications which may develop in typhoid ulcer of
disease
intestine.
 Reed-Sternberg cells: Hodgkin
lymphoma
5) Sequelae
Aschoff bodies  It is pathologic condition following as a
consequence of a disease. For example, intestinal
 Rheumatic heart disease
obstruction following healed tuberculosis of
 Nodules found in the hearts 0f individuals with rheumatic
intestine, mitral stenosis following healed rheumatic
heart disease
heart disease.
 Fully developed Aschoff bodies are granulomatous
structures consisting of the following: 6) Remission & Relapse
 Fibrinoid change
 Remssion
 Lymphocytic infiltration
 It is the process of conversion from active
 Occasional plasma cells
disease to quiescence. Some of the chronic
 Characteristically abnormal macrophages surrounding
diseases are interspersed by periods of
necrotic centres
 quiescence when the patient is relatively in III. Abrasive cytology
good health.  Refers to methods by which cells are dislodged by
 Relapse various tools from body surfaces (skin, mucous
 It is the process in which the signs and membranes, and serous membranes). E.g.
symptoms of disease reappear. preparation of cervical smears
 Such cervical smears, also called Pap smears, can
DIAGNOSTIC TECHNIQUES USED IN PATHOLOGY significantly reduce the mortality from cervical
The pathologist uses the following techniques to diagnose cancer
diseases:  Cervical cancer is the most common type of cancer
a) Histopathology among women.
b) Cytopathology
c) Hematopathology C. HEMATOLOGICAL EXAMINATION
d) Immunohistochemistry  This is a method by which abnormalities of the cells of the
e) Microbiological examination blood and their precursors in the bone marrow are
f) Biochemical examination investigated to diagnose the different kinds of anemia &
g) Cytogenetics leukemia.
h) Molecular techniques
i) Autopsy D. IMMUNOCHEMISTRY
 This is a method is used to detect a specific antigen in the
A. HISTOPATHOLOGICAL TECHNIQUES tissue in order to identify the type of disease
 Histopathological examination studies tissues under the
microscope. E. MICROBIOLOGICAL EXAMINATION
 During this study, the pathologist looks for abnormal  This is a method by which body fluids, excised tissue, etc.
structures in the tissue. are examined by microscopical, cultural and serogical
 Tissues for histopathological examination are obtained by techniques to identify micro-organisms responsible for
biopsy many diseases.
 Biopsy: is a tissue sample from a living person to identify
the disease. F. BIOCHEMICAL EXAMINATION
 Biopsy can be either incisional or excisional.  This is a method by which the metabolic disturbances of
disease are investigated by assay of various normal and
B. CYTOPATHOLOGICAL TECHNIQUES abnormal compounds in the blood, urine, etc.
The main applications of cytology include of the following:
1) Screening for the early detection of asymptomatic cancer. G. CLINICAL GENETICS (CYTOGENETICS)
For example, the examination of scrapings from cervix for  This is a method in which inherited chromosomal
early detection and prevention of cervical cancer. abnormalities in the germ cells or acquired chromosomal
2) Diagnosis of symptomatic cancer - to diagnose tumors abnormalities in somatic cells are investigated using the
revealed by physical or radiological examinations. techniques of molecular biology
3) It can be used in diagnosis of cysts, inflammatory
conditions and infections of various organs. H. MOLECULAR TECHNIQUES
4) Surveillance of patients treated for cancer - for some  Different molecular techniques such as fluorescent in situ
types of cancers, cytology is the most feasible method of hybridization, Southern blot, etc. Can be used to detect
surveillance to detect recurrence. genetic diseases.

Advantages of cytologic examination I. AUTOPSY

 Compared to histopathogical 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 THE CAUSE OF DISEASE
examination.
TYPES OF CYTOLOGICAL TECHNIQUES
I. Fine-needle aspiration cytology (FNAC) ENVIRONMENTAL FACTORS
 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-needles 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.
II. 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 the body cavities (pleura, pericardium,
and peritoneum), nipple discharge and vaginal
discharge.
 Autopsy is examination of the dead body to identify the
cause of death.
 This can be for forensic of clinical purposes.
 Disease can be caused by either environmental factors,
genetics factors or a combination of the two.
Environmental causes of disease are many and are classified into:
1) Physical agents
 These agents apply excess physical energy, in any
form, to the body.
 These may include the ff:
 Trauma
 Radiation
 Extremes of temperature
 Electric power
2) Chemicals agents
 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.
 Another group exhibits a predilection for
certain organs, for example – the effect of
paracetamol and alcohol on liver.
 3) Nutritional deficiencies & excesses
 Nutritional deficiencies may arise as a result of poor
supply, interference with absorption, inefficient
transport within the body, or defective utilization
 Deficiency either of major classes of food, usually
protein and energy, or vitamins or elements
essential for specific metabolic processes, e.g. iron
for hemoglobin production
 Obesity has become increasingly common, with its
attendant dangers of type 2 diabetes, high blood
pressure and heart disease.
4) Infections & infections
 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)
 Others the damage is done by toxins 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
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.
7) Genetic factors
 These are hereditary factors that are inherited
genetically from parents
COURSE OF DISEASE
The course of disease is shown with a simplified diagram as
follows.
Exposure Biological Onset Clinical Onset
Latency Period Permanent Damage
Death
NATURAL HISTORY OF 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
c) Biological onset of disease; this marks the initiation of the
disease process, however, without any sign or symptom.
Following biological onset of disease, it may remain
asymptomatic or subclinical (i.e. without any clinical
manifestations) or may lead to overt clinical disease.
d) Incubation (induction) period refers to variable period of
time without any obvious signs or symptoms from the
time of exposure.
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
CLINICAL & BIOLOGICAL DEATH
I. Clinical Death
 Reversible transmission between life and biological
death.
 Period of respiratory, circulatory and brain arrest
during which initiation of resuscitation can lead to
recovery.
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. Respiration may be restored in
response to stimulation of the receptors.\
 Recovery can occur with resuscitation
II. 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.
CELLS
INTRODUCTION
 The human body consists of 75 trillion cells that vary
considerably in shape and size yet have much in
common.
 Differences in cell shape make different functions
possible.
Composite Cell
A. A composite cell includes many different cell structures
B. A cell consists three main parts
 Nucleus
 Cytoplasm
 Cell membrane
C. Within the cytoplasm are specialized organelles that
perform specific functions for the cell.
Cell Membrane
1) The cell membrane regulates the movement of
substances in and out of the cell, participates in signal
transduction, and helps cells adhere to other cells.
2) General Characteristics
a) The cell membrane is extremely thin and selectively
permeable
b) It has a complex surface with adaptations to
increase surface area.
 3) Cell Membrane Structure:
a) The basic framework of the cell membrane consists
of a double layer of phospholipids, with fatty acid
tails turned inward.
b) Molecules that are soluble in lipids (gases, steroid
hormones) can pass through the lipid bilayer
c) Embedded cholesterol molecules strengthen the
membrane and help make the membrane less
permeable to water-soluble substances
d) Many types of proteins are found in the cell
membrane, including transmembrane proteins and
peripheral membrane proteins.
e) Membrane proteins perform a variety of functions
and vary in shape
f) Some proteins function as receptors on the cell
surface, starting signal transduction
g) Other proteins aid the passage of molecules and
ions
h) Proteins protruding into the cell anchor supportive
rods and tubules
i) Still other proteins have carbohydrates attached;
these complexes are used in cell identification.
Membrane proteins called Cellular Adhesion
Molecules (CAMs) help determine one cell’s
interactions with others
Cytoplasm
1) The cytoplasm consists of a clear liquid (cytosol), a
supportive cytoskeleton, and networks of membranes and
organelles.
a) Endoplasmic reticulum is made up of membranes,
flattened sacs, and vesicles, and provides a tubular
transport system inside the cell
 With ribosomes, endoplasmic reticulum (ER)
is rough ER, and functions in protein
synthesis.
 Without ribosomes, it is smooth ER, and
functions in lipid synthesis
b) Ribosomes are found with ER and are scattered
throughout the cytoplasm. They are composed of
protein and RNA and provide a structural
support for the RNA molecules that come together
in protein synthesis
c) The Golgi Apparatus is composed of flattened
sacs, and refines, packages, modifies, and
delivers proteins
 Vesicles formed on ER travel to the Golgi
apparatus, which modifies their contents
chemically
 The vesicle may then move to the cell
membrane and secrete its contents to the
outside
 Vesicles form a “delivery service”, carrying
chemicals throughout the cell (vesicle
trafficking)
d) Mitochondria are the powerhouses of the cell
and contain enzymes needed for aerobic
respiration.
 The inner membrane of the mitochondrion is
folded into cristae which hold the enzymes
needed in energy transformations to make
ATP
 Very active cells contain thousands of
mitochondria
e) Lysosomes are the “garbage disposals” of the
cell and contain digestive enzymes to break up old
cell components and bacteria
f) Peroxisomes contain enzymes that function in the
synthesis of bile acids, breakdown of lipids,
degradation of rare biochemicals and detoxification
of alcohol.
g) Microfilaments and microtubules are thin,
thread-like structures that serve as the
cytoskeleton of the cell
h) A Centrosome is made up of two hollow cylinders
called centrioles that function in the separation of
chromosomes during cell division
i) Cilia and Flagella are motile extensions from the
cell; shorter cilia are abundant on the free surfaces
of certain epithelial cells (respiratory linings, for
example), and a lengthy flagellum can be found on
sperm cells.
j) Vesicles form from part of the cell membrane, or the
Golgi apparatus, and store materials
Cell Nucleus
 The fairly large nucleus is bounded by a double-layered
nuclear membrane containing relatively large nuclear
pores that allow the passage of certain substances
 The nucleolus is composed of RNA and protein and
is the site of ribosome production
 Chromatin consists of loosely coiled fibers of protein
and DNA
MOVEMENTS THROUGH CELL MEMBRANES
I. The cell membrane controls what passes through it
II. Mechanisms of movement across the membrane may be
passive, requiring no energy from the cell (diffusion,
facilitated diffusion, osmosis, and filtration) or active
mechanisms, requiring cellular energy (active transport,
endocytosis and exocytosis)
Passive Mechanisms
1) Diffusion
 Diffusion is caused by the random motion of
molecules and involves the movement of molecules
from an area of greater concentration to one of
lesser concentration until equilibrium is reached
 Diffusion enables oxygen and carbon dioxide
molecules to be exchanged between the air and the
blood in the lungs, and between blood and tissue
cells.
2) Facilitated Diffusion
 Used membrane proteins that function as carriers to
move molecules (such as glucose) across the cell
membrane
 The number of carrier molecules in the cell
membrane limits the rate of this process.
3) Osmosis
 A special case of diffusion in which water moves
from an area of greater water concentration (where
there is less osmotic pressure) across a selectively
permeable membrane to an area of lower water
concentration (where there is greater osmotic
pressure)
 Osmotic pressure is the ability of osmosis to lift a
volume of water
 A solution with the same osmotic pressure as body
fluids is called isotonic; one with higher osmotic
pressure than body fluids is hypertonic; one with
lower osmotic pressure is hyptonic
4) Filtration
 Because of hydrostatic pressure, molecules can be
forced through membranes by the process of
filtration. Blood pressure is a type of hydrostatic
pressure
Active Mechanisms
1) Active Transport
 Uses ATP to move molecules from areas of low
concentration to areas of high concentration through
carrier molecules in cell membranes.
 As much as 40% of a cell’s energy supply may be
used to fuel this process
 The union of the specific particle to be transported
with its carrier protein triggers the release of cellular
energy (ATP), which in turn alters the shape of the
carrier protein, releasing the particle to the other
side of the membrane.
 Particles that are actively transported include
sugars, amino acids, and sodium, potassium,
calcium, and hydrogen ions, as well as nutrient
molecules in the intestines

2) Endocytosis and Exocytosis
 In endocytosis, molecules that are too large to be
transported by other means are engulfed by an
invagination of the cell membrane and carried into
the cell surrounded by a vesicle
 Exocytosis is the reverse of endocytosis
 Three forms of endocytosis are pinocytosis,
phagocytosis & receptor-mediated endocytosis
 Pinocytosis is a form of endocytosis in which
cells engulf liquids
 Phagocytosis is a form of endocytosis in
which the cell takes in larger particles, such as
a white blood cell engulfing a bacterium
 Receptor-mediated endocytosis allows the
cell to take in very specific molecules
(ligands) that pair up with specific receptors
on the cell surface
THE CELL CYCLE
1) In one type of cell division, meiosis, four cell (sperm or
ova) are produced, each of which contains half of the
parent cell’s genetic information
2) Mitosis is a carefully orchestrated division of the nucleus
of the cell that results in each daughter cell receiving an
exact copy of the mother cell’s genetic material
3) Mitosis is describes as a series of four stages, but the
process is actually continuous
4) Prophase, the first stage of mitosis, results in the DNA
considering into chromosomes, centrioles migrating to the
poles, microtubules of the cytoskeleton reorganizing into
spindle fibers, and the disappearance of the nuclear
membrane
5) Metaphase occurs as spindle fibers attach to
centromeres on the chromosomes and the chromosomes
align midway between centrioles
6) Anaphase occurs as the spindle fibers contract and pull
the sister chromatids toward the centrioles
7) Telophase, the final stage of mitosis, begins when the
chromosomes have completed their migrations, the
nuclear envelope reappears, and the chromosomes begin
to unwind
Cytoplasmic Division
 Cytokinesis begins during anaphase of mitosis and
continues as a contractile ring pinches the two new cells
apart
 The two daughter cells may be have varying amounts of
cytoplasm and organelles, but they share identical genetic
information
Cell Differentiation
 The process by which cells develop into different types of
cells with specialized functions is called differentiation.
 Cell differentiation reflects genetic control of the nucleus
as certain genes are turned on while others are turned off
Cell Death
 Apoptosis is a form of cell death that is a normal part of
development.
GENERAL PATHOLOGY LECTURE 2
CELLULAR REACTIONS TO INJURY
INTRODUCTION
 When a cell is exposed to an injurious agent the possible
outcomes are:
 The cell may adapt to the situation
 The cell may acquire a reversible injury
 The call may obtain an irreversible injury & may die
o The cell may die via:
 Necrosis
 Apoptosis
I. TYPES OF CELLULAR ADAPTATION
The types of cellular adaptation include:
 Hypertrophy
 Atrophy
 Hyperplasia
 Metaplasia
A. Hypertrophy
 Increase in the size. Increased workload leads to
increased protein synthesis & increased size &
number of intracellular organelles which, in turn,
leads to increased cell size. The increased cell size
leads to increased size of the organ
 Example: the enlargement of the left ventricle in
hypertensive heart disease & the increase in
skeletal muscle during strenuous exercise
B. Hyperplasia
 Is an increase in the number of cells. It can lead to
an increase in the size of the organ
 It is usually caused by hormonal stimulation
 It can be physiological as in enlargement of the
breast during pregnancy or it can pathological as in
endometrial hyperplasia
C. Atrophy
 Decrease in the size of a cell but not in the
number
 Can lead to decreased size of the organ
 Physiologic and pathologic
 The atrophic cells shows autophagic vacuoles
which contain cellular debris from degraded
organelles
 Atrophy can be caused by:
 Disuse
 Under nutrition
 Decreased endocrine stimulation
 Denervation
 Old age
D. Metaplasia
 Is the replacement of one differentiated tissue by
another differentiated tissue. There are different
types of metaplasia. Examples include:
1. Squamous metaplasia
 This is replacement of another type of
epithelium by squamous epithelium. For
example, the columnar epithelium of the
bronchus can be replaced by squamous
epithelium in cigarette smokers
2. Osseous metaplasia
 This replacement of a connective tissue by
bone, for example at sites of injury
II. REVERSIBLE CELLULAR CHANGES &
ACCUMULATIONS
 Even though there are many different kinds of reversible
cellular changes & accumulations, here we will only
mention fatty change & accumulation of pigments.
1. Fatty change
 This is accumulation of triglycerides inside
parenchymal cells. It is caused by an
imbalance between the uptake, utilization, and
secretion of fat. Fatty change is usually seen
in the liver, heart, or kidney. Fatty liver may be
caused by alcohol, diabetes mellitus,
malnutrition, obesity & poisoning.
 These etiologies cause accumulation of fat in
the hepatocytes by the following mechanisms:
a) Increased uptake of triglycerides into the
parenchymal cells
b) Decreased use of fat by cells
c) Overproduction of fat in cells
d) Decreased secretion of fat from the cells
2. The accumulation of pigments
 Pigments can be exogenous or endogenous
 Endogenous pigments include melanin,
bilirubin, hemosiderin, & lipofuscin
 Exogenous pigments include carbon
  These pigments can accumulate inside cells
in different situations
a) Melanin
 Is a brownish-black pigment produced by
the melanocytes found in the skin
 Increased melanin pigmentation is caused by
sun tanning and certain disease e.g. nevus, or
malignant melanoma
 Decreased melanin pigmentation is seen in
albinism and vitiligo
b) Bilirubin
 Is a yellowish pigment, mainly produced
during the degradation of hemoglobin. Excess
accumulation of bilirubin causes yellowish
discoloration of the sclera, mucosae, &
internal organs. Such as yellowish
discoloration is called jaundice
 Jaundice is most often caused by:
a. Hemolytic anemia
 Is characterized by increased
destruction of red blood cells
b. Biliary obstruction
 This is obstruction of intrahepatic
or extrahepatic bile ducts. It can
be caused by gallstones.
c. Hepatocellular disease
 This is associated with failure of
conjugation of bilirubin
c) Hemosiderin
 Is an iron-containing pigment derived from
ferritin. It appears in tissues as golden
brown amorphous aggregates & is identified
by its staining reaction (blue color) with the
Prussian blue dye
 Hemosiderin exists normally in small amounts
within tissue macrophages of the bone
marrow, liver & spleen as physiologic iron
stores
 It accumulates in tissues in excess amounts in
certain diseases
The excess accumulation is divided into 2 types:
 Hemosiderosis
 When accumulation of hemosiderin is primarily
within tissue macrophages & is not associated
with tissue damage, it is called hemosiderosis
 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
III. Cell Death
 Cells can die via one of the following two ways:
1. Necrosis
2. Apoptosis
1. Necrosis
 In necrosis, excess fluid enters the cell, swells it, &
ruptures its membrane which kills it. After the cell has
died, intracellular degradative reactions occur within a
living organism
 Necrosis does not occur in dead organisms. In dead
organisms, autolysis & heterolysis take place.
 Necrosis occurs by the following mechanisms:
a) Hypoxia
b) Free radical-induced cell injury
c) Cell membrane damage
d) Increased intracellular calcium level
A. Hypoxia
 Hypoxia is decreased oxygen supply to tissues. It
can be caused by:
1. Ischemia
 Decrease blood flow to or from an
organ. Can be caused by obstruction of
arterial blood flow – the most common
cause, or by decreased perfusion of
tissues by oxygen-carrying blood as
occurs in cardiac failure, hypertension &
shock.
2. Anemia
 A reduction in the number of oxygen-
carrying red blood cells
3. Carbon monoxide poisoning
 CO decreases the oxygen-capacity of
red blood cells by chemical alteration of
hemoglobin
4. Poor oxygenation of blood due to
pulmonary disease
 The cell injury that results following
hypoxia can be divided into early & late
stages:
1) Early (reversible) stages of
hypoxic cell injury
 At this stage, hypoxia results in
decreased oxidative
phosphorylation & ATP
synthesis. Decreased ATP
leads to:
a) Failure of the cell membrane
Na – K pump, which leads to
increased intracellular Na &
water, which cause cellular
& organelle swelling. All of
the above changes are
reversible if the hypoxia is
corrected
b) Disaggregation of ribosomes
& failure of protein synthesis
2) Late (irreversible) stages of
hypoxic cell injury
 This is caused by severe or
prolonged injury. It is caused by
massive calcium influx & very
low pH, which lead to activation
of enzymes, which damage the
cell membrane & organelle
membranes
 Irreversible damage to the
mitochondria, cell membranes,
& the nucleus mark the point of
no return for the cell, that is
after this stage, the cell is
destined to die
 Release of aspartate
aminotransferase (AST),
creatine phosphokinase (CPK)
& lactate dehydrogenase (LDH)
leads to myocardial infarction
B. Free radical –induced injury
 Examples include superoxide & the hydroxyl
radicals. Free radicals are formed by normal
metabolism, oxygen toxicity, ionizing radiation, &
drugs and chemicals, & reperfusion injury. They are
degraded by spontaneous decay, intracellular
enzymes such as glutathione peroxidase, catalase,
or superoxide dismutase & endogenous substances
such as ceruloplasmin or transferrin.
 When the production of free radicals exceeds their
degradation, the excess free radicals cause
membrane pump damage
 ATP depletion & DNA damage. These can cause
cell injury & cell death
 a) Cell membrane damage
 Direct cell membrane damage as in extremes of
temperature, toxins, or viruses, or indirect cell
membrane damage as in the case of hypoxia can
lead to cell death by disrupting the homeostasis of
the cell
b) Increased intracellular calcium level
 The cell membrane damage leads to increased
intracellular calcium level
 The increased cytosolic calcium, in turn, activates
enzymes in the presence of low pH. The activated
enzymes will degrade the cellular organelles
TYPES OF NECROSIS
The types of necrosis include:
1. Coagulative necrosis
 Coagulative necrosis most often results from
sudden interruption of blood supply to an
organ, especially to the heart. It is marked by the
following nuclear changes:
 Pyknosis – which is chromatin clumping &
shrinking with increased basophilia
 Karyorrhexis – fragmentation of chromatin
 Karyolysis – fading of the chromatin material
2. Liquefactive necrosis
 Liquefactive necrosis is characterized by digestion
of tissue. It shows softening & liquefaction of tissue
 Results from ischemic injury to the CNS
 It also occurs in suppurative infections
characterized by formation of pus
3. Fat necrosis
 Fat necrosis can be caused by trauma to tissue with
high fat content, such as the breast or it can also
be caused by acute hemorrhagic pancreatitis in
which pancreatic enzymes diffuse into the inflamed
pancreatic tissue & digest it
 The fatty acids released from the digestion form
calcium salts (soap formation or dystrophic
calcification)
 Elastase enzyme digests the blood vessels & cause
the hemorrhage inside the pancreas, hence the
name hemorrhagic pancreatitis
4. Caseous necrosis
 Caseous necrosis has a cheese-like (caseous,
white) appearance to the naked eye. And it appears
as an amorphous eosinophilic material on
microscopic examination
 Caseous necrosis is typical of tuberculosis
5. Gangrenous necrosis
 This is due to vascular occlusion & most often
affects the lower extremities & the bowel
 It is called wet gangrene if it is complicated by
bacterial infection which leads to superimposed
liquefactive necrosis
 Whereas it is called dry gangrene if there is only
coagulative necrosis without liquefactive necrosis
 Necrosis can be followed by release of intracellular
enzymes into the blood, inflammation or dystrophic
calcification
Apoptosis
 Is the death of single cells within clusters of other cells
 Cell shows shrinkages & increased acidophilic staining of
the cell
 Followed by fragmentation of the cells. These fragments
are called apoptotic bodies
 It can also be seen in pathological conditions caused by
mild injurious agents
 Apoptosis is not followed by inflammation or calcification.
INFLAMMATION
 Inflammation is a local response (reaction) of living
vascularized tissues to endogenous and exogenous
stimuli. The term is derived from the Latin “inflammare”
meaning to burn.
 Inflammation is fundamentally destined to localize and
eliminate the causative agent and to limit tissue injury
 Thus, inflammation is a physiologic (protective) response
to injury, an observation made by Sir John Hunter in 1794
concluded: “inflammation is itself not to be considered as
a disease but as a salutary operation consequent either to
some violence or to some diseases”
Causes of inflammation are apparently causes of diseases such
as:
 Physical agents – mechanical injuries, alteration in
temperature and pressure, radiation injuries
 Chemical agents – including the ever increasing lists of
drugs and toxins
 Biologic agents (infectious) – bacteria, viruses, fungi,
parasites
 Immunologic disorders – hypersensitivity reactions,
autoimmunity, immunodeficiency states, etc
 Genetic / metabolic disorders – examples gout,
diabetes mellitus, etc
Classification
 Inflammation is classified crudely based on duration of the
lesion and histologic appearances into acute and chronic
inflammation
Acute Inflammation
 It is an immediate and early response to an injurious
agent and it is relatively of short duration, lasting for
minutes, several hours or few days
 It is characterized by exudation of fluids and plasma
proteins and the emigration of predominantly neutrophilic
leukocytes to the site of injury
The five cardinal signs of acute inflammation are:
 Redness (rubor) – which is due to dilation of small
blood vessels within damaged tissue as it occurs in
cellulitis
 Heat (calor) – which results from increased blood
flow (hyperemia) due to regional vascular dilation
 Swelling (tumor) – which is due to accumulation of
fluid in the extravascular space which, in turn, is due to
increased vascular
 Pain (dolor) - which partly results from the stretching
& destruction of tissues due to inflammatory edema
and in part from pus under pressure in as abscess cavity.
Some chemicals of acute inflammation, including
bradykinins, prostaglandins, and serotonin are also
known to induce pain
 Loss of function (functio laesa)- the inflammation
area is inhibited by pain while severe swelling may
also physically immobilize the tissue
Events of acute inflammation:
 Acute inflammation is categorized into an
 Early vascular
 A late cellular responses
1. The Vascular response has the following steps:
a) Immediate (momentary) vasoconstriction in seconds due
to neurogenic or chemical stimuli
b) Vasodilatation of arterioles and venules resulting in
increased blood flow
c) After the phase of increased blood flow there is a slowing
of blood flow & stasis due to increased vascular
permeability that is most remarkably seen in the post-
capillary venules.
  The increased vascular permeability oozes protein-rich
fluid into extravascular tissues. Due to this, the already
dilated blood vessels are now packed with red blood cells
resulting in stasis
 The protein-rich fluid which is now found in the
extravascular space is called exudate. The presence of
the exudates clinically appears as swelling
 Chemical mediators mediate the vascular events of acute
inflammation
2. Cellular response
The cellular response has the following stages:
a) Migration, rolling, pavementing & adhesion of
leukocytes
b) Transmigration of leukocytes
c) Chemotaxis
d) Phagocytosis
 Normally blood cells particularly erythrocytes in venules
are confined to the central (axial) zone and plasma
assume the peripheral zone. As a result of increased
vascular permeability, more and more neutrophils
accumulate along the endothelial surfaces (peripheral
zone).
Migration, rolling, pavementing & adhesion of leukocytes
 Margination is a peripheral positioning of white cells along
the endothelial cells
 Subsequently, rows of leukocytes tumble slowly along the
endothelium in a process known as rolling
 In time, the endothelium can be virtually lined by white
cells. This appearance is called pavementing
 Thereafter, the binding of leukocytes with endothelial cells
is facilitated by cell adhesion molecules such as
selectins, immunoglobulins, integrins, (CIM) etc which
result in adhesion of leukocytes with the endothelium
.
Transmigration of leukocytes
 Leukocytes escape from venules and small veins but only
occasionally from capillaries. The movement of
leukocytes by extending pseudopodia through the
vascular wall occurs by a process called diapedesis.
Chemotaxis
 A unidirectional attraction of leukocytes from vascular
channels towards the site of inflammation within the
tissue space guided by chemical gradients (including
bacteria and cellular debris) is called chemotaxis
 The most important chemotactic factors for neutrophils
are:
 Components of the complement system (C5a)
 Bacterial and mitochondrial products of arachidonic
acid metabolism such as leukotriene B4 and
cytokines (IL-8)
 All granulocytes, monocytes and to lesser extent
lymphocytes respond to chemotactic stimuli
 How do leukocytes “see” or “smell” the chemotactic
agent?
o This is because receptors on cell membrane
of the leukocytes react with the
chemoattractants resulting in the activation of
phospholipase C that ultimately leads to
release of cytosolic calcium ions and these
ions trigger cell movement towards the
stimulus
Phagocytosis
 It is the process of engulfing and internalization by
specialized cells of particulate material, which includes
invading microorganisms, damaged cells, and tissue
debris
 These phagocytic cells include polymorphonuclear
leukocytes (particularly neutrophils), monocytes and
tissue macrophages.
Multiple choices
PHAGOCYTOSIS INVOLVES THREE DISTINCT BUT
INTERRELATED STEPS
1. Recognition and attachment of the particle to be
ingested by the leukocytes:
 Phagocytosis is enhanced if the material to be
phagocytosed is coated with certain plasma proteins
called opsonins. These opsonins promote the
adhesion between the particulate material and the
phagocyte’s cell membrane.
 The three major opsonins are:
 The Fc fragment of the immunoglobulin
 Components of the complement system C3b
 Carbohydrate-binding proteins – lectins
 Thus, IgG binds to receptors for the Fc piece of
the immunoglobulin (FcR) whereas
 3cb and 3bi are ligands for complement
receptors CR1 and CR2 respectively
2. Engulfing
 During engulfment, extension of the cytoplasm
(psuedopods) flow around the object to be engulfed,
eventually resulting in complete enclosure of the
particle within the phagosome created by the
cytoplasmic membrane of the phagocytic cell
 As a result of fusion between the phagosome and
lysosome, a phagolysosome is formed and the
engulfed particle is exposed to the degradative
lysosomal enzymes
3. Killing or degradation
 The ultimate step in phagocytosis of bacteria is killing
degradation. There are two forms of bacterial killing
a) Oxygen-independent mechanism:
 This is mediate by some of the constituents of
the primary and secondary granules of
polymorphonuclear leukocytes. These include:
 Bacterial permeability increasing protein
(BPI)
 Lysozymes
 Lactoferrin
 Major basic protein
 Defenses
 Like the vascular events, the cellular events (i.e. the
adhesion, the transmigration, the chemotaxis, & the
phagocytosis) are initiated or activated by chemical
mediators
Chemical mediators of inflammation
 Chemical mediators account for the events of
inflammation. Inflammation has the following sequence:
 Cell injury --- Chemical mediators -- Acute
inflammation (i.e. the vascular & cellular events).
Inflammation Part 2
 Chemical mediators
 Morphologic types of acute inflammation
 Effects of acute inflammation
 Chronic inflammation
 Causes of chronic inflammation
 Cells of chronic inflammation
 Classification of chronic inflammation
 Systemic effects of inflammation
1. what is the term that denotes the cause of a disease is
unknown in its origin (idiopathic etiology)
2. which of the following is NOT a function of the cell (all
function: metabolize & release energy, provides
communication, synthesize molecules)
3. this organelle function in cellular respiration
(mitochondrion)
4. the organelle functions to package and deliver proteins
(golgi apparatus)
5. it is cheap, takes less time and needs no anesthesia to
take specimens. The laboratory procedure examines
individual cells extracted from a tissue to determine the
nature and cause of a disease (Cytopathology)
6. a method by which abnormalities of the cells of the cells
of the blood and their precursors in the bone marrow
(Hematopathology)
7. used to detect a specific antigen in the tissue
(Immunohistochemistry)
8. a method that uses biopsy in tissues to aid physicians in
the identification of a disease (histopatholgy)
9. which of the following is NOT a method of cytopathologic
examinations (all: FNAC, Exfoliative cytology, Pap
smear)
10. a method by which body fluids, excised tissue, etc. are
examined by microscopy, gram stain, culture and
sensitivity (Microbiological examination)
11. a method in which inherited chromosomal abnormalities
in the germ cells investigated using the techniques of
molecular biology (cytogenetics)
12. cell organelles are located within the _____ of the cell
(cytoplasm)
13. which of the following describes an attempt to preserve
viability & function? (homeostasis)
14. which of the following describes how a disease develops
and outlines the steps of development, such as cellular
and molecular changes (Pathogenesis)
15. which of the following describes the origin of disease
(Etiology)
16. pathology is concerned with the morphologic changes
that occur during states of disease (true)
17. the endoplasmic reticulum functions to (transport
materials)
18. genetic material is contained within the ___ of the cell
(nucleus)
19. this organelle is responsible for destroying worn out cell
parts (lysosomes)
20. the ____ controls what enters and leaves the cell (cell
membrane)
21.
22. located within the nucleus, it is responsible for producing
ribosomes (nucleolus)
23. which structure is directly responsible for the formation of
proteins within the cell (ribosomes)
24. it refers to the structural alterations in the cells or tissues
that occur following the pathogenic mechanisms
(morphologic change)
25. this is a method by which body fluid, excised tissue, etc.
are examined by microscopical and culture method
(microbiology method)
26. It is a sure sign of death (biological death)
27. The organelle of the cell which completes post
translational modifications and the packages and
addresses proteins after being synthesized in the rough
endoplasmic reticulum (golgi complex)
28. Its major role is the synthesis of various phospholipid
molecules that constitute all cellular membranes (smooth
endoplasmic reticulum)
29. It is a complex network of proteins which determine the
shape of the cells, movement of organelles and vesicles
and movement of the entire cell (cytoskeleton)
30. It is a process of uptake of material wherein smaller
invaginations of the cell membrane form and entrap
extracellular fluid (pinocytosis)
31. This is refers to the period between exposure and onset
of clinical symptoms is called (incubation period )