Lecture by ○ Which then reverts back to normal after

the stress is removed

● If an injurious stimulus occurs or the cell is
PATHOLOGY unable to adapt to stress, cell injury occurs
○ If it is severe or progressive, the injury
● Derived from two greek words:
can be irreversible (irreversible cell
○ “Pathos”: suffering; “logos”: study
injury)
● Study of structural and functional causes of
○ If it is mild and transient, injury could be
human disease
reversible (reversible cell injury), the cell
● Thus, it is the scientific study of changes in the
can achieve homeostasis again.
structure and function of the body in disease
● Irreversible cell injury leads to cell death by either
necrosis or apoptosis.
FOUR ASPECTS OF PATHOLOGY
Etiology ADAPTATION
● Cause: genetic or acquired

Pathogenesis
● Sequence of cellular, biochemical, and molecular
events that follow the exposure of cells or
tissues to an injurious agent
● Mechanism by which the lesions are produced
● “How” of disease

Morphologic Changes
● Structural changes induced in the cells and
organs of the body
● Consist of examination of diseased tissues
● These can be recognized with the naked eye;
gross or macroscopic changes or are studied by
microscopic examination of tissues
Thus, while hyperplasia is distinct from cancer,
Clinical Manifestations pathologic hyperplasia constitutes a fertile soil in which
● Functional consequences of these changes cancerous proliferations may eventually arise.
● Functional implication of the lesion felt by the
patient are symptoms and those discovered by Hypertrophy
the clinician are signs ● Increase in size of cells
● Example: heart
Note: Underlined words are not found in the mother notes. I just assumed
because it sounds incomplete.
● Example (pathologic): Left Ventricular
Hypertrophy, vessels enlarge due to
hypertension
HOMEOSTASIS
● Normal cell function requires a balance between
physiologic demands and the constraints of cell
structures and metabolic capacity

Gross appearance of a normal uterus (right) and a gravid

uterus (removed for postpartum bleeding) (left)
2nd pic: Normally, the uterus is composed of small
spindle-shaped uterine smooth muscle cells
3rd pic: large plump cells from the gravid uterus, at the
same magnification

● When the normal cell is stressed or there is

increased functional demand, it learns to adapt Hyperplasia
to the changes which are expressed ● Hypertrophy and hyperplasia always go together
morphologically (hypertrophy, atrophy, depending on tissue involved
hyperplasia, metaplasia) ○ If capable of cell division, both.

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 ○ If not capable, definitely only
hypertrophy
● Benign in nature but if pathologic, can have
fertile soil for cancer
○ Ex. Simple endometrial hyperplasia can
lead to endometrial carcinoma
● In endometrial hyperplasia, the endometrial
lining is thickened because the cells increase in
number.
● Microscopically, the normal endometrium is
composed of glands and stroma, in endometrial
hyperplasia, there is an increase in the number of
glands and stroma and cellularity.
Metaplasia of columnar to squamous epithelium. A.
Schematic diagram. B. Metaplasia of columnar
epithelium (left) to squamous epithelium (right) in a
bronchus.

CELL INJURY
● Defined as the effect of a variety of stresses due
to etiologic agents a cell encounters, resulting in
Atrophy changes in its internal and external
● Decrease in both number and size of brain environment.
● Autophagy: cell eats own contents
CAUSES OF CELL INJURY
Oxygen deprivation (hypoxia) and Ischemia
● Most common cause
● Inadequate oxygenation
● Loss of O2-carrying capacity of blood
● Cells of different tissues essentially require
oxygen to generate energy and perform
metabolic functions
● Deficiency of oxygen or hypoxia results in failure
to carry out these activities by the cells
● Hypoxia is the most common cause of cell injury

Physical Agents
● Mechanical trauma (e.g. road accidents)
● Thermal trauma (e.g. by heat and cold); extreme
in temperatures
A. Normal brain of a young adult. B. Atrophy of the brain ● Electricity
in an 82-year-old man with atherosclerotic ● Radiation (e.g. ultraviolet and ionising)
cerebrovascular disease, resulting in reduced blood ● Rapid changes in atmospheric pressure
supply. Note that loss of brain substance narrows the
gyri and widens the sulci. Chemicals and Drug
● Chemical poisons such as cyanide, arsenic,
Metaplasia mercury
● Change in one cell to another type of cell ● Strong acids and alkalis
● Most common: Squamous metaplasia ● Environmental pollutants
○ Columnar to squamous ● Insecticides and pesticides
● Esophagus: normally, squamous ● Oxygen at high concentrations
○ Barrett’s esophagus is columnar which ● Hypertonic glucose and salt
leads to esophageal CA ● Social agents such as alcohol and narcotic drugs
● Therapeutic administration of drugs

Microbial agents
● Injuries by microbes include infections caused by
bacteria, rickettsiae, viruses, fungi, protozoa,
metazoa, and other parasites

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Agents/Reactions ● Dilation of Endoplasmic Reticulum: forms myelin
● Immunity is a ‘double-edged sword’ figures
○ It protects the host against various ● Nuclear alterations: disaggregation of granular
injurious agents but it may also turn and fibrillar elements
lethal and cause cell injury

Derangements (Mutations)

Derangements/Imbalances
● A deficiency or excess of nutrients may result in
nutritional imbalances

MORPHOLOGIC ALTERATIONS IN CELL INJURY

Ultrastructural features of reversible and irreversible cell

injury (necrosis) in a rabbit kidney. A. Electron
micrograph of a normal epithelial cell of the proximal
kidney tubule. Note abundant microvilli (mv) lining the
luminal surface (L). B. Epithelial cell of the proximal
tubule showing early cell injury resulting from
reperfusion following ischemia. The microvilli are lost
and have been incorporated in apical cytoplasm; blebs
have formed and are extruded in the lumen.

MORPHOLOGIC ALTERATIONS IN CELL INJURY:

NECROSIS
● Two processes underlying changes
○ Denaturation of proteins
● Cells may become rapidly nonfunctional after the ○ Enzymatic digestion
onset of injury, although they may still be viable, ● Necrotic cells are more eosinophilic (pink) than
with potentially reversible damage (can go back viable cells
to homeostasis); ● Appear “glassy”, vacuolated cell membranes,
● A longer duration of injury may lead to fragmented
irreversible injury and cell death and typically this ○ The necrotic cell may have a more
precedes ultrastructural, light microscopic, and glassy homogeneous appearance than
grossly visible morphologic changes do normal cells, mainly as a result of the
loss of glycogen particles
Cell Swelling ● Dead cells may be replaced by large, whorled
● Inability to maintain ionic and fluid homeostasis phospholipid masses called myelin figures
due to failure of energy-dependent ion pumps in (which can also be seen in the reversible injury)
the plasma membrane ○ These precipitates are either
● Small clear vacuoles in the cytoplasm; increased phagocytosed or degraded into fatty
eosinophilic staining acids → attract calcium salts, forming
● Eosinophilic: pink fatty soaps
■ This process is called
Fatty Change “saponification”
● Cytoplasmic lipid vacuoles ● Nuclear changes
● Seen in cells involved in fat metabolism ○ Pyknosis: small dense nucleus
○ hepatocytes and myocytes ○ Karyolysis: faint dissolved nucleus
○ Karyorrhexis: fragmented nucleus
ULTRASTRUCTURAL CHANGES ○ Nuclear changes appear in one of three
● Plasma membrane alterations: blebbing, patterns, all due to nonspecific
blunting, loss of microvilli breakdown of DNA
● Mitochondrial changes: swelling, amorphous
densities
○ Mitochondria would have been swollen
during ischemia
○ With reperfusion, they rapidly undergo
condensation and become
electron-dense

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 A. Normal kidney tubules with viable epithelial cells. B.
Early (reversible) ischemic injury showing surface blebs,
increased eosinophilia of cytoplasm, and swelling of
occasional cells. C. Necrosis (irreversible injury) of
epithelial cells, with loss of nuclei, fragmentation of cells,
and leakage of contents.

TISSUE PATTERNS OF NECROSIS

Coagulative Necrosis
● Most common Microscopically, the brain is marked by loss of neurons
● CHON (protein) denaturation with preservation of and neuroglial cells and the formation of a clear space at
cell & tissue framework the center. As it resolves, the liquified area becomes a
● Seen in hypoxic death of all tissue except the cystic space.
brain
● Tissue later undergoes autolysis or heterolysis
● Have characteristic “tombstone” appearance Gangrenous Necrosis
● Not a specific pattern of cell death but a term
commonly used in clinical practice
● Usually applied to describe a limb that has lost
its blood supply → Coagulative necrosis
● If with bacterial infection → Liquefactive
necrosis (bacteria can form pus)
● Dry gangrene: predominantly coagulative
● Wet gangrene: more liquefactive (with abscess)

A. Wedge-shaped kidney infarct (yellow). B. Microscopic

view of the edge of the infarct, with normal kidney (N)
and necrotic cells in the infarct (I) showing preserved
cellular outlines with loss of nuclei and an inflammatory
infiltrate (seen as nuclei of inflammatory cells in
between necrotic tubules).

Liquefactive Necrosis
● Digestion of dead cells, resulting in
transformation of the tissue into a liquid viscous
mass (pus)
● Localized bacterial infections (abscesses) and in
the brain
● Autolysis or heterolysis predominates over
protein denaturation

An infarct in the brain is organizing and being resolved,

liquefactive necrosis leads to resolution with a cystic
Caseous Necrosis
space as the necrotic tissue is removed.
● Tuberculous lesions (mycobacterium
tuberculosis)

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 ● Gross: soft, friable, cheese-like
● Microscopic: amorphous eosinophilic material
with cell debris (fragments of nucleus and
inflammatory cells)
○ Like homogenous pink substance
○ Architecture not preserved
● Mycobacterium tuberculosis: granuloma
formation with presence of multinucleated giant
cells of Langhans type and foreign body type

Fibrinoid Necrosis
● Special form of necrosis usually seen in immune
reactions involving blood vessels
● Antigen-Antibody complexes deposited in walls
of arteries + fibrin leak out of vessels → bright
pink amorphous appearance on H&E stain
● Commonly seen in Immune-mediated vasculitis
Fat Necrosis syndromes
● Lipase activation
○ → release of fatty acids (which attract
calcium salts) → complex with Ca →
soaps (saponification)
● Seen in pancreatitis
● Gross: white chalky areas (fat saponification)
● Microscopic: vague cell outlines (Ca+ deposition)

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 ● ATP: formed through oxidative phosphorylation
and anaerobic respiration
○ Anaerobic respiration uses glycogen

Mitochondrial Damage
● Consequence of increased cytosolic Ca++, ROS
and O2 deprivation
● Damage
○ → formation of mitochondrial
MECHANISMS OF CELL INJURY permeability transition pore → loss of
● Biochemical mechanism mitochondrial membrane potential → ↓
● Intracellular mechanism ATP → necrosis
● Abnormal oxidative phosphorylation
BIOCHEMICAL MECHANISMS ○ → formation of ROS → necrosis
● Responses to stimuli depend on type, duration & ● Damage (due to decreased survival signals; DNA
severity of injury and protein damage)
● Consequences depend on type, state & ○ → ↑ permeability of the outer
adaptability of injured cell mitochondrial membrane (note:
● Involves the following: mitochondria which houses cytochrome
○ ATP depletion
C, which are caspases responsible for
○ Mitochondrial damage
○ Influx of intracellular calcium & loss of protein breakdown) → leakage of
calcium homeostasis caspases (protein will be degraded) →
○ Accumulation of oxygen-derived free apoptosis
radicals (ROS) ● Mitochondria supply energy by producing ATP.
○ Defects in membrane permeability ● The mitochondria sequester between their outer
and inner membranes several proteins that are
ATP Depletion
● Fundamental cause of necrotic cell death capable of activating apoptotic pathways
● Consequence of ischemic & toxic injury including caspases.
● Reduced Na pump activity (due to hypoxia) ● Increased permeability of the outer
○ ↑ influx of Na, H20 and Ca → cell mitochondrial membrane may result in leakage
swelling of these proteins into the cytosol and death by
● Hypoxia apoptosis.
○ ↑ glycolysis (Breakdown of glucose) →
glycogen depletion, increased lactic
acid, intracellular acidosis
● Ribosomal detachment
○ ↓ protein synthesis

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 but they are degraded and removed by cellular
defense systems.
○ Thus, cells are able to maintain a steady
state in which free radicals may be
present transiently at low
concentrations but do not cause
damage.

Properties of the Principal Free Radicals Involved in Cell

Injury

Ca++ Influx and Loss of Homeostasis

● Calcium ions are important mediators of cell
injury. In keeping with this, depleting calcium
protects cells from injury induced by a variety of
harmful stimuli.
○ Cytosolic free calcium is normally
maintained at very low concentrations.
● Most intracellular calcium is sequestered in
mitochondria and the Endoplasmic reticulum.
○ Ischemia and certain toxins cause an
increase in cytosolic calcium
concentration, initially because of
release of Ca2+ from intracellular stores
and later due to increased influx across
the plasma membrane.
● Ischemia/Toxins → Ca influx + release of Ca
from mitochondria and ER →
○ Activates phospholipases→ degrades
membrane phospholipids
■ leading to increase membrane
Defects in Membrane Permeability
permeability, leads to cell
● Consistent feature of most forms of cell injury
swelling or leakage of
except apoptosis
caspases
● Mechanisms
○ Activates proteases → breaks down
○ ROS
membrane and cytoskeleton proteins
○ Decreased phospholipid synthesis
○ Activates ATPases → ATP depletion
○ Increased phospholipid breakdown
○ Activates endonucleases → chromatin
○ Cytoskeletal abnormalities
fragmentation
● Consequences
○ Mitochondrial membrane damage
Accumulation of O2-derived Free Radicals (Oxidative
○ Plasma membrane damage
Stress)
○ Injury to lysosomal membranes
● Free radicals
● Lysosomes contain RNases, DNases, proteases,
○ Chemical species that have a single
phosphatases, and glucosidases.
unpaired electron in an outer orbit
○ Activation of these enzymes leads to
○ “Attack” and modify adjacent molecules
enzymatic digestion of proteins, RNA,
(proteins, lipids, carbohydrates, nucleic
DNA, and glycogen, and the cells die by
acids)
necrosis.
○ Ex: ROS (reactive oxygen species)
■ If increased → oxidative stress
● ROS are produced normally in cells during
mitochondrial respiration and energy generation,

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 ● Resulting inflammation and recruitment of PMNs
● Activation of complement

Chemical Injury
● Direct – binding to critical molecular component
● Indirect – conversion to reactive toxic
metabolites

APOPTOSIS
“Programmed Cell Death”
● Induced by a tightly regulated suicide program in
which cells destined to die activate intrinsic
enzymes that degrade the cells’ own nuclear
DNA and nuclear and cytoplasmic proteins
● Apoptotic cells break up into fragments, called
apoptotic bodies, which contain portions of the
cytoplasm and nucleus
Causes:
A. PHYSIOLOGIC
● Programmed destruction of cells in
embryogenesis
CLINICOPATHOLOGIC EXAMPLES OF CELL INJURY AND ● Hormone-dependent involution of tissues
NECROSIS ● Cell deletion in proliferating cell populations
Ischemic and Hypoxic Injury ● Death of cells that have served their purpose
● Most common type of injury ● Deletion of potentially harmful self-reactive
● Hypoxia: reduced O2 delivery lymphocytes
● Mechanical obstruction in arteries → Ischemia ● Cell death induced by cytotoxic T-cells to
→ Reduced venous drainage, compromised eliminate virally infected or neoplastic cells
delivery of substrates for glycolysis B. PATHOLOGIC
● Death due to injurious stimuli
Mechanism of Ischemic Cell Injury ● Viral infections (e.g. hepatitis)
● Sequence of events: ● Pathologic atrophy in parenchymal organs after
○ Decreased O2 tension duct obstruction
○ Loss of oxidative phosphorylation ● Cell death in tumors
○ Decreased production of ATP
○ Failure of sodium pump → loss of K → Morphologic features
influx of Na and water → cell swelling ● Cell shrinkage (cytoplasm is very dense)
○ Influx of Ca ● Chromatin condensation and fragmentation
○ Progressive loss of glycogen, decreased ○ the most characteristic feature of
CHON synthesis apoptosis.
● More ATP depletion → further deterioration ○ chromatin aggregates peripherally
● Cytoskeleton disperses → blebs under the nuclear membrane into dense
● Myelin figures from membrane destruction masses of various shapes and sizes.
● Mitochondrial swelling, Endoplasmic reticulum ● Cellular blebbing and fragmentation into
dilation membrane-bound apoptotic bodies composed of
● If O2 is restored, these changes are reversible cytoplasm and tightly packed organelles with or
● Persistent ischemia → irreversible injury and without nuclear fragments.
necrosis ● Phagocytosis of apoptotic bodies by adjacent
● Severe swelling, plasma membrane damage, healthy cells or macrophages
swelling of ysosomes ○ apoptotic bodies are rapidly ingested by
● Massive Ca influx phagocytes and degraded by the
● Cell components degraded → intracellular phagocytes lysosomal enzymes
enzymes leak out ● Lack of inflammation (compared to necrosis)
● Dead cells replaced by amorphous phospholipid
masses

Ischemia-Reperfusion Injury
● Death of cells after blood flow resumes
● Associated with neutrophilic infiltration

Mechanisms of Ischemia-Reperfusion Injury

● Increased generation of O2-derived free radicals

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 ○ TNFR1 and Fas

Mechanisms of apoptosis
● Initiation phase
○ Intrinsic (mitochondrial pathway)
○ Extrinsic (death receptor) pathway
● Execution phase: enzymes cause cell death
(activation of cascade of caspases)
● Removal of dead cells: by phagocytosis

Intrinsic (Mitochondrial) Pathway

A. Cell viability is maintained by the induction of
anti-apoptotic proteins such as BCL2 by survival signals.
● These proteins maintain the integrity of
mitochondrial membranes and prevent leakage
of mitochondrial proteins.
B. The loss of survival signals, DNA damage, and other
insults activate sensors that antagonize the anti-apoptotic
proteins and activates the pro-apoptotic proteins like BAX
and BAK which forms channels in the mitochondrial
membrane, so the subsequent leakage of cytochrome C
and other proteins leads to caspase activation and
apoptosis.
● due to increased mitochondrial permeability Execution Phase

● Proapoptotic > antiapoptotic proteins

● Activates caspase 9
● Anti-apoptotic proteins: BCL2, BCL-XL, and ● The two pathways of apoptosis differ in their
MCL1 induction and regulation, and both culminate in
● Pro-apoptotic: BAX and BAK the activation of caspases.
● Sensors: BAD, BIM, BID, Puma, and Noxa ● In the mitochondrial pathway, proteins of the
BCL2 family, which regulate mitochondrial
Extrinsic (Death receptor) Pathway permeability, become imbalanced and leakage of
● Activation of death receptors on the cell various substances from mitochondria leads to
membrane caspase activation.

B1M1: The Generalities 9 of

 ● In the death receptor pathway, signals from
plasma membrane receptors lead to the
assembly of adaptor proteins into a
“death-including signaling complex,” which
activates caspases, and the end result is the
same.

Examples of apoptosis
● Growth factor deprivation
● DNA damage
● Protein misfolding
● TNF family receptors
● Cytotoxic T lymphocytes

NECROPTOSIS
● shares aspects of both necrosis and apoptosis Caused by:
○ resembles necrosis morphologically ● Excessive entry of free fatty acids into the liver
and apoptosis mechanistically ● Enhanced fatty acid synthesis
○ “programmed necrosis” ● Increased esterification of fatty acids into the
● Causes: TNF and viral proteins liver to Triglycerides
● Caspase-independent; activates RIP1 and RIP3 ● Decreased fatty acid oxidation
(receptor Interacting Proteins) complexes → ↑ ● Decreased apoprotein synthesis
ROS and ↓ mitochondrial ATP production → ● Impaired lipoprotein secretion from liver
necrosis
Lipids: Cholesterol & cholesterol esters (Gall bladder in
INTRACELLULAR ACCUMULATIONS picture)
● Normal endogenous substance produced at a ● Atherosclerosis
normal rate but the metabolic rate is inadequate ● Xanthomas
to remove it ● Inflammation & necrosis
● Normal or abnormal endogenous substance ● Cholesterolosis
accumulation due to genetic or acquired defects ● Niemann-Pick disease type C
in metabolism, packaging, transport or secretion ● “Strawberry Gallbladder”
● Abnormal exogenous substance accumulation
due to lack in machinery to degrade them
● Lipids, Proteins, Hyaline Change, Glycogen,
Pigments

Lipids
● Triglycerides: most common
● Cholesterol
● Cholesterol esters
● Phospholipids

Lipids: Steatosis
● Fatty change
● Occurs when a normal constituent (triglycerides)
● accumulates, leading to increase in intracellular
lipids
● Most commonly seen in liver
○ Reversible → may lead to cirrhosis if in
excess
Proteins
● Defective intracellular transport and secretion of
intracellular proteins and secretion of critical
proteins
● Toxicity of aggregated, abnormally folded
proteins
○ as seen in neurodegenerative disorders

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 ○ Glycogen granules in hepatocytes, renal
tubular epithelium and cardiac
myocytes

Pigments
A. Exogenous
● Carbon or coal dust (anthracosis)
● Tattooing
B. Endogenous
● Lipofuscin
○ Lipids + phospholipids in complex with
Hyaline change
protein
● Alteration that imparts a homogenous glassy
○ Sign of lipid peroxidation
pink appearance in H&E-stained sections; not
○ “wear and tear” pigment
specific
● Melanin
● Intracellular Hyaline: α1-antitrypsin deficiency
● Homogentisic acid
● Extracellular Hyaline: Hyaline arteriosclerosis in
○ in alkaptonuria (ochronosis)
HPN and DM
● Hemosiderin

CALCIFICATION
Glycogen
● Abnormalities in glucose and glycogen
metabolism
● Excessive deposits seen as vacuoles
● Glycogen storage disease
○ Glycogen granules in cells due to
inherited defects in glycogen
metabolism
● Diabetes mellitus

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 ● Increase DNA damage and decreased repair
● Accumulation of oxidative damage in proteins
and lipids
● Accumulation of advanced glycation end
products causing protein cross-linking

Morphologic alterations
● Irregular, abnormally lobed nuclei
● Pleomorphic & vacuolated mitochondria
● Decreased cytoplasmic endoplasmic reticulum
● Distorted Golgi apparatus

Mechanisms that Counteract Aging

● Decreased IGF-1 signaling
○ Insulin-like effect
■ anabolic: increased cell growth
○ If decreased, there's also decreased
chance of cell damage
● Increased sirtuins
○ Sirtuins are proteins that function in
response to food deprivation and DNA
damage and are found in red wine
○ If increased, produced substances that
promote longevity

CELLULAR AGING
● Result of a progressive decline in cellular
function and viability caused by genetic
abnormalities and the accumulation of cellular
and molecular damage due to the effects of
exposure to exogenous influences

Diminished metabolic functions

● Reduced ATP generation
● Diminished synthesis of structural, enzymatic
and regulatory proteins
● Decreased capacity for nutrient uptake

B1M1: The Generalities 12

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