What is disease?

A condition in which the presence of an abnormality

causes a loss of normal health
Manifests in signs and symptoms
subjective: e.g., pain
objective: confirmed by diagnostic tests
Duration of disease: short lasting - acute
long lasting - chronic
Outcome: varies; may be lethal

What is pathology?
The study (logos) of suffering (pathos)
Devoted to the study of
- the cause of the disease (etiology)
- the mechanism(s) of disease development
(pathogenesis)
- the structural alteration induced in cells and tissues
by the disease (morphologic change)
- the functional consequences of the morphologic
changes (clinical significance)
The morphologic change may be focal (localized
abnormality) or diffuse

Teaching program of pathology for

medical students
General pathology
Basic reactions of cells and tissues to
abnormal stimuli, i.e. common features of
various disease processes in various cells
and tissues
Systematic pathology
The descriptions of specific diseases as they
affect given organs or organ systems

Pathology of cellular injury and death

Cells react to adverse influences by
1) Reversible cell injury
Changes that can be reversed when the stimulus is
removed
2) Irreversible cell injury
Changes that cause cell death
3) Cellular adaptation
Stimuli result in new but altered state that maintains
the viability of the cell

Intracellular mechanisms vulnerable to

cellular injury
Maintenance of membrane integrity
Critical for cell and organellar ionic and osmotic
homeostasis
Aerobic respiration, involving mitochondrial oxidative
phosphorilation and ATP production
Synthesis of enzymes and structural proteins

Preservation of the integrity of the genetic apparatus

Common cellular injuries

1.Hypoxic injury

2.Injury induced by O2-derived free radicals

3.Chemical injury

Hypoxia
Reduction in available oxygen

Common causes
1. Upper airway obstruction (eg., sudden swelling of
laryngeal mucosa)
2. Inadequate oxygenation of blood in lung diseases

3. Inadequate O2 transport in blood because of

decreased number of RBCs (anemia)
4. Inadequate perfusion of blood in the tissues in heart
failure

Ischemia:
inadequate blood supply to an organ or part of it
due to impeded arterial flow or reduced venous
drainage

Reversible hypoxic injury

1.Hydropic change
2.Fatty change
1. Hydropic change (synonym: cell swelling)
Example: in the kidneys
ATP depletion malfunction of Na+/K+ ATPase
influx of sodium and water from the extracellular
space
Grossly, the kidneys are enlarged
Electron microscopy (EM)....
Light microscopy (LM)....

Hydropic change in the proximal tubule by EM: accumulation

of water in the cytoplasm, in the invaginations of the surface
plasma membrane (hydropic vacuoles), in the cisterns of the
RER, and in the mitochondria; loss of microvilli.

Hydropic change by LM: the cells are vacuolated,

and the brush border is lost.

Hydropic change
Clinical consequence: acute renal failure

2. Fatty change
Accumulation of lipid vacuoles in the cytoplasm of
cells involved in or dependent on fat metabolism,
e.g., hepatocytes and myocardial cells

Fatty change of liver. The hepatocytes are vacuolated;

representing accumulations of neutral lipids that have
been removed by lipid solvents during tissue processing

2. Fatty change
Clinical consequence:
- liver function tests may be abnormal
- decrease in myocardial contractility

Irreversible hypoxic injury

The transition from reversible to irreversible
state is gradual and occurs when adaptive
mechanisms have been exhausted
Depletion of ATP, influx of Ca 2+, activation of
multiple cellular enzymes, such as
phospholipases degradation of membrane
phospholipids
proteases degradation of membrane and
cytoskeletal protein
ATPases enhance ATP depletion
endonucleases chromatin fragmentation

EM features of irreversible injury

Rupture of cell and plasma membranes

Lysis of cell and nuclear components
(leakage of lysosomal enzymes result in
digestion of organelles and other cytosolic
components)
Amorphous densities in swollen mitochondria

The mitochondria are swollen, their membranes are

ruptured, and amorphous densities are in their matrix

Reversible hypoxic injury

Irreversible hypoxic injury: rupture of cell

membranes and lysis of chromatin

Dead cells show typical nuclear changes

by LM
Pyknosis (pyknos, dense) - condensation of
chromatin
Karyorrhexis - (rhexis, tearing apart)
fragmentation of nuclear material
Karyolysis - lysis of chromatin due to the action
of endonucleases

Full-blown picture: loss of nuclear staining, the

cytoplasm is eosinophilic (pink)

LM features of irreversible hypoxic injury: loss of

nuclear staining, the cytoplasm is eosinophilic (pink)

Injury induced by O2-derived free radicals

Inflammation, radiation, chemicals, reperfusion

lead to the formation of O2derived free radicals:
superoxide anion radical (O2.-),
hydrogen peroxide (H2O2),
hydroxyl radical (OH.),
nitric oxide (NO.)

These molecules cause

lipid peroxidation membrane damage
cross-link proteins inactivation of enzymes
cause DNA breaks blockade of DNA
transcription,
termed collectively as oxidative stress of cells

Injury induced by O2-derived free radicals

Insidiously ongoing oxidative stress of cells plays a
role in the process of aging

Chemical injury
2 mechanisms
Direct damage, by binding to some critical
molecular component of cell membrane proteins,
causing permeability
Indirect damage, by conversion to reactive toxic
metabolites, which cause cell injury by
- direct binding to membrane proteins and lipids
- formation of free radicals

Laboratory markers of irreversible cell injury

Cytoplasmic enzymes are released through
damaged cell membranes into the blood
Creatine kinase (CK) - cardiac or skeletal muscle
injury
Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) - liver cell injury
Lactate dehydrogenase (LDH) is released from
ruptured RBCs

Necrosis morphology of irreversible

injury
Necrosis (necros, dead): death of cells, tissues, or
organs in a living organism
Necrotic area is always surrounded by living
tissues reactive changes
Histological signs: loss of nuclear staining
Outcome: may result in death; in survivors, repair
by fibrous scarring occurs

Main types of necrosis

Grossly
visible

1. Coagulative necrosis
2. Liquefactive necrosis
3. Caseation
4. Fat necrosis
5. Gangrene
6. Fibrinoid necrosis

Coagulative necrosis

Most common form of necrosis, predominated

by protein denaturation with preservation of the
cell and tissue framework
Arterial occlusion distally: hypoxic (anoxic)
death in tissues (exception: brain)
Types:
anemic infarct
hemorrhagic infarct

Anemic infarct
Cause: occlusion of an end artery
In the heart, spleen, kidney

Gross:
circumscribed yellowish lesion, the margins
are hyperemic

Circumscribed yellowish lesion, the margins are hyperemic

Anemic infarct
Cause: occlusion of an end artery
In the heart, spleen, kidney

Gross:
yellowish lesion, the margins are hyperemic
LM:
dead cells become eosinophilic with loss of
nuclear staining, the border of necrotic tissue
is hyperemic and infiltrated by neutrophils

LM of myocardial infarction: eosinophilia of necrotic fibers,

disappearance of nuclear staining. Neutrophils in the
interstitium

Hemorrhagic infarct
In the lungs, due to occlusion of a segmental
pulmonary artery; sec. hemorrhage via
bronchial arteries

Hemorrhagic infarct of lung: wedge shaped, raised, dark-red

area

Hemorrhagic infarct
In the small bowels, due to occlusion of the
mesenteric superior artery;
sec. hemorrhage via anastomosing arcades

Hemorrhagic infarct of small bowels

36

Liquefactive necrosis
The necrotic tissue undergoes softening due to
action of hydrolytic enzymes
Examples
1. Brain infarct
2. Abscess

1.Brain infarct
Occlusion of cerebral artery leads to anemic
infarct; then enzymes released from dead cells
liquefy the necrotized area

Brain infarct: the necrotic area is softened and pale

Infarcted area

Caudate nucleus

Internal capsule

Brain infarct. Macrophages scavenge necrotic, lipid-rich debris.

Liquefactive necrosis
2. Abscess - localized purulent inflammation.
Hydrolytic enzymes derived from neutrophil
granulocytes induce necrosis of infected area

Liquefactive necrosis: abscess

Caseous necrosis
Distinctive form of coag. necrosis in foci of
tuberculous infection of the lung
Grossly, caseous necrosis is white and
cheesy

LM features: the necrotic area is eosinophilic,

amorphous, and is surrounded by activated
macrophages (epitheloid cells) which mediate the
necrosis and kill the bacteria

Enzymatic fat necrosis

Occurs in pancreatitis, induced by the action
of lipases derived from injured pancreatic cells
Lipases catalyse decomposition of
triglycerides to fatty acids, which complex with
calcium to create calcium soaps

The swollen pancreas displays several

yellowish foci of necrosis

Gangrene
This (mostly) clinical term refers to the
severemost forms of necrosis
Total destruction of all tissue components
Often putrefactive bacteria invade the necrotic
tissue
Three types (detailed in Inflammation chapter)

One subtype: dry gangrene

In the leg of patients suffering from

atherosclerosis-related occlusion of the tibial
arteries
The affected tissues appear black because of
the deposition of iron sulphide from degraded
hemoglobin

Dry gangrene of the great toe

Fibrinoid necrosis
Limited to medium-sized and small arteries,
arterioles, and glomeruli affected by
autoimmune disoders (e.g., SLE, arteritis) or
malignant hypertension
The wall of these vessels undergo necrosis
and is impregnated with fibrinogen and other
plasma proteins

It can be recognized only in histologic slides

Fibrinoid necrosis of small arteries. The necrotized

smooth muscle cells are eosinophilic. Inflammatory
cells have infiltrated the periarterial space

Apoptosis: programmed cell death

A form of energy-dependent process for
selective deletion of unwanted individual cells
An internal suicide program becomes activated
The dead cells membrane remain intact

The dead cell is rapidly cleared by phagocytosis

before its content have leaked out; therefore,
apoptosis does not induce an inflammatory reaction
Remember! Features of necrosis: loss of membrane
integrity, enzymatic digestion of cells, and frequently
an inflammatory reaction

Apoptosis
Prevented or induced by a variety of stimuli
Apo contributes to cell accumulation, e.g.
neoplasia
Apo results in extensive loss, e.g. atrophy

Extrinsic (death receptor) pathway of

apoptosis
Mitochondrion
Bcl-2 , Bax

Execution
caspases

Death receptors Cytotoxic

T-cells

If death receptors on the cell surface (TNF-R, FAS-R)

cross-link with the ligand, activation of execution
caspases occurs.

Intrinsic (mitochondrial) pathway of

apoptosis
Mitochondrion

Bcl-2 inhibits
Bax activates

Execution
caspases

When cells are deprived of survival signals or subjected

stress,
anti-apoptotic Bcl-2 protein is replaced by pro-apoptotic
Bax protein in the mitochondrial membrane
and in turn, the execution caspases become activated

Execution pathway of apoptosis

Bax

Death receptors Cytotoxic

(TNF, FAS)
T-cells

Execution caspases:
cascade of proteolytic
enzymes

Breakdown of cytoskeleton
Cell shrinkage
Chromatin condensation
and fragmentation
Formation of apoptotic
bodies

Apoptosis of tubular epithelial cells (cell shrinkage, and

condensation of nucleus) induced by cytotoxic T- lymphocytes
in acute T-cell-mediated rejection of transplanted kidney

Adaptations
Changes that occur in cells and tissues in
response to prolonged stimulation or
chronic injury
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia (to be lectured later)
Intracellular accumulation of various
substances

Atrophy
Decreased cell mass: reduction in size of
cells (nucleus and cytoplasm), tissue, or
organs.

Atrophied organs are smaller than normal.

Normal weight (g) of parenchymal organs:
- spleen 150
- kidneys 150-150
- heart 300 to 350
- lungs 400-400
- brain 1300
- liver 1500

Physiologic atrophy
- Involution of the thymus in adolescence
- Senile atrophy in aging
- Atrophy of female genitalia in menopause

Pathologic atrophy
1.Disuse. Atrophy of skeletal muscles in people who
do not use them (prolonged bed rest, immobilization
of limb for healing of bone fracture)
2. Loss of innervation of skeletal muscle

3. Lack of trophic hormones in pituitary disease

4. Ischemia. Slow but progressive reduction of blood
supply leads to renal atrophy or atrophy of the brain
5. Malnutrition cause marasmus: atrophy of skeletal
muscles, parenchymal organs, and general wasting
6. Increased pressure, e.g., hydrocephalus or
hydronephrosis

Obstruction of the CSF flow leads to pressure atrophy

of the brain, with the enlargement of ventricles:
hydrocephalus

Hydronephrosis: obstruction of the ureter leads to

sac-like dilation of renal pelvis and calyces, and
pressure atrophy of parenchyma

Hypertrophy
An increased cell mass leading to an increased
size of organs
Physiologic:
hypertrophy of uterus in pregnancy,
compensatory hypertrophy of the remnant kidney
after unilateral nephrectomy,
exercise

Increased exercise leads

to hypertrophy of muscles

Hypertrophy
An increased cell mass leading to an increased
size of organs
Physiologic: ...
Pathologic: in the muscles

Muscles are not able to divide, therefore an

increased demand for action can be met only by
enlarging the size of cells
Examples: hypertrophy of the myocardium,
hypertrophy of the detrusor muscles of urinary
bladder

Hypertrophy of heart, triggered by action of mechanical

stimuli ( workload) and vasoactive substances (e.g.,
angiotensin II). Free wall thickness: above 15 mm

Hypertrophy of the muscles of urinary bladder due to urethral

obstruction

Hyperplasia
Hormonal stimulation results in an increase in
the size of a tissue or organ due to an
increased number of constituent cells. The
cells may have an increased volume.

Physiologic:
- proliferation of the glandular epithelium of the
breast during lactation

Pathologic hyperplasias
- Endometrial hyperplasia, induced by estrogens;
clinical feature: bleeding from the uterus between
menstrual periods (metrorrhagia)
- Hyperplasia of prostate, induced by
dihydrotestosterone, estrogens and peptide growth
factors; clinical consequence: urinary tract obstruction
- Bilateral adrenal cortex hyperplasia, induced by
increased ACTH secretion; clinical consequence:
increased production of corticosteroids leading to the
Cushings sy
- etc.

Metaplasia
Replacement of one adult cell type by another
adult cell type; reversible.
Squamous metaplasia of the bronchus: chronic
irritation-induced replacement of bronchial
stratified columnar epithelium by squamous
epithelium in smokers
Gastric metaplasia of the oesophagus: chronic
irritation induced by gastric juices in gastrooesophageal reflux leads to the replacement of
squamous epithelium by gastric epithelium

If the adverse circumstances persist, metaplasia

may progress to dysplasia (precancerous)

Bronchus: squamous metaplasia (right)

Intracellular accumulations
Lipids - triglycerides, cholesterol
Proteins
Pigments

Accumulation of triglycerides

Most common in the liver, but also occurs in

the heart; reversible
Fatty change/steatosis of liver: due to
- alcohol abuse
- morbid obesity
- diabetes
- protein-energy malnutrition
- hypoxia
- hepatotoxins
Biochemical pathways of uptake and metabolism of fatty acids by
the liver, formation of triglycerides, and secretions of lipoproteins:
not detailed here

Steatosis: the liver is enlarged, yellow and greasy,

resembles to goose liver

Courtesy of E. Kemny, SZTE Patholog

The lipid molecules accumulate in large vacuoles

Frozen section, Oil Red O

 In atherosclerosis, cholesterols and

cholesterol esters accumulate extra- and
intracellularly in the intima of aorta and large
arteries and form atheromatous plaques.

Atheromatous plaque: the lipids are dissolved during

normal histologic processing

The dissolved cholesterol crystals appear as

cleftlike cavities

Accumulation of lipids in macrophages

In cerebral infarction, macrophages
phagocytose membrane lipids derived from
dead oligodendrocytes and transform into
foamy macrophages

Accumulation of proteins

Hyaline change: any alteration within cells that

imparts a homogeneous, glassy pink
appearance in H&E-stained histologic sections
- Hyaline droplets in proximal tubular cells in
heavy proteinuria
- Mallory-hyaline in hepatocytes in alcoholic
liver injury

Hyaline droplets in proximal tubular epithelial cells

Mallory-hyalin

Accumulation of pigments
Exogeneous
- Inhaled coal dust (black) - leading to anthracosis
of lungs; stored in pulmonary macrophages
- Pigments of tattooing, taken up by macrophages

Endogeneous
- Lipofuscin (brown), associated with tissue
atrophy, in the myocardium of elderly people
- Hemosiderin (brown), hemoglobin-derived
intracellular pigment composed of aggregated
ferritin, indicates previous hemorrhage.
Systemic accumulation: termed hemosiderosis
- Melanin (brown): product of nevus cells
- Jaundice (icterus): systemic bilirubin retention;
yellow skin and sclera discoloration

Pathologic calcification
Abnormal deposition of Ca-salts in soft tissues

Dystrophic
In nonviable or dying tissues;
the serum Ca++ level is normal.
Precipitation of a crystalline Ca-phosphate starts with
nucleation (initiation) on membrane fragments, followed by
propagation of crystal formation.
Very common, with serious clinical consequences
Examples
Arteries in atherosclerosis
Damaged heart valves
Areas of various necrosis

Dystrophic calcification of aortic valves

(calcifying aortic stenosis)

Metastatic calcification
Results from hypercalcemia
Destruction of bones by myeloma, metastases,
Increased secretion of parathormone in
hyperparathyroidism
Etc.

Deposits in the arteries, and at sites of acidification:

kidneys, lungs, and stomach

Metastatic calcification of arteries in end-stage renal disease

Radial art.
Ulnar art.

Bereczki Csaba, SZTE Pediatrics

Jaundice: yellowish discoloration of skin

Jaundice (should be learned in the 2nd semester)

The bilirubin metabolism should be reviewed first
200-300 mg bilirubin is produced daily in the body, and stems predominantly from
senescent RBCs
Transformation of heme into biliverdin in the mononuclear phagocytic cells
(including the spleen)
Biliverdin is reduced to bilirubin released into the blood
Binding of bilirubin to albumin (the complex is not water soluble; unconjugated or
indirect bilirubin)
Uptake of albumin-bound bilirubin by hepatocytes, and conjugation of bilirubin to
glucuronic acid (water-soluble; conjugated or direct bilirubin)
Excretion of bilirubin glucuronides in bile
Deconjugation of most bilirubin glucuronides by bacteria in the intestine
formation of colorless urobilinogen (UBG)
Conjugated bilirubin and UBG are excreted in feces
Some UBG and bile acids are reabsorbed in the gut and are
returned to the liver (enterohepatic circulation)

Jaundice (icterus)
Yellow discoloration of the skin, sclerae, and mucous
membranes due to increased levels of bilirubin in circulation (>
40 umol/L)
Normally, blood contains < 20 umol/L of bilirubin, most of it in an
unconjugated form

Laboratory classification of hyperbilirubinemia

Predominantly unconjugated
Mixed
Predominantly conjugated
Pathogenetic forms of jaundice
Prehepatic jaundice resulting from hemolysis increased biru is
predominantly in an unconjugated form

Hepatic jaundice resulting from liver cell injury increased biru is

partially in a conjugated and partially in an unconjugated form

Posthepatic jaundice resulting from the obstruction of major

extrahepatic biliary ducts increased biru is predominantly in a conjugated
form

Main causes of predominantly unconjugated hyperbilirubinemia

Autoimmune hemolytic anemias
Malaria
Erythroblastosis fetalis
Mismatched transfusion (should not happen)
Main causes of mixed hyperbilirubinemia
Hepatitis (viral, drug-induced, alcoholic)
Cirrhosis (usually mild)
Main causes of predominantly conjugated hyperbilirubinemia
Associated with an elevation of alkaline phosphatase in the blood;
progressively worsening jaundice and pale (acholic) stool

Gallstone in the common bile duct

Carcinoma (head of pancreas, common bile duct, ampulla of
Vater)
Stenosis (sclerosis) of ampulla of Vater
Primary biliary cirrhosis and primary sclerosing cholangitis