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; can 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 alterations induced in cells and tissues
by the disease (morphologic change)
- the functional consequences of the morphologic
changes (clinical significance)

• The morphologic change can 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

The descriptions and terms used are the basis of

medical language
Students are expected to attend the lectures, the
autopsy and histopathology practicals, and the organ
demonstrations.

Attendance at the practicals the attendence is always

verified. There is no possibility for missed practicals
to be repeated later.

Students who are absent from more than 25% of the

practicals, automatically fail the semester.
The grade achieved in the fall-semester
examinations will be calculated from the sum of the
following:
- the first mid-term assessment (maximum 5 points)
- the second mid-term assessment (max. 5 points)
- the histology examination (max. 5 points)
- the autopsy examination (max. 5 points)
- the final test (max. 80 points).

The final grades: from 0 to 50 points: failed (grade 1),

from 51 to 59 points: passed (grade 2); from 60 to 69
points: accepted (grade 3); from 70 to 79 points:
good (grade 4); from 80 to 100 points: very good
(grade 5).
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 particularly
vulnerable to cellular injury
• Maintenance of membrane integrity - critical for ionic
and osmotic homeostasis of the cell

• Aerobic respiration - oxidative

phosphorilation and ATP production in mitochondria

• Synthesis of enzymes and structural proteins

Common cellular injuries

• Hypoxic/ischemic injury

• O2-derived free radicals

• Others: chemical injury (acid and alkali

solutions), burns, frostbite, trauma, electric
shock, etc.
Hypoxia

Reduction in available oxygen

Common causes
1. Upper airway obstruction (eg., sudden swelling of
laryngeal mucosa, foreign body aspiration)

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
Aspiration of gastric content caused obstruction of airways and led to death in the
patient with deep coma
Ischemia
• Inadequate blood supply to an organ or part of it
due to impeded arterial flow or reduced venous
drainage
Reversible ischemic injury
• Leads to hydropic change of cells
• Commonly observed in kidney biopsies

Pathomechanism
• A decrease of blood pressure for hours
• Hypoxia of tubular epithelial cells  ATP depletion
 malfunction of Na+/K+ ATPase  influx of sodium
and water into tubular cells
Morphologic features
• Light microscopy (LM)....
• Electron microscopy (EM)....
LM: the tubular epithelial cells are vacuolated, and
the brush border of proximal tubules is lost.
 Hydropic change on 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 of proximal tubules
Clinical consequence
• Acute renal failure: decreased urinary
output; hemodialysis is necessary
• If systemic hypotension can be corrected,
the renal function normalizes within days
Irreversible ischemic injury and cell death
• 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 indicative of death of ischemic
cells

• Within 2 to 3 hours after the death of cells

• Ruptured cell and plasma membranes

• Lysis of cell and nuclear components

(leakage of lysosomal enzymes result in
digestion of organelles and other cytosolic
components)
 Irreversible hypoxic injury: rupture of cell
Reversible hypoxic injury membranes and lysis of chromatin
LM features indicative of death of ischemic
cells

• Evident approximately 24 hours after the death

of ischemic cells

• Loss of nuclear staining

• Eosinophilia of the cytoplasm

Important
• The cellular function is lost before cell death
occurs, and the morphologic features of cell
death lag far behind loss of function
Injury induced by O2-derived free radicals

Inflammation, radiation, chemicals, reperfusion lead to

the formation of
• superoxide anion radical (O2.-)
• hydrogen peroxide (H2O2)
• hydroxyl radical (OH.)
• nitric oxide (NO.)

These molecules cause oxidative stress of cells:

• lipid peroxidation  membrane damage
• cross-linkage of proteins  inactivation of
enzymes
• DNA breaks  blockade of DNA transcription
Note
Insidiously ongoing oxidative stress of cells plays a
role in the process of aging
Laboratory markers of irreversible cell injury

Cytoplasmic enzymes 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) – from ruptured

RBCs
Necrosis - morphology of irreversible injury

• Necrosis (necros, dead): death of cells in a

living organism characterized by loss of
membrane integrity and enzymatic digestion of
cells

• Histological sign: loss of nuclear staining

• Healing: substances released from dead cells

induce a local inflammatory reaction, which
serves to eliminate the debris and initiates the
repair process
 Types of necrosis

1. Coagulative necrosis
2. Liquefactive necrosis
Grossly 3. Caseation
visible 4. Fat necrosis
5. Gangrene

1. 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

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,
surrounded by activated macrophages (epitheloid cells) which
mediate the tissue 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
• Occurs in arteries, arterioles, and capillaries; seen
in autoimmune disoders (SLE, arteritis) for
example

• The wall of these vessels undergo necrosis and is

impregnated with fibrinogen and other plasma
proteins
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 cell’s 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 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

 Intrinsic (mitochondrial) pathway of
apoptosis
Mitochondrion

Bcl-2 inhibits Execution

Bax activates caspases

When cells are deprived of survival signals or

subjected to 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
 Extrinsic (death receptor) pathway of
apoptosis

Mitochondrion Execution
caspases
Bcl-2 , Bax

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.
 Execution pathway of apoptosis

Bax Execution caspases:

cascade of proteolytic
enzymes

Death receptors Cytotoxic

(TNF, FAS) T-cells
• 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. In skeletal muscles due to
- disuse as in prolonged bed rest or immobilization of
limb for healing of bone fracture
- loss of innervation
2. Loss of endocrine stimulation - lack of trophic
hormones in pituitary disease
3. Diminished blood supply. Slow but progressive
reduction of blood supply leads to renal atrophy or
atrophy of the brain
4. Malnutrition. Atrophy of parenchymal organs,
skeletal muscles, and general wasting (marasmus)
5. 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 (arrow)
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
Cushing’s sy
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 gastrooeso-
phageal 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. Kemény, SZTE Patholog

The hepatocytes are vacuolated; representing accumulations
of neutral lipids that have been removed by lipid solvents during
tissue processing

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
• Jaundice (icterus): systemic bilirubin retention;
yellow skin and sclera discoloration

• Hemosiderin (brown), hemoglobin-derived

intracellular pigment composed of aggregated
ferritin, indicates previous hemorrhage. Systemic
accumulation: termed hemosiderosis

• Melanin (brown): product of nevus cells

Jaundice: yellowish discoloration of skin
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