Introduction to pathology

• Pathology is the study (logos) of suffering (pathos)

• Pathology is devoted to the study of structural

and functional changes in cells, tissues and organs
that underlie diseases
 Pathology

General pathology
Basic reactions of cells
and tissues to abnormal
stimuli, i.e. common Systematic pathology
features of various The descriptions of
disease processes in specific diseases as
various cells and tissues they affect given
organs or organ
systems
 Pathology focuses on 5 aspects of disease

1) Occurrence in populations (epidemiology)

2) Its cause (etiology)
environmental, genetic, multifactorial, etc.
3) The mechanism of its development
(pathogenesis)
4) The structural alterations induced in organs,
tissues and cells: macroscopical and
microscopical (patho)morphology
5) The functional consequences: clinical
significance
 Pathology of cellular injury and death
Cells react to adverse influences by

Reversible cell
injury
Changes that can be
reversed when the
stimulus is removed
 Pathology of cellular injury and death
Cells react to adverse influences by

Reversible cell Irreversible

injury cell injury
Changes that can be Changes that cause
reversed when the cell death
stimulus is removed
 Pathology of cellular injury and death
Cells react to adverse influences by

Reversible cell Irreversible Cellular

injury cell injury adaptation
Changes Changes that cause Stimuli result in new
that can be reversed cell death but altered state that
when the stimulus is maintaines the
removed viability of the cell
 Causes of cellular injury

Hypoxia
• Ischemia (loss of
blood supply)
• Inadequate
oxygenation
(cardioresp. failure)
• Loss of oxygen
carrying capacity of
the blood (e.g.,
anemia, CO
poisoning)
 Causes of cellular injury

Hypoxia Physical Infectious

(⇓ of O2) agents agents
• Ischemia (loss of • Trauma • Bacteria
blood supply) • Heat • Viruses
• Inadequate • Cold • Fungi
oxygenation • Radiation • Rickettsiae
(cardioresp. failure) • Electric shock • Parazites
• Loss of oxygen
carrying capacity of
the blood (e.g.,
anemia, CO
poisoning)
 Causes of cellular injury

Hypoxia Physical Infectious

• Ischemia (loss of agents agents
blood supply) • Trauma • Bacteria
• Inadequate • Heat • Viruses
oxygenation • Cold • Fungi
(cardioresp. failure) • Radiation • Rickettsiae
• Loss of oxygen • Electric shock • Parazites
carrying capacity of
the blood (e.g., Others
anemia, CO Chemical
poisoning) agents and • Immunologic
reactions
drugs • Genetic
derangements
• Nutritional
imbalances
 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
 Features of

Hypoxic Injury Chemical

injury induced by injury
free
radicals
 Hypoxic injury
Main biochemical events
• ATP depletion

• Influx of intracellular Ca ++ ions and loss of Ca++

homeostasis
Ca ++ ions activates
phospholipases ⇒ degradation of membrane
phospholipids
proteases ⇒ membrane and cytoskeletal protein
degradation
ATPases ⇒ enhance ATP depletion
endonucleases ⇒ chromatin fragmentation
 Reversible hypoxic injury

• Hypoxia prevents oxidative phosphorilation, thus

reducing the capacity to generate ATP
• ATP provides fuel for the Na+/K+ ATPase, which acts
as a pump, keeping the high concentration of sodium
in the intercellular fluid and the high concentration of
potassium inside the cell
 Reversible hypoxic injury

• ATP provides fuel for the Na+/K+ ATPase, which acts

as a pump, keeping the high concentration of sodium
in the intercellular fluid and the high concentration of
potassium inside the cell
• Hypoxia prevents oxidative phosphorilation ⇒ ATP ⇓

• Hypoxia ⇒ malfunction of Na+/K+ ATPase ⇒ influx

of sodium and water from the extracellular space ⇒
cellular swelling: hydropic change
 Reversible hypoxic injury

• ATP provides fuel for the Na+/K+ ATPase, which acts

as a pump, keeping the high concentration of sodium
in the intercellular fluid and the high concentration of
potassium inside the cell
• Hypoxia prevents oxidative phosphorilation ⇒ ATP ⇓

• Hypoxia ⇒ malfunction of Na+/K+ ATPase ⇒ influx

of sodium and water from the extracellular space ⇒
cellular swelling: hydropic change
• Anaerobic glycolysis starts ⇒ depletion of cytoplas-
mic glycogen ⇒ ⇑ of lactic acid in the cytoplasm ⇒
⇓ of the intracellular pH, ⇓action of enzymes
Hydropic change in the proximal tubule: 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 in the proximal tubule: 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.

The
changes
are rever-
sible if
oxygena-
tion is
restored
 Irreversible hypoxic injury

• The transition from reversible to irreversible state is

gradual and occurs when adaptive mechanisms have
been exhausted

• Signs of irreversible injury

- Amorphous densities in swollen mitochondria
- Formation of myelin figures from whorls of
mitochondrial membranes
-
 Irreversible hypoxic injury

• The transition from reversible to irreversible state is

gradual and occurs when adaptive mechanisms have
been exhausted

• Signs of irreversible injury

- Amorphous densities in swollen mitochondria
- Formation of myelin figures from whorls of
mitochondrial membranes
- Surface membrane blebs
- Rupture of cell and plasma membranes
- Leakage of lysosomal enzymes ⇒ digestion of cell
and nuclear components
 The mitochondria are swollen, their membranes are
ruptured, and amorphous densities are in their matrix
 Lethal hypoxic injury:
rupture of cell membranes
Sublethal hypoxic injury and lysis of chromatin
LM features of lethal hypoxic injury: loss of nuclear
staining, the cytoplasm is eosinophilic (pink)
 Dead cells show typical nuclear changes

• Pyknosis (pyknos, dense) - condensation of chromatin

• Karyorrhexis - (rhexis, tearing apart) - fragmentation
of nuclear material
• Karyolysis - lysis of chromatin due to the action of
endonucleases (loss of nuclear staining)
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 and many other cells
 Can hypoxic cell injury be reversed or
repaired by providing the cells with adequate
oxygen?
• Irreversibly damaged cells cannot be revived by O2

• The function of reversibly damaged cells can be

improved by O2
 Can hypoxic cell injury be reversed or
repaired by providing the cells with adequate
oxygen?
• Irreversibly damaged cells cannot be revived by O2
• The function of reversibly damaged cells can be
improved by O2
• Reestablished blood flow to a myocardium made
hypoxic to coronary obstruction may cause
reperfusion injury of still living myocardial cells at
the marginal zone of a myocardial infarction
 Can hypoxic cell injury be reversed or
repaired by providing the cells with adequate
oxygen?

• Irreversibly damaged cells cannot be revived by O2

• The function of reversibly damaged cells can be
improved by O2
• Reestablished blood flow to a myocardium made
hypoxic to coronary obstruction may cause
reperfusion injury of still living myocardial cells at
the marginal zone of a myocardial infarction
• Reperfusion injury is caused by oxygen-derived free
radicals that may form under such conditions, and is
an irreversible damage to cells injured previously by
hypoxia
 Oxygen free radicals

• Superoxide anion radical (O2.-), hydrogen peroxide

(H2O2), hydroxyl radical (OH.) and nitric oxide (NO.)

• Free radicals
cause lipid peroxidation ⇒ membrane damage
cross-link proteins ⇒ inactivation of enzymes
cause DNA breaks ⇒ blockade of DNA transcription
 Chemical injury

• Two 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
 Necrosis
(morphology of irreversible injury)

• Necrosis (necros, dead) is death of cells, tissues, or

organs in a living organism
• Histological signs: same as those of irreversible
hypoxic injury: cell membrane rupture, nuclear
changes: pyknosis, karyorrhexis or karyolysis
Main types of necrosis

• Coagulative necrosis
• Liquefactive necrosis
• Caseation
• Fat necrosis
• Gangrene
• Fibrinoid necrosis
 Main types of necrosis

• Coagulative necrosis
Grossly • Liquefactive necrosis
visible • Caseation
• Fat necrosis
• Gangrene
• Fibrinoid necrosis
 Coagulative necrosis

• Most common form of necrosis, predominated

by protein denaturation with preservation of the
cell and tissue framework
• This pattern is characteristic of hypoxic death in
all tissues except the brain
 Coagulative necrosis

Anaemic infarct Haemorrhagic

• Cause: occlusion of an infarct
end artery
• In the heart, spleen, kidney
• Gross: pale tissue, with
well-defined boundaries;
later it becomes yellowish
because the lysosomal
enzymes of the necrotized
cells autodigest the
infarcted area
• Healing: by connective
tissue replacement (fibrosis)
 Coagulative necrosis
Anaemic infarct
• In the heart, spleen, kidney
• Cause: occlusion of an
endartery
• Gross: pale, firm tissue,
with well-defined bounda-
ries; later yellowish
because the lysosomal
enzymes of the necrotized
cells autodigest the
infarcted area
• Healing: by connective
tissue replacement (fibrosis)
Haemorrhagic
infarct
• In the lungs
• Cause: occlusion of a
segm. pulmonary artery
• The necrotized area
undergoes secondary
haemorrhage via
bronchial arteries
• Firm, wedge-shaped,
pleural-based, haemorr-
hagic, airless focus
• Healing: by fibrosis
Anaemic infarction of the myocardium, the margins
are hyperaemic
The infarcted myocardial fibers are eosinophilic, there is no
nuclear staining; neutrophilic granulocytes accumulated at
the margins of infarction (vital sign)
 Liquefactive necrosis: softening of the necrotic
tissue due to action of hydrolytic enzymes released
from

• Dead cells, as in brain infarct

• Healing: with glial scar
Liquefactive necrosis: softening of the necrotic
tissue due to action of hydrolytic enzymes released
from

• Dead cells, as • Neutr. granulocytes invading

in brain the tissue, as in an abscess
infarct • Healing: with fibrosis
•Healing: with
glial scar
 Caseous necrosis
• Distinctive form of coag. necrosis in foci of
tuberculous infection
• Gross: caseous necrosis is white and cheesy
 The necrotic area is eosinophilic, amorphous, and is
surrounded by epitheloid cells and Langhans’ giant cells.
Healing: by fibrosis + calcification
 Fat necrosis
• Refers to necrosis in adipose tissue, induced by
the action of lipases derived from injured
pancreatic cells or macrophages

• Lipases catalyse decomposition of triglycerides to

fatty acids, which complex with calcium
to create calcium soaps
 Fat necrosis
• Refers to necrosis in adipose tissue, induced by
the action of lipases derived from injured
pancreatic cells or macrophages

• Lipases catalyse decomposition of triglycerides to

fatty acids, which complex with calcium
to create calcium soaps

• Observed in the course of pancreatitis, or in

traumatic injury of subcutis or breast

• Healing: by fibrosis
Yellowish foci of enzymatic fat necrosis in acute
pancreatitis
 Gangraene

• Gangraene results when putrefactive bacteria

invade necrotic tissue
• Three types (detailed later)

• Dry gangraene: in the leg of patients suffering

from atherosclerosis-related occlusion of the
tibial arteries
 Gangraene

• Gangraene results when putrefactive bacteria

invade necrotic tissue
• Three types (detailed later)

• Dry gangraene: 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
haemoglobin
Gangraene of the great toe
 Fibrinoid necrosis

• Limited to medium-sized and small arteries

• The wall of these vessels undergo necrosis and is

impregnated with fibrinogen and other plasma
proteins

• It can be recognized only in histologic slides

• Observed in malignant hypertension, arteritis,

rejection
Fibrinoid necrosis of small arteries, the
necrotized SMCs are eosinophilic
 Apoptosis: programmed cell death

• A form of energy-dependent process for

deletion of unwanted individual cells
• Cell death occurs by activation of the internal
suicide program
 Apoptosis: programmed cell death

• A form of energy-dependent process for

deletion of unwanted individual cells
• Cell death occurs by activation of the internal
suicide program

• Prevented or induced by a variety of stimuli

• ⇓ Apo contributes to cell accumulation, e.g.

neoplasia

• ⇑ Apo results in extensive loss, e.g. atrophy

 Inhibitors

• Growth factors
• Sexual steroids (e.g., testosteron)
 Inducers

• Growth factor withdrawal

• Glucocorticoids
• Injuries:
- Viruses (hepatitis virus, HIV)
- Free radicals
- Ionising radiation
- DNA damage
 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 lost from the
mitochondrial membrane, and is replaced by pro-apoptotic
Bax protein
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. Cytotoxic molecules derived from
CD8+ T-cells directly activate these caspases
 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: cell shrinkage, and condensation of nucleus
induced by cytotoxic T- lymphocytes
 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

• Disuse. Muscles atrophy in people who do

not use them (prolonged bed rest,
immobilization of an extremity for healing
of fracture)
• Loss of innervation of skeletal muscle
• Lack of trophic hormones in pituitary
disease
•
 Pathologic atrophy
• Disuse. Muscles atrophy in people who do
not use them (prolonged bed rest,
immobilization of an extremity for healing
of fracture)
• Loss of innervation of skeletal muscle
• Lack of trophic hormones in pituitary disease
• Ischaemia. Reduced blood supply leads to
renal atrophy or atrophy of the brain
• Malnutrition. Protein-energy deficiency
cause atrophy of skeletal muscles,
parenchymal organs, and general wasting
(marasmus)
• 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
Hydronephrosis: dilated calices, atrophied
papillae, thinned 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
(in both conditions, cell division is also present)
 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
(in both conditions, cell division is also present)

• Pathologic: occurs e.g. 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
Increased exercise
leads to
hypertrophy
of muscles
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 urethra obstruction
 Hyperplasia
• 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: hormonal hyperplasia:
- proliferation of the glandular epithelium of the breast
during lactation;
- compensatory hyperplasia of liver after partial
hepatectomy
 Hyperplasia
• 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: hormonal hyperplasia:
- proliferation of the glandular epithelium of the breast
during lactation;
- compensatory hyperplasia of liver after partial
hepatectomy
• Pathologic: due to hormonal stimulation
- endometrial hyperplasia, induced by oestrogens
- adrenal cortex hyperplasia, induced by ACTH
- hyperplasia of prostate, induced by dihydrotestosterone,
oestrogens and peptide growth factors
- hyperplasia of thyroid, induced by anti-TSH antibodies
 Metaplasia
• Replacement of one mature cell type by another
type.
• E.g.:
- Squamous metaplasia of the bronchus: chronic
irritation-induced replacement of bronchial
stratified columnar epithelium by squamous
epithelium in smokers
 Metaplasia
• Replacement of one adult cell type by another
adult cell type; reversible.
• E.g.,
- 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
Squamous metaplasia of the bronchus
 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 triglyce-
rides, and secretions of lipoproteins: not detailed here
Steatosis: the liver is enlarged, yellow and greasy,
resembles to goose liver
The lipid molecules accumulate in large vacuoles

Frozen section, Oil Red O

 Accumulation of cholesterols and
cholesterol esters
• In the intima of aorta and large arteries in
atherosclerosis.
• In macrophages
- in hyperlipidaemia: collections of foamy
macrophage produce yellowish nodules in the
palpebra (xanthomas)
-
 Accumulation of cholesterols and
cholesterol esters
• In the intima of aorta and large arteries in
atherosclerosis.
• In macrophages
- in hyperlipidaemia: collections of foamy
macrophage produce yellowish nodules in the
palpebra (xanthomas)
- in cholesterolosis: foamy macrophages
accumulate in the lamina propria of gallbladder
-
 Accumulation of cholesterols and
cholesterol esters
• In the intima of aorta and large arteries in
atherosclerosis.
• In macrophages
- in hyperlipidaemia: collections of foamy
macrophage produce yellowish nodules in the
palpebra (xanthomas)
- in cholesterolosis: foamy macrophages
accumulate in the lamina propria of gallbladder
- in cerebral infarction: macrophages
phagocytosemembrane lipids derived from
dead oligodendrocytes
Atheromatous plaque: the lipids are dissolved
during normal histologic processing
The dissolved cholesterol crystals appear as
cleftlike cavities
Foamy macrophages scavenge necrotic debris rich in lipids
 Accumulation of proteins

• Hyaline change: any alteration within cells that

imparts a homogeneous, glassy pink appearance in
H&E-stained histologic sections
•
 Accumulation of proteins

• Hyaline change: any alteration within cells that

imparts a homogeneous, glassy pink appearance in
H&E-stained histologic sections
• Intracellular:
- 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-hyaline in chronic alcohol abuse
 Accumulation of pigments
• Exogeneous
- Inhaled coal dust (black) - leading to
anthracosis of lungs; stored in pulmonary
macrophages
- Pigments of tattooing, taken up by macrophages
 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
 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
- Haemosiderin (brown), haemoglobin-derived
intracellular pigment composed of aggregated ferritin,
indicates previous haemorrhage.
Systemic accumulation: termed haemosiderosis
- Melanin (brown): product of naevus 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.

•Arteries in atherosclerosis
•Damaged heart valves
•Areas of various necrosis

Precipitation of a crystalline
Ca-phosphate starts with
nucleation (initiation) on
membrane fragments,
followed by propagation of
crystal formation
 Pathologic calcification
Abnormal deposition of Ca- salts in soft tissues
Dystrophic Metastatic
In nonviable or dying Results from hypercalcaemia:
tissues; the serum Ca++ • ⇑ secretion of parathormone
level is normal. in hyperparathyroidism
• Destruction of bones by
•Arteries in atherosclerosis myeloma, metastases, acce-
•Damaged heart valves lerated bone turnover, or
•Areas of various necrosis immobilization [space travel]
• Vitamin D-intoxication
Precipitation of a crystalline • Systemic sarcoidosis
Ca-phosphate starts with • In chronic renal failure ⇒
nucleation on membrane sec. hyperparathyroidism due
fragments, followed by to phosphate retention
propagation of crystal Deposits in the arteries,
formation kidneys, lungs, and stomach
Dystrophic calcification: calcifying aortic stenosis
Metastatic calcification of arteries in ESRD

Radial art.

Ulnar art.

Bereczki Csaba, SZTE Pediatrics

Metastatic calcific deposits of the lung
The calcific deposits fill the alveolar spaces