PATHOPHYSIOLOGY

LECTURE

Prepared by

Habtamu Bayih (MD)

1
Introduction
 Pathology
 is "Scientific study of disease"

 Study of structural and functional changes in disease.

 deals with knowledge of what causes disease, how disease

starts, progresses & it explains the reason for signs and

symptoms of patient"
 Branches of Pathology:
 Histopathology / Anatomic Pathology : Pathologists

specialising in anatomical changes in disease. Usually using a

tissue biopsy.
 Cytopathology: Pathologists specialising in study of body

fluids & Cells.

 Haematology: Study of blood and blood forming organs.

2
  Morbid Anatomy: Autopsy or Post mortem study for legal

or educational purpose.
 Aspects of disease
 Disease (dis+ease)? "Discomfort due to Structural or

functional abnormality
 Pathology of a disease is formally studied under four

subdivisions/aspects.
 Etiology - Study of cause / causative agent of disease
 Pathogenesis- Study of disease progression or evolution.
 Morphology - Study of structural changes in disease (Gross &
microscopic)
 Clinical Significance - Study of how clinical features are related
to changes.

3
 Factors causing disease
 are mainly two types.

1. Environmental or external factors /acquired

 Physical
 Chemical
 Nutritional
 Infections
 Immunological
 Psychological
1. Genetic or Internal factors.
 Age
 Gene

4
  Congenital disease Diseases which present since

birth .
 Familial diseases Diseases which occur in families

 Major groups of diseases

1. Inflammatory disorders
 are due to damage to tissues by various injuries (physical,
chemical, infections etc.)

1. Degenerative disorders
 are due to lack of growth or ageing.

1. Neoplastic disorders
 are due to excess cell division forming tumours.

5
CELLULAR PATHOLOGY

Cellular Physiology & Pathology

To understand diseases of the body systems or

individual organs,
requires knowledge of the function &

dysfunction of individual cells.

This is a topic of great complexity and only the

basic principles can be outlined.

6
Cellular Physiology is characterized by:
Close interdependence of the various cellular

components and activities (though it is convenient to

describe them separately).
Balancing control mechanisms aimed at

maintaining constant conditions (i.e. homeostasis)

 Very efficient compensatory and repair

mechanisms to minimize damage

7
Plasma Membranes

 Main function
maintain integrity of cell

Contact with extra cellular environment

 e.g. = cell surface receptors

Transport of substances

 Passage of ions through permeable channels e.g. = Na+, k+

 Passage of complex molecules by pinocytosis or phagocytosis

Any disorder may lead to dysfunction or cell death

8
Mitochondria

Main site of ENERGY Production.

Disorder of energy Production affects all cellular

functions.

Source Production O2 + Glucose 

Oxidative phosphorylation (ADP  ATP)  Release
of energy  Utilization for cellular activities

9
Nucleus
The nucleus controls all cellular activities through
action of at least 50 000 genes,
Each of which encodes a protein with structural,
enzymatic or control functions.
Damage leads to
Development abnormalities

Hereditary disease

Susceptibility to diseases

10
Lysosomes
Contain hydrolytic enzymes and responsible for
Digestion and disposal of complex substances.

Disorder may lead to

escape of enzymes or

cellular over leading (e.g.: lysosomal storage

disorders)

11
Cell injury
The environment around cells is dynamic and

constantly changing.
In this fluid environment, cells are exposed to

numerous stimuli, some of which may be

injurious.
A wide variety of noxious agents can damage

cells (causes of cell injury).

12
 Injury is defined as
an alteration in cell structure or function

resulting from some stress that exceeds the

ability of the cell to compensate through
normal physiologic adaptive mechanisms.
Cells typically respond to potentially
injurious stress in one of two ways:
Adaptation - Cells can alter their structure and/or
biochemical processes in order to achieve a new
"steady state" and maintain near-normal
physiologic functions (homeostasis).

Injury - If stressed cells cannot adequately adapt,

critical cell functions may be impaired, and the cell
is said to be injured.
Reversible and irreversible
injury
If injured cells recover their normal functions
when the stress is removed, the injury is said
to be reversible.

If the injury is severe enough, however, a

“Point of no return” is reached and the cell
suffers irreversible injury and dies.
Cellular Responses to
Stress and Noxious Stimuli
Causes of Cellular Injury
1. Hypoxia
 Most common cause of injury

 Definition: lack of oxygen leads to the inability of the cell to

synthesize sufficient ATPby aerobic oxidation

 Major causes of hypoxia
 Ischemia:
 loss of blood supply
 Most common cause of hypoxia .
 Decreased arterial flow or decreasevenous outflow
 e.g., arteriosclerosis, thrombus, thromboembolus
 Cardiopulmonaryfailure
 Decreasedoxygen-carryingcapacity of the blood (example: anemia)

17
2. Infections
Viruses,bacteria, parasites, and fungi (and

probably prions)
Mechanism of injury
 Direct infection of cells
 Production of toxins
 Host inflammatory response

3. lnununologic reactions
Hypersensitivity reactions

Autoimmune diseases

18
4. Congenital disorders
Inborn errors of metabolism (i.e., inherited

disorders )
 i. Enzyme defects leading to the accumulation of toxic
products
 ii. Enzyme defects leading to a deficiency of an important
product
 iii. Genetic defects in structural proteins
 iv. Cytogenetic disorders
 v. Congenital malformations caused by abnormal
development

19
5. Chemical injury
a. Drugs

b. Poisons (cyanide, arsenic, mercury, etc.)

c. Pollution

d. Occupational exposure (CCI4'

asbestosis,carbon monoxide, etc.)

e. Social/lifestyle choices (alcohol, cigarette

smoking, intravenous [IVDA], etc.)

20
6. Physical forms of injury
 a. Trauma (blunt/penetrating/crush injuries,

gunshot wounds, etc.)

 b. Burns

 c. Frostbite

 d. Radiation

 e. Pressure changes

7. Nutritional or vitamin imbalance

 a. Inadequate calorie/protein intake
 i. Marasmus and kwashiorkor
 ii. Anorexia nervosa
21
 b. Excess caloric intake
 i. Obesity
 ii. Atherosclerosis
 c. Vitamin deficiency
 i. VitaminA  night blindness, squamous metaplasia, immune
deficiency
 ii. Vitamin C  scurvy
 iii. Vitamin D  rickets and osteomalacia
 iv. Vitamin K  bleeding diathesis
 v. Vitamin BI2  megaloblasticanemia, neuropathy, and
spinal cord degeneration
 vi. Folate  megaloblastic anemia and neural tube defects
 vii. Niacin  pellagra (diarrhea, dermatitis, and dementia)
 d. Hypervitaminosis

22
Mechanism of cell injury
Four intracellular vulnerable sites for action of the
stimuli (causes of cell injury)
 Plasma membrane

 Mitochondrial aerobic respiration

 Genetic apparatus, and

 protein synthesis

The structural and biochemical elements of the cell

are so closely interrelated that whatever the
precise point of initial attack, injury at one point
leads to wide-ranging secondary effects

23
24
The underlying mechanisms of cellular injury
usually fall into one of two categories:
hypoxic injury

free radical injury

Hypoxic cell injury

Hypoxia is a lack of oxygen in cells and tissues

that generally results from ischemia.

Ischemia: reduction in arterial blood flow (e.g.,

occlusion of arteries, such as coronary artery

atherosclerosis)
25
 During periods of hypoxia, aerobic metabolism of the

cells begins to fail.

Consequences of Hypoxic Cell Injury

1.Decreased synthesis of ATP: reversible change

 Anaerobic glycolysis is used for ATP synthesis and is
accompanied by:
 Activation of phosphofructokinase caused by low citrate
levels and increased adenosine monophosphate
 Decrease in intracellular pH caused by an excess of lactate

26
2.Impaired Na, K+ -ATPase pump, resulting in
diffusion of Na+ and H20 into cells and causing

cellular swelling

3.Decreased protein synthesis, resulting from

the detachment of ribosomes from the rough

endoplasmic reticulum

4.Impaired calcium (Ca 2+)-ATPase pump, resulting in

increased cytosolic Ca2+

Increased cytosolic Ca2+, which leads to:

27
Enzyme activation
a. Activates phospholipase:
 increases cell and organelle membrane permeability

b. Activates proteases:

 damages membrane and structural proteins

c. Activates endonucleases:

 damages nuclear chromatin, causing fading (karyolysis)

Reentry of Ca2+ into mitochondria:

increases mitochondrial membrane permeability,

with release of cytochrome c (activates apoptosis)

28
Free Radical Cell Injury
Free radicals are compounds with unpaired

electrons in the outer orbit.

A.O2-derived free radicals

 Superoxides (O2.): neutralized by superoxide
dismutase
 Hydroxyl ions (OH •): neutralized by glutathione
peroxidase
 Peroxides (H2O2): neutralized by catalase (located
in peroxisomes) and glutathione peroxidase

29
B. Drug and chemical free radicals:
 conversion to free radicals occurs via the cytochrome P-
450 system in the liver.

1.Free radicals from acetaminophen

 may be neutralized by glutathione peroxidase,
 lead to liver and kidney injury.

2.Carbon tetrachloride (CCl4)

 is converted to CCl3
 leading to liver cell necrosis with fatty change.

 Exogenous sources of free radicals include tobacco

smoke, organic solvents, pollutants, radiation and

pesticides.
30
Free radicals are generated as by-products of
normal cell metabolism
They are inactivated by free radical–scavenging
enzymes within the body such as
Catalase and

glutathione peroxidase

When excess free radicals are formed from

exogenous sources or the free radical protective
mechanisms fail, injury to cells can occur.

31
Free radicals are highly reactive and can injure
cells through:
 Peroxidation of membrane lipids

 Damage of cellular proteins

 Mutation of cellular DNA

Free radical injury has been implicated as

playing a key role in the
 normal aging process

 in a number of disease states such as diabetes

mellitus, cancer, atheroscelrosis, Alzheimer’s

disease and rheumatoid arthritis
32
Note
Protective Factors against Free Radicals
Antioxidants
 Vitamins A, E, and C

Superoxide dismutase
 Superoxide  hydrogen peroxide

Glutathione peroxidase
 Hydroxyl ions or hydrogen peroxide  water

Catalase
 Hydrogen peroxide  oxygen and water
33
Cellular Changes During Injury

1. General
a. Cellular responses to injury
i. Adaptation

ii. Reversible injury

iii. Irreversible injury and cell death

(necrosis/apoptosis)

34
b. Cellular response to injury depends on

several important factors

i. The type of injury

ii. The duration of injury

iii. The severity and intensity of injury

iv. The type of cell injured

v. The cell's metabolic state

vi. The cell's ability to adapt

35
Eg:

Reversible damage:
 Small dose of toxin
 Brief period of ischemia

 Irreversible cell damage:

 Large dose of toxin
 Long period of ischemia

Mild injury can be reversed (reversible cell injury) and

severe injury results in cell death (irreversible injury).

36
On the other hand the effect of cellular injury on
tissue depends on the following four factors:
 The duration of the injury;
 the longer the duration of the injury the severe will be the
outcome.

 The natures of the injurious agent,

 ischemic injury are often followed by more severe injury.

 The proportion and type of cells affected;

 nerves and skeletal muscle injury of massive nature are
usually attended by irreversible outcomes.

 The ability of the tissue to regenerate,

 tissues with good regenerative capacity like epithelial cells
usually maintain their functional integrity
37
Depending on the extent of the injury and

capacity of the cell for repair the resultant

damage may range
from reversible cell injury

through cellular adaptation

to irreversible injury and

finally to cell death.

38
Reversible cell injury
Reversible cell injury is the mild form of cell injury which
can come to normal if the injurious agents are mild
enough and can be controlled by the cell.
Morphology
 Cellular Swelling ( Hydropic degeneration)
 Cytoplasm accumulates fluid and common in many of the cells

 Fatty change ( Steatosis)

 Manifested by appearance of lipid vacuoles in the cytoplasm of the
injured cells
 Common in cells involved in fatty acid metabolism e.g. Liver

39
Effects of reversible cell injury
a. Decreased synthesis of ATP by oxidative

phosphorylation
b. Decreased function of Na+K+ATPase

membrane pumps & this results in

 i. Influx of Na+and water
 ii. Efflux of K+
 iii. Cellular swelling (hydropic swelling)
 iv. Swelling of the endoplasmic reticulum

40
c. Switch to glycolysis

 i. Depletion of cytoplasmic glycogen

 ii. Increased lactic acid production
 iii. Decreased intracellular pH

d. Decreased protein synthesis

 i. Detachment of ribosomes from the rough

endoplasmic reticulum

e. Plasma-membrane blebs and myelin figures

may be seen

41
Irreversible cell injury ( lethal cell injury )
 If the injuries agent is so severe and persists

for long time irreversible cell injury ensues.

The sequence of events will end up in the

ultimate digestion of the lethally injured cell

by a process of lysosomal enzymes called
autolysis and / or Heterolysis.

42
Irreversible cell injury is associated with sub-

cellular changes of severe swelling of

mitochondria, extensive damage of the plasma
membrane and swelling of the lysosomes.
There are two important morphologic patterns

of irreversible cell injury and cell deaths

Necrosis and

Apoptosis

43
Necrosis

Necrosis is defined as a spectrum of morphologic

changes that follow cell death in living tissues

It occurs from the progressive degradative action

of enzymes on the lethally injured cells.

The morphologic appearance of necrosis is the result

of two essentially concurrent Processes and these
are

44
Enzymatic digestion of the dead cell by enzymes
derived from two sources:
lysosamal enzymes of the dead cell in which

case the process of cell death is called autolysis.

lysosamal enzymes of the immigrant leukocytes

in which case the process of cell death is called

Hetrolysis.
Denaturation of Proteins:
this will happen through denaturation of

structural Proteins found in the cell.

45
 Morphology of necrosis
 Necrotic cells show the following morphologic changes at light

microscopic level.
 Cytoplasm

 Increased eosinophilia due to loss of the normal basophilia

imparted by RNA and the presence of denatured cytoplasmic
proteins

 Nucleus

 nuclear changes could be in the form of one of the following three

patterns
 Karyolysis – which means loss of the normal basophilia of nuclear
chromation
 Pyknosis – Which indicates nuclear shrinkage and increased
basophilia
 Karyrrhexis winch is characterized by nuclear fragmentation and
eventual disappearance of the nucleus.
46
Morphologic types of necrosis

Coagulative necrosis
which is the Comments type of necrosis

characterized by

 preservation of the basic outline of the necrotic cells and

 the predominant mechanism of degradation is through
denaturation of proteins.
 Micro: loss of the nucleus but preservation of cellular shape
 Common in most organs including the heart, liver, and kidney

47
Liquefactive necrosis
This morphologic form of necrosis is characterized by

 complete digestion of the dead cells with resultant formation of

a liquid viscous mass of the necrotic tissue.
 It is mainly found in bacterial and fugal infections and also
hypoxic death of cells of the central nervous system.
 The mechanism of degradation is mainly through enzymatic
digestion of the necrotic cells.

49
 Gangrenous necrosis (Gangrene)
 It is a kind of necrosis characterized by

 putrefaction of the tissues usually following certain bacterial

infections like the clostridia.

 There are two types of gangrene identified in clinical practices:-

1.Dry gangrene
 is a type of gangrene that occurs due to loss of blood supply

 Particularly affects the lower extremity usually following diseases

states like arteriosclerosis and diabetes mellitus.

 The process of tissue degradation is through coagulative necrosis

of the affected cells.

51
2.Wet gangrene
is a type of gangrene that usually occurs following bacterial

infection like clostridial infection in venous obstruction and

the type of tissue degradation is through liquefactive

necrosis of the involved cells.

Caseous necrosis
is a type of coagulative necrosis whereby the necrotic

tissue assumes a cream-cheesy appearance.

Most often seen in tuberculosis infection.

52
Gangrene - Amputated Diabetic foot
Gangrene Intestine - Thrombosis.
Fat necrosis
 is a special type of necrosis that occurs in fat containing

tissues which are rich with fat enzymes like the lipases.
 E.g. Pancreas, breast, liver

 Naked eye appearance is chalky white.

Fibriniod necrosis
 is a special type of necrosis that occurs in smooth muscles

of the arteries in the setting of malignant Hypertension.

 It is characterized by deposition fibrin in the wall of the

vessels.

57
Apoptosis
 Apoptosis is a from of cell death designed to eliminate

unwanted host cells from the body and

 for this reason it is sometimes called programmed cell death

 it can occur in both physiologic and pathologic stats.

 In general Apoptosis occurs in the following Physiologic and

pathologic settings:
 When cells are damaged by disease or noxious agents

 Cell death in aging.

 Cell death in tumors and neoplasm

 Cell death in certain viral infection.

 As a defense mechanism such as in immune reactions and

Immunologic tolerance.

58
Morphology
The morphologic patterns seen in apoptosis

under ordinary light microscope are:-

 Cell shrinkage- Cells became small with dense
cytoplasm
 It tends to affect single cells surrounded by viable
groups of cells.

59
The Difference between Necrosis and Apoptosis

Necrosis Apoptosis
1. Refers to a group of cell death 1. a Discrete morphological change on
single cell

2. It always occurs due to pathologic 2. It occurs as either - Physiologic ,-

condition Adaptive
or - Pathologic Conditions

3. It is not programmed 3. It is a programmed cell death especially

during embryonic life

4. Inflammation exists surrounding the 4. Inflammation almost invariably absent

necrotic cell

5. Its occurrence usually depends on the 5. Dependent on gene regulated enzymatic

balance between. activity
a) Protein Denaturation
b) Enzymatic liquefaction

60
Cellular Adaptations
Cellular adaptations lies between reversible cell

damage and cell death

where the cell attempts to adapt to the insulting

mechanism by several adaptive responses.

Cells can respond to excessive physiologic or

pathologic stresses by undergoing a number of

physiologic and morphologic cellular adaptations.
In this case a new but altered steady state is

achieved preserving the viability of the cell.

61
These adaptive response involves
 changes in the number of cellular growth which is called
hyperplasia;
 change in the size of the cell which could either be
 in the form of increase in the size called hypertrophy or
 decrease in the size called atrophy and
 change in the cellular differentiation called metaplasia.

The causes of this adaptive response could be

 any physiological stress or any kind of Pathological stimuli and

 as such can be classified as physiological or pathological in

origin.

62
Hyperplasia
 is an increase in the number of cells in a tissue or organ

 Some cell types are unable to exhibit hyperplasia

(e.g.,nerve, cardiac, skeletalmuscle cells)

 Physiologic causes of hyperplasia

 Compensatory (e.g., after partial hepatectomy)

 Hormonal stimulation (e.g., breast development at puberty)
 Antigenic stimulation (e.g.,lymphoid hyperplasia)

 Pathologic causes of hyperplasia

 Endometrial hyperplasia
 Prostatic hyperplasia of aging

63
Hypertrophy

Hypertrophy is a type of adaptive change associated with an

increase the size of a cell and subsequent increase in the size of
the organ following any kind of cellular injury.

The increase in the size of the cell is not due to cellular swelling
but the synthesis of new structural proteins.

Though hyperplasia and hypertrophy are two distinct processes,

they usually occur together and may be triggered by the same
mechanisms.

64
Among the physiologic causes of hypertrophy are
 The gravid uterus,

 the lactating breast and

 athlete’s muscle

Among the Pathologic causes of hypertrophy are

 The failing heart following Hypertension, valvular

heart diseases and coronary heart diseases

 In both conditions, regardless of the cause,
hypertrophy is brought about by either
 an increase in functional demand and / or

 hormonal stimulation of the organ.

65
Atrophy / Hypoplasia
They are associated with a decrease in both the
number and size of the cells.
Hypoplasia refers when the process occurs before
the full development of the organ, which could be
either in the prenatal or postanatal period.
Atrophy is a condition of later life after full
maturation and development of the organ.
When a sufficient of cells are involved in the
process of atrophy or hypoplasia the entire tissue
or organ becomes atrophic or hypoplastic.

66
 Among the physiologic causes of atrophy are
 Decreased Work load which is called disuse atrophy
 Loss of endocrine stimulation as it occurs in the breast, uterus,
genitalias following menopause
 Organ changes in aging called senile atrophy
 Among the pathologic causes of atrophy are
 Persistent Pressure following for example a tumor in the
adjacent organ is called pressure atrophy as in the case of
pituitary Adenoma.
 Loss of innervations to a particular tissue which is called
denervation atrophy.
 Inadequate nutrition as in the case of protein- energy
malnutrition.
 Inadequate blood supply to a particular organ which is called
ischemic atrophy

67
Metaplasia
Metaplasia is an adaptive response to injury in

which one adult type mature cell is replaced by

another mature cell type.
In other words it is the process of transformation of

cells from those sensitive to a particular injury by

cells type better able to withstand the stress.
Metaplasia is usually a fertile ground for malignant

transformation.

68
  Some of the examples of metaplasic transformation that

occurs in human body include:

 The normal ciliated columnar epithelium of the respiratory tree to
squamous epithelium in chronic smokers
 The normal columnar epithelium of the endocervix to squamous
epithelium in chromic inflammatory process usually following
infections

Dysplasia
 an abnormal proliferation of cells that is characterized by

changes in cell size, shape, and loss of cellular organization

 Dysplasiais not cancer but may progress to cancer

(preneoplastic lesion)
 Example: cervical dysplasia

69
70