Pathophysiology: Prepared By

PATHOPHYSIOLOGY LECTURE

Prepared by Habtamu Bayih (MD)

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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.

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 Factors causing disease  are mainly two types. 1.

1.

Environmental or external factors /acquired 

Physical



Chemical



Nutritional



Infections



Immunological



Psychological

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.

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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.

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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

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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

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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

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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

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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)

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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).

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 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.)

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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

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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

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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:

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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)

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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 P450 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.

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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)

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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

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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).

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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.

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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

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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

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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

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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.

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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

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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

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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

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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.

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 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.

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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.

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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.

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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.

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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.

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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 condition

2. It occurs as either - Physiologic ,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 necrotic cell

4. Inflammation almost invariably absent

5. Its occurrence usually depends on the balance between. a) Protein Denaturation b) Enzymatic liquefaction

5. Dependent on gene regulated enzymatic activity

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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.

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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.

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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

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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.

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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

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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.

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 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

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