BIOL 2200

Pathophysiology

“Without diagnosis, there is no rational treatment.”

Carl Gerhardt, 1873
 What is Pathophysiology?
pathos – suffering (Greek), disease
physio – pertains to functioning of organisms
ology – the study of …

Pathophysiology: The study of functional changes in

cells, tissues and organs altered by disease or injury

Pathology: the study of cell and tissue physical changes

associated with disease

1103 and 1203 gone wrong …

 What is disease?

An acute or chronic illness that one acquires or is

congenital which causes physiologic dysfunction in
one or more body systems.

Each disease generally has specific signs and

symptoms that characterize its pathology and
identifiable etiology.

Porth p4
Poll Question 1

4
 Cell Adaptation, Injury, and Death

• Alteration in cell or tissue function underlies every

disease
• Cells can be altered through:
1. Adaptation
2. Injury: reversible or irreversible
3. Death: necrosis or apoptosis
4. Aging
5. Neoplasia (covered later)

Porth – chapter 5
Is reversible
When life gives you stress, you have to adapt…
Cellular Adaptations
• Changes in size, number, or type of cell to permit the
survival and maintenance of function when under
stress
• Can occur as a result of either normal or adverse
conditions
• For example
– Normal adaptation: uterine cells increase in size and
number as a result of pregnancy
– Adaptation due to adverse conditions: heart muscle cells
increase in size due to chronically elevated blood pressure

• There are 5 principal types of adaptation

Porth p101 - 104
 Types of Cell Adaptation:
BRAIN ATROPHY
1. Atrophy – decrease in size.
May be normal (e.g. thymus gland)
or pathological (e.g muscles, brain)

CARDIAC MUSCLE HYPERTROPHY

2. Hypertrophy – increase in size.

Especially in skeletal muscle and
heart muscle which cannot undergo
mitosis; they adapt to increased
workload by increasing size.
3. Hyperplasia – increase in the number of cells (cells are normal).
Occurs in tissues with cells capable of mitosis
E.g. the liver (can be reduced by 50-60% and completely
regenerate within a month), breast growth at puberty, wound
healing

4. Metaplasia – reversible replacement of one

mature cell type by another, sometimes less
differentiated, cell type
• Not due to change in phenotype of existing cells
but reprogramming of undifferentiated stem cells

• E.g., In smokers: replacement of columnar ciliated cells along

respiratory tract with stratified squamous epithelial cells
– a trade-off between the function of the ciliated cells and greater protection
offered by the stratified cells
5. Dysplasia
• Abnormal changes in size, shape and organization of
mature cells

• Atypical hyperplasia. Implicated as a precursor to cancer.

Rate of mitosis often increased but not required for
dysplasia. Can be reversed if causative stimulus is removed
• E.g., often associated with cancerous cells in cervix or
respiratory tract
Other forms of cellular adaptation
6. Intracellular Accumulation
• Represent buildup of material that the cell cannot metabolize
a) Can be endogenous; something normally produced by the cell
i) Substance produced faster than it is used
• E.g., in alcoholism – impaired liver is unable to process all fatty
acids delivered to it, resulting in excess storage of triglycerides or
“fatty liver"
ii) Pigments
• E.g., lipofuscin- a yellow / brown pigment, seen usually in liver,
heart, neurons from accumulation of undigested material
produced during normal cell structure turnover (the “wear and
tear” pigment)

b) Can be exogenous (external source)

E.g., coal dust, tattoo pigment
Accumulation of intracellular lipofuscin
(liver cells from 80 yr old man)
7. Calcification
• Represents buildup of calcium salts in tissues

• Can occur in:

• damaged tissue (damaged heart valves, healed
TB lesions, advanced atherosclerosis)
• Excess calcium comes from damaged/dead
cells or circulation

• normal tissue due to excess serum calcium Calcific aortic stenosis

levels (e.g.,hyperparathyroidism)
• Can occur in lung, kidney, blood vessels
Poll Question 2

14
 Cell Injury
When the cell can no longer maintain
homeostasis or cannot adapt:
• Most diseases begin or are first identified by some
form of cell injury
• Can be reversible or not (recovery or death)
• Caused by any factor that disrupts the structure, or
deprives the cell of oxygen and/or nutrients

Porth p106-112
 4 major causes of cell injury

Physical Agents Chemical

- mechanical - drugs
- alcohol
- electrical - heavy metals
- radiation

Biological Nutritional
Microorganisms: Deficiencies:
- viruses -macronutrients
- bacteria -micronutrients
- parasites Excess:
- fats
- carbs
- vitamins 17
Three mechanisms of cell injury:

1. Hypoxia
2. Impaired calcium homeostasis
3. Free radicals
1. Hypoxia: Lack of sufficient oxygen for cells
The most common cause of cell injury
Causes
• most commonly, ischemia (reduced blood supply to
cells in one area)
– gradual narrowing of arteries (arteriosclerosis)
– sudden acute anoxia (embolisms)
• Other causes:
– decreased oxygen in the air
– loss of hemoglobin or RBC
– diseases of respiratory and cardiovascular systems
– poisons/toxins
Hypoxia: Pathophysiological effects
[Link] O2 availability decreases ATP production
resulting in:
a. Increased anaerobic respiration lactic acid buildup 
pH DNA clumping and decreased activity of many enzymes

b. Reduced activity of ATP-dependent enzymes  phospholipid

synthesis reduced  damaged membranes:
• Lysosomal membrane damage leading to leakage of degradative
enzymes into cell which breaks down macromolecules and
results in necrosis
• Mitochondrial membrane damage leads to change in membrane
permeability and decreased ATP synthesis resulting in necrosis
• Plasma membrane damage leads to influx of fluids & ions and
loss of cellular contents resulting in necrosis
Hypoxia: Pathophysiological effects
c. Reduced activity of ATP-dependent sodium-potassium pump
Intracellular ion concentrations are altered. Water enters the cell
following the increase in intracellular sodium resulting in:
• Cellular edema (swelling)
 rough endoplasmic reticulum swelling  loss of ribosomes 
no protein synthesis

d. Reduced activity of ATP-dependent calcium pump

• resulting in increased intracellular levels of Ca2+
• calcium also released from damaged intracellular sources
(mitochondria and ER)
• see next section on “impaired calcium homeostasis” for effects!
In summary, hypoxia leads to:
• changes in pH
• membrane disruption
• cellular edema
which can all lead to:
• necrosis or apoptosis
These effects can be detected when cells leak
their contents
- leaked cell enzymes reflect disease and can be
measured and used to indicate degree of injury
Poll Question 3

23
Mechanisms of cell injury continued…
2. Impaired calcium homeostasis
Note: There are many reasons for an increase in intracellular calcium (apart
from hypoxia), such as toxins
High intracellular calcium results in:
a. Activation of inappropriate enzymes that cause cell damage:
- membrane damage (phospholipase, protease)
- nuclear damage (endonuclease)
Ca2+
- decreased ATP (ATPase)
enzyme Activated
enzyme

b. Increased mitochondrial permeability that causes:

- decrease in ATP production
 Mechanisms of Cell Injury Continued…
3. Free Radical Injury
• Free radicals are chemical species with Free
Radicals
an unpaired outer electron
• Highly reactive - non-specifically attack
proteins, fats, nucleic acids
carbohydrates, causing damage
• May be exogenous (environmental agents) or endogenous (by-
products of metabolism)
– Produced by phagocytes (e.g. neutrophils)
• why would WBCs produce damaging chemicals?
– Generated by absorption of radiation from X-rays or UV light
– Generated during the metabolism of many drugs
Reactive oxygen species (ROS)
= endogenous free radicals
• E.g., superoxide, hydrogen peroxide, and hydroxy radical
• Implicated in ageing and cancer
• ROS are kept in check by ROS scavengers
– enzymes e.g., superoxide dismutase (SOD)
– antioxidants e.g. vitamins E and C
A final note on cell injury:

Different people exposed to the same

conditions may end up with different levels of
injury depending on:

• the type of cell and how well it can adapt

to changes
• the severity and duration of injurious
stimulus (brain versus kidney)
• general health, age and nutritional status
of the person involved
Summary:
Mechanisms of injury

Phospholipase, protease,
ATPase, endonuclease

e.g. membrane damage

Porth Fig. 5.7

Poll Question 4

29
Outcomes of Cell Injury

Porth p113-115
 Apoptosis

• Programmed cell death caused by both normal and pathologic tissue

changes (cell suicide)
• Examples: intestinal epithelia during turnover, endometrial cell
breakdown during menstrual cycle, cell death induced by cytotoxic T
lymphocytes
• Active process
• Only affects selected cells; unlike necrosis
• Cell shrinks
• No inflammation involved
Normal
Apoptosis
Normal Apoptosis
Apoptosis

Membrane
blebbing

Apoptotic Bodies
• cell structures shrink (A)
• nucleus is destroyed by regulated enzymes (caspases)-> DNA fragments (B & C)
• membrane protrudes (blebs; D) and enclosed fragments pinch off as apoptotic
bodies (E) which are engulfed and cleared away by phagocytes (F)
 Necrosis
Unregulated passive cell death due to injury = “messy”
• Cell swells and bursts
– leakage of enzymes and self-digestion = autolysis
• Frequently causes damage to nearby tissues (groups
of cells)
• Frequently elicits inflammatory response
– often interferes with tissue regeneration

Four types of necrosis are described, reflecting their

gross appearance…
1. Coagulative necrosis Kidney infarct

• Caused by hypoxia and

characteristic of infarcts (areas
of ischemic necrosis)
• Is the manifestation of protein
denaturation (coagulation)
• Causes the tissue to
become firm and opaque
• Occurs primarily in the kidneys,
heart and adrenal glands
 2. Liquefactive necrosis
• Occurs in focal bacterial or
fungal infections (neutrophils
release hydrolytic enzymes)
• Tissues soften and liquefy: cells
completely digested
• An abscess (pus-filled pocket)
forms
• Can also occur in the brain due to
ischemia
3. Caseous necrosis
• Most often seen in lungs due
to tuberculosis infections
• Caseous means “cheese-
like” – crumbly yellowish
appearance
• a combination of coagulative
and liquefactive necrosis
• often enclosed within a
distinctive inflammatory
border (granuloma)
 4. Fat necrosis
• Areas of fat destruction
• Typically results from leakage of
pancreatic lipases into peritoneal
cavity
• Peritoneal fat digested into
glycerol and fatty acids which
liquefies
• Fatty acids combine with ions, like
calcium, in the tissue to make
soap “saponification”
• Tissue appears opaque and white Fat necrosis in mesentery
peritoneum – resulting from
acute pancreatitis
 Gangrene (gangrenous necrosis)
• Results from severe hypoxic injury
• Refers to significant tissue area whose cells
have undergone necrosis
– Dry gangrene – due to coagulative
necrosis, skin becomes dry, wrinkled and
dark. Usually due to interference with
arterial blood supply. Typically occurs in
extremities.
– Wet gangrene – due to liquefactive
necrosis usually in internal organs, where
area becomes cold, swollen and black
with a foul odour due to bacterial action.
Can easily spread to other tissues.
– Gas gangrene – specific condition caused
by infection with a species of bacteria
(Clostridium species); bacteria produce Dry gangrene in toes – a
enzymes that destroy connective tissue
and cause bubbles of gas to form. complication of disrupted
arterial blood flow
Poll Question 6

40
 Aging
• Inevitable and normal. Causes structural and functional
changes that eventually lead to cellular death by apoptosis
• Biological basis is poorly understood
• Theories can be grouped into two categories:
1. Programmed (molecular) theories: changes that occur with
aging are programmed genetically
E.g. fruit flies with INDY gene that doubles lifespan
2. Damage (senescence) theories: changes result from an
accumulation DNA damage due to random events (eg. effects
of free radical damage)
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?????????????The life of a cell…