Introduction to Pathophysiology:

The term Pathophysiology is the physiology of the altered health. The term
combines the words pathology and physiology, pathology (from Greek’s pathos,
meaning disease) deals with study of the structural and functional changes in cells,
tissues and organs of the body that caused by the disease. Physiology, deals with
functions of the human body, thus Pathophysiology deals not only with the cellular
and organ changes that occur with the disease, but with the effects that these
changes have on total body function.

Disease:

Defined as an interruption, cessation or disorder of a body system or organ

structure that is characterized usually by a recognized etiologic agent or agents,
groups of signs and symptoms and consistent anatomic alterations.

The aspect of the disease process includes etiology, pathogenesis, morphologic

changes, clinical manifestations, and clinical course.

Etiology:

The causes of the disease known as etiologic factors, among the common
etiologic factors are; Biologic agents (bacteria, viruses, etc...), physical agents
(burns, radiations and trauma), chemical agents (poisons and alcohols) and
nutritional excesses or deficits.

Etiologic agents are non-specific for a single disease and the diseases can also be
caused by more than one causative agent. So most of the diseases were
multifactorial, this is true for cancers, heart diseases and diabetes.

Diseases may also be categorized as congenital or acquired (before and after

birth).

Pathogenesis
Pathogenesis is the sequence of cellular and tissue events that take place
from the time of initial contact with an etiologic agent until the ultimate
expression of a disease.
Morphology:

Refers to fundamental structure or form of the cells or tissues .Morphologic

changes are concerned with both the gross anatomic and microscopic changes that
are characteristic of a disease.

The changes can be detected by histological examination of the tissue,

radiographic, ultrasonic and other imaging techniques.

Clinical manifestation:

Diseases can manifest in different ways, for example fever, headache, and
vomiting, abdominal pain etc., or may be silent while the disease is so advanced.

Clinical course:

It means the evolution of the disease, whether acute, chronic or sub-acute

depending on the severity of symptoms and duration.

Acute disease, means sever onset but of self-limiting. Chronic diseases, Implies a
continuous and long term process, usually take exacerbation (aggravation of
symptoms and severity of disease) and remission (periods of decrease severity and
symptoms). Sub-acute is an intermediate between the two.

Cell injury and tissue responses:

PATHOPHYSIOLOGIC CHANGES

The cell faces a number of challenges through its life. Stressors, changes in the
body's health, disease, and other extrinsic and intrinsic factors can change the cell's
normal functioning (homeostasis).

Cell adaptation

Cells are generally able to continue functioning despite changing conditions or

stressors. However severe and prolonged stress or changes may injure or even kill
cells.
ADAPTIVE CELL CHANGES

Cells adapt to stressors within the body by one of the ways shown below.

Atrophy, Hypertrophy, Hyperplasia, Metaplasia, and Dysplasia.

Atrophy
Atrophy is a reduction in the size of a cell or organ that may occur when cells
face reduced workload or disuse, insufficient blood flow, malnutrition, or reduced
hormonal and nerve stimulation. Examples of atrophy include loss of muscle mass
and tone after prolonged bed rest.

The general causes of atrophy can be grouped into five categories: (1) disuse,
(2) denervation, (3) loss of endocrine stimulation, (4) inadequate nutrition, and
(5) ischemia or decreased blood flow.

Hypertrophy

In contrast, hypertrophy is an increase in the size of a cell or organ due to an

increase in workload. The three basic types of hypertrophy are physiologic,
compensatory, and pathologic.

Physiologic hypertrophy reflects an increase in workload that is not caused by

disease — for example, the increase in muscle size caused by hard physical labor
or weight training.

Compensatory hypertrophy takes place when cell size increases to take over for
nonfunctioning cells. For instance, one kidney will hypertrophy when the other is
not functioning or is removed.

Pathologic hypertrophy is a response to disease. An example is hypertrophy of the

heart muscle as the muscle pumps against increasing resistance in patients with
hypertension.

Hyperplasia

Hyperplasia is an increase in the number of cells caused by increased workload,

hormonal stimulation, or decreased tissue density. Like hypertrophy, hyperplasia
may be physiologic, compensatory, or pathologic.
Physiologic hyperplasia is an adaptive response to normal changes. An example is
the monthly increase in number of uterine cells that occurs in response to estrogen
stimulation of the endometrium after ovulation.

Compensatory hyperplasia occurs in some organs to replace tissue that has been
removed or destroyed. For example, liver cells regenerate when part of the liver is
surgically removed.

Pathologic hyperplasia is a response to either excessive hormonal stimulation or

abnormal production of hormonal growth factors. Examples include acromegaly, in
which excessive growth hormone production causes bones to enlarge, and
endometrial hyperplasia, in which excessive secretion of estrogen causes heavy
menstrual bleeding and possibly malignant changes. Skin warts are an example of
hyperplasia caused by growth factors produced by certain viruses, such as the
papillomaviruses.

Metaplasia

Metaplasia is the replacement of one cell type with another cell type. A common
cause of metaplasia is constant irritation or injury that initiates an inflammatory
response. The new cell type can better endure the stress of chronic inflammation.

Metaplasia may be either physiologic or pathologic.

Physiologic metaplasia is a normal response to changing conditions and is

generally transient. For example, in the body's normal response to inflammation,
monocytes that migrate to inflamed tissues transform into macrophages.

Pathologic metaplasia is a response to an extrinsic toxin or stressor and is

generally irreversible. For example, after years of exposure to cigarette smoke,
stratified squamous epithelial cells replace the normal ciliated columnar epithelial
cells of the bronchi. Although the new cells can better withstand smoke, they don't
secrete mucus nor do they have cilia to protect the airway. If exposure to cigarette
smoke continues, the squamous cells can become cancerous.
Dysplasia

In dysplasia, abnormal differentiation of dividing cells results in cells that are

abnormal in size, shape, and appearance.

Although dysplastic cell changes aren't cancerous, they can precede cancerous
changes. Common examples include dysplasia of epithelial cells of the cervix or
the respiratory tract.

Cell injury
Injury to any cellular component can lead to illness as the cells lose their ability to
adapt.

Causes of cell injury

Cell injury can be caused by a number of agents, including physical agents,

chemicals, biologic agents, radiation injury, and nutritional factors the ways by
which cells are injured have

 Oxygen deprivation ( hypoxia, ischemia)

 Nutritional imbalances
 Physical agents (Mechanical Forces, Extremes of Temperature,
Electrical Forces).
 Chemical agents and drugs
 Infectious agents
 Immunologic reactions
 Genetic derangements

Hypoxia and ischemia oxygen deficiency affects the normal aerobic cellular
respiration which is an important cause of cell injury and death.

*Hypoxia can result from an inadequate amount of oxygen in the air, respiratory
disease, ischemia (i.e., decreased blood flow due to vasoconstriction or vascular
obstruction), anemia, edema, or inability of the cells to use oxygen.

*Hypoxia causes a power failure in the cell, with widespread effects on the cell’s
structural and functional components. As oxygen tension in the cell falls, oxidative
metabolism ceases, and the cell reverts to anaerobic metabolism, using its limited
glycogen stores in an attempt to maintain vital cell functions.

* Cellular pH falls as lactic acid accumulates in the cell. This reduction in pH can
have adverse effects on intracellular structures and biochemical reactions. Low pH
can alter cell membranes and cause chromatin clumping and cell volume changes.

-Ischemia:

* Ischemia refers to a critical lack of blood supply to a localized area.

*It is reversible in that tissues are restored to normal function when oxygen is
again supplied to them, but if late progress to ischemic infraction Pathophysiology

* It usually occurs in the presence of atherosclerosis in the major arteries.

*The classic conditions resulting from ischemia is Angina pectoris.

Toxins: Substances that originate in the body (endogenous factors) or outside the
body (exogenous factors) may cause toxic injuries. Common endogenous toxins
include products of genetically determined metabolic errors, gross malformations,
and hypersensitivity reactions. Exogenous toxins include alcohol, lead, carbon
monoxide, and drugs.

Infection, Viruses, fungi, protozoa, and bacteria can cause cell injury or death.
For example, human immunodeficiency virus alters the cell when the virus is
replicated in the cell's RNA.

Physical injury: Physical injury results from a disruption in the cell or in the
relationships of the intracellular organelles.

Burns, radiation therapy for cancer, X-rays, and ultraviolet radiation.

Mechanical injuries include surgery, trauma from motor vehicle accidents, and
frostbite.

Deficit injury: When a deficit of water, oxygen, or nutrients occurs, or if constant

temperature and adequate waste disposal aren't maintained, Irreversible cell injury
occurs when there's a breakdown of organelles and cell membrane.
Genetic defects and immunological reactions

Cell degeneration

Degeneration is a type of nonlethal reversible cell damage that generally occurs

in the cytoplasm and that doesn't affect the nucleus. Degeneration usually affects
organs with metabolically active cells, such as the liver, heart, and kidneys, and is
caused by these problems:

Increased water in the cell (hydropic or vacuolar degeneration) or cellular swelling

by fatty infiltrates (fatty degeneration).

When changes in cells are identified, prompt health care can slow degeneration
and prevent cell death. An electron microscope can help identify cellular changes,
and thus diagnose a disease, before the patient complains of any symptoms.

Reversible Cell Injury

Reversible cell injury, although impairing cell function, does not result in cell
death. Two patterns of reversible cell injury can be observed under the microscope:
cellular swelling and fatty change. Cellular swelling occurs with impairment of the
energy-dependent Na+/ K+-ATPase membrane pump, usually as the result of
hypoxic cell injury.
Programmed Cell Death

In most normal non-tumor cells, the number of cells in tissues is regulated by

balancing cell proliferation and cell death. Cell death occurs by necrosis or a form
of programmed cell death called apoptosis. Apoptosis, from the Greek apo for “
apart” and ptosis for “ fallen,” means “ fallen apart.” Apoptosis is a highly
selective process that eliminates injured and aged cells, thereby controlling tissue
regeneration. Cells undergoing

Apoptosis have characteristic morphologic features, as well as biochemical

changes. Shrinking and condensation of the nucleus and cytoplasm occur. The
chromatin aggregates at the nuclear envelope, and DNA fragmentation occurs.
Then, the cell becomes fragmented into multiple apoptotic bodies in a manner that
maintains the integrity of the plasma membrane and does not initiate inflammation.
Changes in the plasma membrane induce phagocytosis of the apoptotic bodies by
macrophages and other cells, thereby completing the degradation process.

Apoptosis is the genetically programmed cell death. This accounts for the constant
cell turnover in the skin's outer keratin layer and the lens of the eye.
Cell death (necrosis)

Like disease, cell death may be caused by internal (intrinsic) factors or external
(extrinsic) factors that contribute to cell damage. When a stressor is severe or
prolonged, the cell can no longer adapt and it dies.

Cell death, or necrosis, may manifest in different ways, depending on the tissues
or organs involved.

Necrosis refers to cell death in an organ or tissue that is still part of a living person.
Necrosis differs from apoptosis in that it involves unregulated enzymatic digestion
of cell components, loss of cell membrane integrity with uncontrolled release of
the products of cell death into the extracellular space, and initiation of the
inflammatory response. In contrast to apoptosis, which functions in removing cells
so new cells can replace them; necrosis often interferes with cell replacement and
tissue regeneration.

Liquefaction necrosis occurs when a lytic (dissolving) enzyme liquefies necrotic

cells. This type of necrosis is common in the brain, which has a rich supply of lytic
enzymes. Liquefaction necrosis occurs when some of the cells die but their
catalytic enzymes are not destroyed. An example of liquefaction necrosis is the
softening of the center of an abscess with discharge of its contents.

In caseous necrosis, the necrotic cells disintegrate but the cellular pieces remain
undigested for months or years.

This type of necrotic tissue gets its name from its crumbly, cheese like (caseous)
appearance. It commonly occurs in lung tuberculosis.

In fat necrosis, enzymes called lipases break down intracellular triglycerides into
free fatty acids. These free fatty acids combine with sodium, magnesium, or
calcium ions to form soaps. The tissue becomes opaque and chalky white.

Coagulation necrosis commonly occurs when the blood supply to any organ
(except the brain) is interrupted in infarcted areas (Infarction (i.e., tissue death)
occurs when an artery supplying an organ or part of the body becomes occluded
and no other source of blood supply exists). It typically affects the kidneys, heart,
and adrenal glands. Lytic (lysosomal) enzyme activity in the cells is inhibited, so
that the necrotic cells maintain their shape, at least temporarily.

Gangrenous necrosis, a form of coagulated necrosis, typically results from a lack

of blood flow (ischaemia) and is complicated by an overgrowth and invasion of
bacteria. It commonly occurs in the lower legs as a result of arteriosclerosis or in
the GI tract. Gangrene may be classified as dry or moist.

The term gangrene is applied when a considerable mass of tissue undergoes

necrosis. Gangrene may be classified as dry or moist. In dry gangrene, the part
becomes dry and shrinks, the skin wrinkles, and its color changes to dark brown or
black. The irritation caused by the dead tissue produces a line of inflammatory
reaction (line of demarcation) between the dead tissue of the gangrenous area and
the healthy tissue.

In moist or wet gangrene, the area is cold, swollen, and pulseless. The skin is
moist, black, and under tension. Blebs form on the surface, liquefaction occurs, and
a foul odor is caused by bacterial action. There is no line of demarcation between
the normal and diseased tissues, and the spread of tissue damage is rapid.

Necrotic changes

When a cell dies, enzymes inside the cell are released and start to dissolve
cellular components. This triggers an acute inflammatory reaction in which white
blood cells migrate to the necrotic area and begin to digest the dead cells. At this
point, the dead cells — primarily the nuclei — begin to change morphologically in
one of three ways:

pyknosis, in which the nucleus shrinks, becoming a dense mass of genetic material
with an irregular outline.

karyorrhexis, in which the nucleus breaks up, strewing pieces of genetic material
throughout the cell.

karyolysis, in which hydrolytic enzymes released from intracellular structures

called lysosomes simply dissolve the nucleus.
Mechanism of cell injury:
Intracellular accumulations

Intracellular accumulations represent the buildup of substances that cells cannot

immediately use or eliminate. The substances may accumulate in the cytoplasm
(frequently in the lysosomes) or in the nucleus. In some cases the accumulation
may be an abnormal substance that the cell has produced, and in other cases the
cell may be storing exogenous materials or products of pathologic processes
occurring elsewhere in the body. These substances can be grouped into three
categories: (1) normal body substances, such as lipids, proteins, carbohydrates,
melanin, and bilirubin that are present in abnormally large amounts; (2) abnormal
endogenous products, such as those resulting from inborn errors of metabolism;
and (3) exogenous products, such as environmental agents and pigments that
cannot be broken down by the cell.

Pathologic Calcification:

The deposition of mineral salts of calcium is a normal process in the formation of

bone from cartilage. Calcium entry into dead or dying cells is usual, owing to the
inability of such cells to maintain a steep calcium gradient. Pathologic calcification
is the abnormal deposition of calcium salts in soft tissue, together with smaller
amounts of iron, magnesium, and other minerals. It is known as dystrophic
calcification when it occurs in dead or dying tissue and as metastatic calcification
when it occurs in normal tissue.

- Dystrophic Calcification:

Dystrophic calcification refers to the macroscopic deposition of calcium salts in

injured tissues. It represents an extracellular deposition of calcium from the
circulation or interstitial fluid.

Dystrophic calcification requires the persistence of necrotic tissue. It is often

visible to the naked eye, and ranges from gritty, sand-like grains to firm, rock-hard
material.

Metastatic Calcification:
 Whereas dystrophic calcification has its origin in cell injury, metastatic
calcification reflects deranged calcium metabolism, a change associated with an
increased serum calcium concentration (hypercalcemia). In general, almost any
disorder that increases the serum calcium level can lead to calcification in such
inappropriate locations as the alveolar septa of the lung, renal tubules, and blood
vessels.

Causes of Metastatic Calcification:

1. Increased secretion of parathyroid hormone.

2. Destruction of bone tissue as occurs with primary tumors of bone marrow (e.g.
multiple myeloma) or by diffuse skeletal metastasis (e.g. breast cancer)
3. Vitamin D - related causes including vitamin D intoxication and systemic
sarcoidosis.
4. Renal failure (causing secondary hyperparathyroidism).

Q1/ enumerate how can the cells adaptation with changes and
explain one of them?
Q2/ Differentiation between the programmed cell deaths and cell
death (necrosis).
Q3/ Define the Cell degeneration and Pathologic Calcification:
Q4/ enumerate the necrosis type and explain one of them.
Q5) morphologically changes of nuclei in necrosis
Q6) Pathophysiological changes of coagulative necrosis.
Q7) Causes of Metastatic Calcification
Q8) Causes of cell injury