Satkynbai Tentishev Memorial

Asian Medical Institute

By: Dr. Aminov Shamil

Pathophysiology is the study of the disturbance of normal mechanical, physical,
and biochemical functions, either caused by a disease, or resulting from a
disease or abnormal syndrome or condition that may not qualify to be called a
disease. An alternate definition is "the study of the biological and physical
manifestations of disease as they correlate with the underlying abnormalities
and physiological disturbances.

The study of the essential nature of disease, disease processes,

and the structural and functional changes in organs and tissues
that cause or are caused by disease
Overview of Pathology
1) Etiology (causes ): Genetic, Acquired
2) Pathogenesis: sequence and patterns of cellular injury that lead to disease
3) Morphologic changes : Gross changes, Microscopic changes
4) The study of mechanisms of disease outcome (recovery mechanisms,
mechanisms of dying).
5) Clinical significance: Signs and symptoms , Disease course, Prognosis.
Development of the principles of treatment of the disease (etiotropic,
pathogenetic, sanogenetic, symptomatic).
6) Prevention of diseases, as well as the methodology, obtained knowledge
about the disease (disease of comprehension received knowledge from the
standpoint of philosophy: the formation of hypotheses, theories, concepts of
illness, etc.).
The basic method of pathophysiology - method pathophysiological
experiment. Its essence - the modeling of disease or pathological process in an
experiment to study. Types of pathophysiological experiments: 1. Method
pathophysiological experiment - modeling of human disease in animal experiments. 2.
Method pathophysiological experiment on humans ("natural experiment" - on
volunteers), Pathophysiological features of the experiment is that it consists of three
phases: 1. Physiological phase - the study of healthy body functions. 2.
Pathophysiological phase - modeling of disease or pathological process and the study
of functions on the background of the disease. 3. Phase experimental therapy - the use
of experimental therapy and follow-up restoration functions. Auxiliary research
methods in a pathophysiological experiment: 1. Physiological, 2. Morphological, 3.
Biochemical, 4. Immunological, 5. Physico-chemical, 6. Physical, 7. Mathematical, 8.
Clinical, 9. The comparative evolutionary method, 10. The method of studying isolated
organs and tissues in culture in vitro.
Understanding cells
The cell is the body’s basic building block. It’s the smallest
living component of an organism. Many organisms are made
up of one independent, microscopically tiny cell. Other
organisms, such as humans, consist of millions of cells
grouped into highly specialized units that function together
throughout the organism’s life. Large groups of individual cells
form tissues, such as muscle, blood, and bone. Tissues form
the organs (such as the brain, heart, and liver), which are
integrated into body systems (such as the central nervous
system [CNS], cardiovascular system, and digestive system).
Cells are composed of various structures, or organelles, each
with specific functions. The organelles are contained in the
cytoplasm—an aqueous mass—that’s surrounded by the cell
membrane. The largest organelle, the nucleus, controls cell
activity and stores deoxyribonucleic acid (DNA), which carries
genetic material and is responsible for cellular reproduction
or division.
The typical animal cell is characterized by several additional
elements: • Adenosine triphosphate, the energy that fuels
cellular activity, is made by the mitochondria. • Ribosomes
and the endoplasmic reticulum synthesize proteins and
metabolize fat within the cell. • The Golgi apparatus holds
enzyme systems that assist in completing the cell’s metabolic
functions. • Lysosomes contain enzymes that allow
cytoplasmic digestion to be completed.
 Conception of cell injury
Influences,
Stresses, Other causes of cellular injury

Cell
Cell Injury
Adaptation

Pathological
reaction

Pathological
process

Disease
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 ATP by aerobic oxidation
Major causes of Hypoxia :
Ischemia- loss of blood supply , decreased arterial flow or
decrease venous outflow
e.g., arteriosclerosis, thrombus, thromboembolus .
Cardiopulmonary failure
Decreased oxygen-carrying capacity of the blood
2) Infections
Viruses, bacteria, parasites and fungi (probably prions)
Mechanism of injury : Direct infection of cells, Production of toxins,
Host inflammatory response
3) Immunologic reactions
Hypersensitivity reaction , Autoimmune diseases
4) Congenital disorders
Inborn errors of metabolism (inherited disorders)
Enzyme defects leading to the accumulation of toxic product
Enzyme defects leading to a deficiency of important
Genetic defects in structural proteins
Cytogenetic disorders
Congenital malformations caused by abnormal development
5) Chemical injury : Drugs , Poisons, Pollution, Occupation
exposure, Social/ lifestyle choices
6) Physical forms of injury: Trauma, Burns, Frostbite,
Radiation, Pressure changes, Electrical
7) Nutritional or vitamin imbalance:
Inadequate calorie/protein intake
Excess caloric intake
Vitamin deficiency
Hypervitaminosis
Cellular responses to injury : Adaptation, Reversible injury, Irreversible injury and cell death(
necrosis/ apoptosis)
Cellular response to injury depends on several important factors : The type of injury , the
duration of injury, the severity and intensity of injury, the type of cell injured , the cell's metabolic
state, the cell's ability to adapt
The critical intracellular system that are susceptible to injury:
DNA, Production of ATP via aerobic respiration, Cell membranes, Protein synthesis.
Important mechanisms of cell injury:
Damage to DNA, proteins, lipid membranes and circulating lipids by peroxidation caused by
oxygen- derived free radicals: Superoxide anion(O2-), Hydroxyl radical (OH-), Hydrogen peroxide
(H2O2)
ATP depletion, Increased cell membrane permeability
Influx of calcium: Second messenger Activates a wide spectrum of enzymes :
Proteases  protein breakdown, ATPase contributes to ATP depletion, Phospholipases cell
membrane injury, Endonucleases DNA damage
Mitochondrial dysfunction:
Decreased oxidative phosphorylation , Formation of mitochondrial permeability transition
channels , Release of cytochrome C in a trigger for apoptosis
CIRCULUS VITIOSUS
Reversible cell injury
Decreased synthesis of ATP by oxidative phosphorylation , Decreased
function of Na+ K+ ATPase membrane pumps (in Na & H20 , out Ca).
Switch to glycolysis (↓glycogen, ↑ lactic acid, ↓ Ph) . Decreased
protein synthesis . Plasma-membrane blebs and myelin figures may be
seen .
Irreversible cell injury
Severe membrane damage( massive influx of Ca, efflux of enzymes and
proteins into the circulation), Marked mitochondrial dysfunction ,
Rapture of the lysosomes (release digestive enzymes), Nuclear
changes( Pyknosis- degeneration, and condensation of nuclear
chromatin; Karyorrhexis- nuclear fragmentation; Karyolysis –the
dissolution of the nucleus ).
In humans, as in all other multicellular organisms, the rates of
cell proliferation and cell death determine the net cell
production. An abnormality in any of these rates can cause
disorders of cell accumulation (e.g., hyperplasia, cancer,
autoimmune diseases) or disorders of cell loss (atrophy,
degenerative diseases, AIDS, ischemic injury). Therefore, the
balance (homeostasis) between cell production and cell death
must be carefully maintained
▲ Schematic diagram showing the relationship between cell death and cell division. Under
normal physiologic conditions (homeostasis), the rates of cell division and cell death are
similar. If the rate of cell death is higher than that of cell division, then a net loss of cell
number will occur. Such conditions are categorized as cell loss disorders. When the situation is
reversed and the rate of cell division is higher than the rate of cell death, then the net gain in
cell number will be prominent, leading to a variety of disorders of cell accumulation.
Homeostasis
The body is constantly striving to maintain a dynamic, steady state of internal balance
called homeostasis. Every cell in the body is involved in maintaining homeostasis, both
on the cellular level and as part of an organism.
Any change or damage at the cellular level can affect the entire body. When an
external stressor disrupts homeostasis, illness may occur. A few examples of external
stressors include injury, lack of nutrients, and invasion by parasites or other organisms.
Throughout the course of a person’s life, many external stressors affect the body’s
internal equilibrium.
Maintaining the balance
Three structures in the brain are responsible for maintaining homeostasis:
the medulla oblongata, the part of the brain stem that’s associated with vital
functions, such as respiration and circulation
the pituitary gland, which regulates the function of other glands and thereby a
person’s growth, maturation, and reproduction
the reticular formation, a group of nerve cells or nuclei that form a large network of
connected tissues that help control vital reflexes, such as cardiovascular function and
respiration.
Feedback mechanisms
Homeostasis is maintained by self-regulating feedback mechanisms. These
mechanisms have
three components:
a sensor mechanism that senses disruptions in homeostasis
a control center that regulates the body’s response to disruptions in homeostasis
an effector mechanism that acts to restore homeostasis.
An endocrine (hormone-secreting) gland usually controls the sensor mechanism. A
signal is sent to the control center in the CNS, which initiates the effector mechanism.
There are two types of feedback mechanisms:
a negative feedback mechanism, which works to restore homeostasis by correcting a
deficit within the system
a positive feedback mechanism, which occurs when hormone secretion triggers
additional hormone secretion. This indicates a trend away from homeostasis.
Can you help teacher
find negative
feedback?
Accentuate the negative. For negative feedback mechanisms to be
effective, they must sense a change in the body—such as a high blood
glucose level—and attempt to return body functions to normal.
In the case of a high blood glucose level, the effector mechanism
triggers increased insulin production by the pancreas, returning the
blood glucose level to normal and restoring homeostasis.

And the positive

The positive feedback mechanism is far from positive. It takes the
original response and exaggerates it.
It’s said to be positive because the change that occurs proceeds in the
same direction as the initial disturbance, causing a further deviation
from homeostasis.
A positive feedback mechanism is responsible for intensifying labor
contractions during childbirth.
Hypoxia, toxic injury, or even mitochondrial aging can lead to significantly increased
levels of intracellular oxidative stress.
Cell death may occur as a result of acute cell injury or an
internally encoded suicide program. Cell death may result
from accidental cell injury or mechanisms that cause cells to
self-destruct. The major two different mechanisms of cell
death are necrosis and apoptosis. • Necrosis, or accidental
cell death, is a pathologic process. It occurs when cells are
exposed to an unfavorable physical or chemical environment
(e.g., hypothermia, hypoxia, radiation, low pH, cell trauma)
that causes acute cellular injury and damage to the plasma
membrane. Under physiologic conditions, damage to the
plasma membrane may also be initiated by viruses, or
proteins called perforins. Rapid cell swelling and lysis are two
characteristic features of this process.
• Apoptosis represents a physiologic process. During apoptosis, cells
that are no longer needed are eliminated from the organism. This
process may occur during normal embryologic development or other
normal physiologic processes, such as follicular atresia in the ovaries.
Cells can initiate their own death through activation of an internally
encoded suicide program. Apoptosis is characterized by controlled
autodigestion , which maintains cell membrane integrity; thus, the cell
“dies with dignity” without spilling its contents and damaging its
neighbors. In addition, certain cells or their secretions found in the
immune system are toxic to other cells (e.g., cytotoxic T lymphocytes,
natural killer [N K ] cells); they initiate processes that destroy designated
cells (e.g., cancer transformed or virus-infected cells). In contrast to
necrosis and apoptosis, cytotoxic death does not involve one specific
mechanism. For example, cell death mediated by cytotoxic T
lymphocytes combines some aspects of both necrosis and apoptosis.
Necrosis begins with impairment of the cell's ability to maintain
homeostasis. As a result of cell injury, damage to the cell membrane
leads to an influx of water and extracellular ions. Intracellular organelles
such as the mitochondria, rER, and nucleus undergo irreversible changes
that are caused by cell swelling and cell membrane rupture (cell lysis).
As a result of the ultimate breakdown of the plasma membrane, the
cytoplasmic contents, including lysosomal enzymes, are released into
the extracellular space. Therefore, necrotic cell death is often associated
with extensive surrounding tissue damage and an intense inflammatory
response.
Apoptosis is a mode of cell death that occurs under normal physiologic
conditions. In apoptosis, the cell is an active participant in its own
demise (“cellular suicide”). This process is activated by a variety of
extrinsic and intrinsic signals.
Cells undergoing apoptosis show the following characteristic
morphologic and biochemical features
• D N A fragmentation occurs in the nucleus and is an irreversible event
that commits the cell to die. DNA fragmentation is a result of Ca2+-
dependent and Mg2+- dependent activation of nuclear endonucleases.
These enzymes selectively cleave DNA, generating small
oligonucleosomal fragments. Nuclear chromatin then aggregates, and
the nucleus may divide into several discrete fragments bounded by the
nuclear envelope.
• Decrease in cell volume is achieved by shrinking of the cytoplasm. The
cytoskeletal elements become reorganized in bundles parallel to the cell
surface. Ribosomes become clumped within the cytoplasm, the rER
forms a series of concentric whorls, and most of the endocytotic vesicles
fuse with the plasma membrane.
• Loss of mitochondrial function is caused by changes in the
permeability of the mitochondrial membrane channels. The integrity of
the mitochondrion is breached, the mitochondrial transmembrane
potential drops, and the electron-transport chain is disrupted. Proteins
from the mitochondrial intermembrane space, such as cytochrome C
and SMAC /DIABLO (second mitochondria-derived activator of
caspases/direct inhibitor of apoptosis-binding protein with low
isoelectric point [pi]) are released into the cytoplasm to activate a
cascade of proteolytic enzymes called caspases that are responsible for
dismantling the cell. The regulated release of cytochrome C and
SMAC/DIABLO suggests that mitochondria, under the influence of Bcl-2
proteins, are the decision makers for initiating apoptosis. Thus, many
researchers view mitochondria either as the “headquarters for the
leader of a crack suicide squad” or as a “high-security prison for the
leaders of a military coup.”
 • Membrane blebbing results from cell membrane alterations. One
alteration is related to translocation of certain molecules (e.g.,
phosphatidylserine) from the cytoplasmic surface to the outer surface of
the plasma membrane. These changes cause the plasma membrane
blebbing formation of apoptotic bodies .
• Formation of apoptotic bodies, the final step of apoptosis, results in
cell breakage . These membrane-bounded vesicles originate from the
cytoplasmic bleb containing organelles and nuclear material. They are
rapidly removed without a trace by phagocytotic cells. The removal of
apoptotic bodies is so efficient that no inflammatory response is
elicited. Apoptosis occurs more than 20 times faster than mitosis;
therefore, it is challenging to find apoptotic cells in a routine H&E
preparation
Apoptosis( specialized form of programmed cell death)
Apoptosis is an active process regulated by genes and involves RNA and protein
synthesis. Often affects only single cells or small groups of cells
Morphologic appearance: 1.Cell shrinks in size and has dense eosinophilic cytoplasm. 2
Nuclear chromatin condensation followed by fragmentation. 3 Formation of
cytoplasmic membrane blebs.4 Breakdown of the cell into fragments( apoptotic
bodies). 5 Phagocytosis of apoptotic bodies by adjacent cells or macrophages. 6 A lack
of an inflammatory response
Stimulus for apoptosis : Cell injury and DNA damage ; lack of hormones, citokines or
growth factors; Receptor-ligand signals (Fas binding to the fas ligand , tumor necrosis
factor(TNF) binding to TNF receptor 1 )
Apoptosis is regulated by genes : bcl-2(inhibits apoptosis) , p-53 (stimulates apoptosis)
Execution of apoptosis:
Mediated by cascade of caspases (Caspases digest nuclear and cytoskeletal proteins ,
also activate endonucleases)
Physiologic examples of apoptosis ( hormone depend apoptosis- menstrual cycle)
Pathologic examples (Viral disease viral hepatitis, Graft versus host disease )
Morphologic types of necrosis:
Coagulative necrosis(firm, gray mass){acidosis develops, hypoxic
injury} ;
Liquefaction necrosis (undergoes liquefaction){catalytic enzymes} ;
Caseous necrosis (soft, cheezy){dead cells persist};
Fat necrosis{lipases};
Fibrinoid necrosis{resembles fibrine};
Gangrenous necrosis:
Dry{arteria},
Wet{vein},
Gas{clostridium}
Behcet's disease. Erythematous papules and pustules of the lower limb . Leukocytoclastic
vasculitis with fibrinoid necrosis of the vessels
1.General:
Cellular adaptation is the result of a persistent stress or injury.
Adaptive responses are potentially reversible once the stress has
been removed. Some forms of adaptation may precede or progress
to malignancy.
2.Atrophy ( decrease in cell size and functional ability)
Causes of atrophy : Deceased workload/ disuse; Ischemia; Lack of
hormonal or neural stimulation; Malnutrition; Aging
3. Hypertrophy ( an increase in cell size and functional ability due to
increased synthesis of intracellular components)
Causes of hypertrophy : Increased mechanical demand ; Increased
endocrine stimulation
Hypertrophy is mediated by: Growth factors, cytokines and other
trophic stimuli. Increased expression of gens and increased protein
synthesis .
4. Hyperplasia ( an increase in the number of cells in a tissue or organ)
Some cell types are unable to exhibit hyperplasia ( nerve, cardiac,
skeletal muscle cells)
Hypertrophy and hyperplasia often occur together.
Physiologic causes of hyperplasia :Compensatory , Hormonal
stimulation, Antigenic stimulation
Pathologic causes of hyperplasia: Endometrial hyp. , Prostatic hyp. of
aging.
Hyperplasia is mediated by: Growth factors, cytokines and other trophic
stimuli, Increased expression of growth-promoting genes (proto-
oncogenes) , Increased DNA synthesis and cell division
5. Metaplasia- a reversible change of one cell type to another, usually
in response to irritation.
It has been suggested that the replacement cell is better able to
tolerate the environmental stresses.
Proposed mechanism: the reserve cells (or stem cells) of the irritated
tissue differentiate into a more protective cell type due to the influence
of growth factors, cytokines and matrix components
6.Dysplasia- an abnormal proliferation of cells that is characterized by
changes in cell size, shape and loss of cellular organization.
Dysplasia is not cancer but may progress to cancer.
The most common sites of dysplasia are the respiratory tract (especially
the squamous cells present as a result of metaplasia) and the cervix.
Cervical dysplasia usually results from infection of the cells with the
human papilloma virus (HPV). Dysplasia is usually rated on a scale to
reflect its degree, from minor to severe.
Other Cellular Alterations During Injury
Intracellular accumulations
1) Lipids : Triglycerides (fatty change in liver),
Cholesterol(atherosclerosis), Complex
lipids(Gaucher's disease)
2) Proteins : (Russell bodies) , (proteinuria)
3)Glycogen storage diseases (Andersen's disease)
4)Exogenous pigments (anthracotic pigmentation of the lung)
5)Endogenous pigments: Lipofuscin –perinuclear yellow-
brown pigment, common in the liver and heart. Melanin-
black-brown pigment, found in melanocytes and substancia
nigria. Hemosiderin –Golden yellow-brown granular pigment
(found in areas of hemorrhage or bruises)
Hyaline change- nonspecific term used to describe any
intracellular or extracellular alteration.
Examples of intracellular hyaline : Renal proximal tubule
protein reabsorption droplets,
Russell bodies, Alcoholic hyaline.
Examples of extracellular hyaline : Hyaline arteriolosclerosis,
Amyloid, Hyaline membrane disease of newborn.
Pathologic forms of calcification – precipitation of calcium phosphate in
dying or necrotic tissues.
Examples: fat necrosis saponification; Psammoma bodies- laminated
calcifications that occur in meningiomas and papillary carcinomas of the
thyroid and ovary; Mönckeberg's medial calcific sclerosis;
Atherosclerotic plaques.
Metastatic calcification- precipitation of calcium phosphate in normal
tissue due to hypercalcemia
Causes : Hyperparathyroidism; Parathyroid adenomas; Renal failure;
Paraneoplastic syndrome; Vitamin D intoxication ; Milk-alkali syndrome;
Sarcoidosis; Paget disease; Multiple myeloma; Metastatic cancer of the
bone.
Location of calcifications: interstitial tissues of the stomach, kidney,
lungs and blood vessels.
Cell can be damaged by a variety of mechanisms.
Hypoxia causes a loss of ATP production secondary to oxygen deficiency and can be caused
by ischemia, cardiopulmonary failure, or decreased oxygen-carrying of the blood.
Infections can injure cells directly, or indirectly, via toxin production or host inflammatory
response.
Hypersensitivity reactions and autoimmune diseases may kill or injure cells.
Congenital causes of cellular injury include enzyme defects, chromosomal disorders and
congenital malformations.
Chemical agents, physical agents and nutritional imbalances can also injure cells.
The response of cell to an insult on both the state of the cell and the type of insult. The
response can range from adaptation to reversible injury to irreversible injury with cell
death.
Intracellular sites and systems particularly vulnerable to injury include DNA, ATP
production, cell membranes and protein synthesis.
Reversible cell injury is primarily related to decreased ATP synthesis by oxidative
phosphorylation, leading to cellular swelling and inadequate protein synthesis.
Irreversible cell injury often additionally involves severe damage to membranes,
mitochondria, lysosomes and nucleus.
Death of tissues can produce a variety of histologic patterns, including coagulative necrosis,
liquefaction necrosis, caseous necrosis, fibrinoid necrosis and gangrenous necrosis.
Apoptosis is a specialized form of programmed cell death that can be regulated genetically
or by cellular or tissue triggers.
Materials:
USMLE Pathology Kaplan medica. John Barone, M.D.
Carol Mattson Porth -Essentials of Pathophysiology
PATHOPHYSIOLOGY Basic overview for medical students 1 st revised (only electronic) version
MIROSLAV KUBA, ZUZANA KUBOVÁ