Learning Objectives: After studying this chapter, the student is expected to

• 1. Explain the role of pathophysiology in the diagnosis and treatment of disease.

• 2. Use appropriate terminology.

• 3. Explain the importance of a patient's medical history.

• 4. Describe common cellular adaptations and possible reasons for the occurrence of each.

• 5. Identify precancerous cellular changes.

• 6. List the common causes of cell damage.

• 7. Describe the common types of cell necrosis and possible outcomes.

Chapter 1. Introduction to Pathophysiology:Introduction to Cellular Changes

Homeostasis: Cells tend to preserve their immediate environment and intracellular environment.

Causes of cell injury: Oxygen Deprivation (Hypoxia, due to restriction of blood “ischemia”), Chemical, Infectious,and Immunologic agents, Genetic defects, Nutritional imblances, physical agents, and aging.

Cell injury could be reversible (e.g. adaptation), and cells return to a stable baseline; however, with severe or persistent stress, irreversible injury (cell death by necrosis or apoptosis) results.

INTRODUCTION

WHAT IS PATHOPHYSIOLOGY?

Pathophysiology involves the study of functional

or physiologic changes in the body that result

from disease processes.

This subject builds on knowledge of the normal structure, and function of the human body. As a disease develops, the changes in the normal anatomy and/or physiology of the body may be obvious or maybe hidden, occurring at the cellular level. As such, pathophysiology includes some aspects of pathology (histopathology), the laboratory study of cell and tissue changes associated with disease.

Normal heart (center), Cardiac hypertrophy(left) and dilatation (right)

CELLULAR ADAPTATION TO INJURY1- Atrophy• Shrinkage in the size of the cell by the loss of

cell substance. When a sufficient number of cells is involved, the entire tissue or organ diminishes in size. Cells are not dead..

• Causes of atrophy include:1- Decreased workload (e.g., immobilization of

a fractured limb to permit healing)2- Loss of innervation 3- Diminished blood supply4- Inadequate nutrition5- Loss of endocrine stimulation6- Aging.

• 2-hypertrophy

• Hypertrophy is an increase in the size of cells and consequently an increase in the size of the organ.

• Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by specific hormonal stimulation.

• Hypertrophy and hyperplasia can also occur together, and obviously both result in an enlarged (hypertrophic) organ

Uterine hypertrophy during pregnancy

3-hyperplasia• Hyperplasia constitutes an increase in the

number of cells in an organ or tissue. • Physiologic hyperplasia is divided into (1)

hormonal hyperplasia, (2) compensatory hyperplasia,

• Most forms of pathologic hyperplasia are instances of excessive hormonal or growth factor stimulation.

• Hyperplasia could be precancerous.

4- metaplasia.Is a reversible change in which one

differentiated (adult) cell type is replaced by another differentiated (adult) cell type.

It might be protective adaptive mechanism e.g. cigarette smoking but it involves loss of function

CELLULAR ADAPTATION TO INJURY (cont.)

Thyroid-diffuse hyperplasia Graves disease

Cell Damage and NecrosisThere are many ways of injuring cells in the

body, including:

ischemia, or deficit of oxygen in the cells, due to respiratory problems or circulatory obstruction;

physical agents, excessive heat or cold, or radiation exposure;

mechanical damage such as pressure or tearing of tissue;

chemical toxins or foreign substances; microorganisms such as bacteria, viruses,

and parasites; abnormal metabolites accumulating in cells; nutritional deficits; and imbalance of fluids or electrolytes.

The most common cause of injury is ischemia where sensitive cells suffer hypoxia (reduced oxygen in the tissue) > interferes with energy (ATP) production > loss of the sodium pump > increase in sodium ions inside the cell > cell swelling & rupture

At the same time, in the absence of oxygen, anaerobic metabolism occurs in the cell, leading to a decrease in pH (acidosis) and further metabolic impairment.

Cell lysis releases destructive lysosomal enzymes into the tissue, which cause inflammation (swelling, redness and pain) as well as damage to nearby cells.

The enzymes released from the dead cells can diffuse into the blood, providing helpful clues in blood tests that indicate the type of cells damaged.(e.g. diagnostic test of myocardial infarction)

Irreversible Cell Injury: 1- Necrosis

Definition: denotes death of a group of cells. It is characterized by cell swelling, denaturation of cytoplasmic proteins, and enzymatic digestion of the cell.

Morphology:

Early: Common changes are: cell swelling + nuclear changes (pyknosis, Karyrrhexis, Karyolysis)

Late: different types of necrosis:

1- Coagulative necrosis. Implies preservation of the basic structural outline of the cell or tissue for a span of days. The injury or the subsequent increasing acidosis denatures not only the structural proteins but also the enzyme proteins, thus blocking cellular proteolysis. The process of coagulative necrosis, with preservation of the general tissue architecture, is characteristic of hypoxic death of cells in all tissues except the brain.

- Infarction is coagulative necrosis resulting from hypoxia.

2- Liquefactive necrosis. Characteristic of focal bacterial or fungal infections, due to accumulation of white cells, and hypoxic death within the central nervous system. Liquefaction completely digests the dead cells.

- Gangrenous necrosis is ischemic coagulative necrosis (frequently of a limb> dry gangrene); when there is superimposed infection with a liquefactive component, the lesion is called "wet gangrene”. Gangerenous tissue must be removed surgically.

3- Caseous necrosis in tuberculous infection. The term "caseous" is derived from the cheesy, white gross appearance of the central necrotic area. The necrotic focus is composed of structureless, amorphous granular debris within a ring of granulomatous inflammation. The tissue architecture is completely lost.

4- Fat necrosis. Focal areas of fat destruction, typically occurring after pancreatic injury > release of activated pancreatic enzymes into adjacent parenchyma or the peritoneal cavity. The released fatty acids combine with calcium to produce grossly visible chalky white aresas (fat saponification)

Kidney infarct exhibiting coagulative necrosis, with preservation of basic outlines of glomerular and tubular

architecture . A tuberculous lung with a large area of caseous necrosis .

Fat necrosis with saponification in the mesentery. White-yellow chalky deposits

represent calcium soap formation.

Irreversible Cell Injury: 2- APOPTOSIS (PROGRAMMED CELL DEATH)

It is single cell death in the middle of living tissue due to activation of internal “suicide” program with characteristic morphology (cell shrinkage) that does not cause tissue disruption or inflammation.

• Causes, importance (It occurs in): 1- embryogenesis, organogenesis, and developmental

involution 2- Hormone-dependent physiologic involution. 3- Cell deletion in proliferating populations, such as

intestinal crypt epithelium, or cell death in tumors 4- Deletion of autoreactive T cells in the thymus.5- Deletion of virally infected cells. 6- Mild injury (heat, radiation, cytotoxic cancer drugs, etc.)

that cause irreparable DNA damage (e.g., via the tumor suppressor protein TP53).

Somatic DeathSpecific types of cells die at different rates. Brain cells die quickly (4 to 5 minutes) when deprived of oxygen, whereas heart muscle can survive for approximately 30 minutes. Formerly, death of the body (somatic death) was assumed to occur when heart action and respiration ceased. Now, because cardiac and respiratory function can be maintained artificially, the diagnosis of death is more complex. Currently, brain death provides the criteria for somatic death. Brain death is based on the lack of any electrical activity in any neurons in the brain as demonstratedby electroencephalography (EEG) and bythe absence of responses (see Chapter 22).

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