Atlas of pathophysiology, 2 Edition

Part I - Central concepts

Cells, homeostasis, and disease

The cell is the smallest living component of a living organism. Organisms can be made up of a single cell, such as bacteria, or billions of cells, such as human beings. In large organisms, highly specialized cells that perform a common function are organized into tissue. Tissues, in turn, form organs, which are integrated into body systems.

Cell components

Cells are complex organizations of specialized components, each component having its own specific function. The largest components of a normal cell are the cytoplasm, the nucleus, and the cell membrane. (See Cell components.)

Cytoplasm

The cytoplasm consists primarily of a fluid in which the tiny structures that perform the necessary functions to maintain the life of the cell are suspended. These tiny structures, called organelles, are the cell's metabolic machinery. Each performs a specific function to maintain the life of the cell. Organelles include:

·   mitochondria—spherical or rod-shaped structures that are the sites of cellular respiration—the metabolic use of oxygen to produce energy, carbon dioxide, and water (They produce most of the body's adenosine triphosphate, which contains high-energy phosphate chemical bonds that fuel many cellular activities.)

·   ribosomes—the sites of protein synthesis

·   endoplasmic reticulum—an extensive network of two varieties of membrane-enclosed tubules: rough endoplasmic reticulum, which is covered with ribosomes; and smooth endoplasmic reticulum, which contains enzymes that synthesize lipids

·   Golgi apparatus—synthesizes carbohydrate molecules that combine with protein produced by the rough endoplasmic reticulum and lipids produced by the smooth endoplasmic reticulum to form such products as lipoproteins, glycoproteins, and enzymes

·   lysosomes—digest nutrients as well as foreign or damaged material in cells (A membrane surrounding each lysosome separates its digestive enzymes from the rest of the cytoplasm. The enzymes digest nutrient matter brought into the cell by means of endocytosis, in which a portion of the cell membrane surrounds and engulfs matter to form a membrane-bound intracellular vesicle. The membrane of the lysosome fuses with the membrane of the vesicle surrounding the endocytosed material. The lysosomal enzymes then digest the engulfed material. Lysosomes digest the foreign matter ingested by white blood cells (WBCs) by a similar process, which is called phagocytosis.)

·   peroxisomes—contain oxidases, enzymes that chemically reduce oxygen to hydrogen peroxide and hydrogen peroxide to water

·   cytoskeletal elements—a network of protein structures that maintain the cell's shape

·   centrosomes—contain centrioles, short cylinders adjacent to the nucleus that take part in cell division

·   microfilaments and microtubules—enable movement of intracellular vesicles (allowing axons to transport neurotransmitters) and formation of the mitotic spindle, the framework for cell division.

Nucleus

The cell's control center is the nucleus, which plays a role in cell growth, metabolism, and reproduction. Within the nucleus, one or more nucleoli (dark-staining intranuclear structures) synthesize ribonucleic acid (RNA), a complex polynucleotide that controls protein synthesis. The nucleus also stores deoxyribonucleic acid (DNA), the double helix that carries genetic material and is responsible for cellular reproduction or division.

Cell membrane

The semipermeable cell membrane forms the cell's external boundary, separating it from other cells and from the external environment. The cell membrane consists of a double layer of phospholipids with protein molecules embedded in it. These protein molecules act as receptors, ion channels, or carriers for specific substances.

Cell division

Each cell must replicate itself for life to continue. Cells replicate by division in one of two ways: mitosis (produces two daughter cells with the same DNA and chromosome content as the mother cell) or meiosis (produces four gametocytes, each containing half the number of chromosomes of the original cell). Most cells divide by mitosis; meiosis occurs only in reproductive cells. Some cells, such as nerve and muscle cells, typically lose their ability to reproduce after birth.

Cell functions

In the human body, most cells are specialized to perform one function. Respiration and reproduction occur in all cells. The specialized functions include:

·   movement—the result of coordinated action of nerve and muscle cells to change the position of a specific body part, contents within an organ, or the entire organism

·   conduction—the transmission of a stimulus, such as a nerve impulse, heat, or sound wave, from one body part to another

·   absorption—movement of substances through a cell membrane (for example, nutrients are absorbed and transported ultimately to be used as energy sources or as building blocks to form or repair structural and functional cellular components)

·   secretion—release of substances that act in another part of the body

·   excretion—release of waste products generated by normal metabolic processes.

Cell types

Each of the following four types of tissue consists of several specialized cell types, which perform specific functions.

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·   Epithelial cells line most of the internal and external surfaces of the body. Their functions include support, protection, absorption, excretion, and secretion.

·   Connective tissue cells are present in skin, bones and joints, artery walls, fascia, and body fat. Their major functions are protection, metabolism, support, temperature maintenance, and elasticity.

·   Nerve cells comprise the nervous system and are classified as neurons or neuroglial cells. Neurons perform these functions:

§  generating electrical impulses

§  conducting electrical impulses

§  influencing other neurons, muscle cells, and cells of glands by transmitting impulses.

Neuroglial cells support, nourish, and protect the neurons. The four types include:

§  oligodendroglia—produce myelin within the central nervous system (CNS)

§  astrocytes—provide essential nutrients to neurons and assist neurons in maintaining the proper bioelectrical potentials for impulse conduction and synaptic transmission

§  ependymal cells—involved in the production of cerebrospinal fluid

§  microglia—ingest and digest tissue debris when nervous tissue is damaged.

·   Muscle cells contract to produce movement or tension. The three types include:

§  skeletal (striated) muscle cells—extend along the entire length of skeletal muscles. These cells cause voluntary movement by contracting or relaxing together in a specific muscle. Contraction shortens the muscle; relaxation permits the muscle to return to its resting length.

§  smooth (nonstriated) muscle cells—present in the walls of hollow internal organs, blood vessels, and bronchioles. By involuntarily contracting and relaxing, these cells change the luminal diameter of the hollow structure and thereby move substances through the organ.

§  striated cardiac muscle cells—branch out across the smooth muscle of the chambers of the heart and contract involuntarily. They produce and transmit cardiac action potentials, which cause cardiac muscle cells to contract.

Age Alert

In older adults, skeletal muscle cells become smaller and many are replaced by fibrous connective tissue. The result is loss of muscle strength and mass.

Pathophysiologic concepts

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 alter the cell's normal functioning.

Adaptation

Cells generally continue functioning despite changing conditions or stressors. However, severe or prolonged stress or changes may injure or destroy cells. When cell integrity is threatened, the cell reacts by drawing on its reserves to keep functioning, by adaptive changes, or by cellular dysfunction. If cellular reserve is insufficient, the cell dies. If enough cellular reserve is available and the body doesn't detect abnormalities, the cell adapts by atrophy, hypertrophy, hyperplasia, metaplasia, or dysplasia. (See Adaptive cell changes, page 4.)

Cell components

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Atrophy

Atrophy is a reversible reduction in the size of a cell or organ due to disuse, insufficient blood flow, malnutrition, denervation, or reduced endocrine stimulation. An example is loss of muscle mass after prolonged bed rest.

Hypertrophy

Hypertrophy is an increase in the size of a cell or organ due to an increase in workload. It may result from normal physiologic conditions or abnormal pathologic conditions. Types include:

·   physiologic hypertrophy—reflects an increase in workload that isn't caused by disease (for example, the increase in muscle size caused by hard physical labor or weight training)

·   pathologic hypertrophy—an adaptive or compensatory response to disease; for example, an adaptive response is thickening of heart muscle as it pumps against increasing resistance in patients with hypertension. An example of a compensatory response is when one kidney enlarges if the other isn't functioning or present.

Hyperplasia

Hyperplasia is an increase in the number of cells caused by increased workload, hormonal stimulation, or decreased tissue. Hypertrophy and hyperplasia may occur together and are commonly triggered by the same mechanism. Hyperplasia may be physiologic, compensatory, or pathologic.

·   Physiologic hyperplasia is an adaptive response to normal changes—for example, monthly increase in the number of uterine cells in response to estrogen stimulation after ovulation.

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·   Compensatory hyperplasia occurs in some organs to replace tissue that has been removed or destroyed—for example, regeneration of liver cells 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—for example, acromegaly, in which excessive growth hormone production causes bones to enlarge.

Adaptive cell changes

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Metaplasia

Metaplasia is the replacement of one adult cell type with another adult cell type that can better endure the change or stressor. It's usually a response to chronic inflammation or irritation.

·   Physiologic metaplasia is a normal response to changing conditions and is generally transient. For example, in the body's normal response to inflammation, monocytes migrate to inflamed tissues and 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 or have cilia to protect the airway. If exposure to cigarette smoke continues, the squamous cells can become cancerous.

Dysplasia

In dysplasia, deranged cell growth of specific tissue results in abnormal size, shape, and appearance. Although dysplastic cell changes are adaptive and potentially reversible, 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 disease as the cells lose their ability to adapt. Cell injury may result from any of several intrinsic or extrinsic causes:

·   toxins—may be endogenous or exogenous (common endogenous toxins include products of genetically determined metabolic errors and hypersensitivity reactions; exogenous toxins include alcohol, lead, carbon monoxide, and drugs that alter cellular function)

·   infection—may be caused by viruses, fungi, protozoa, or bacteria

·   physical injury—disruption of a cell's structure or the relationships among the organelles (for example, two types of physical injury are thermal and mechanical)

·   deficit injury—loss of normal cellular metabolism caused by inadequate water, oxygen, or nutrients.

Clinical Tip

Oxygen deficiency is the most common cause of irreversible cell injury and cell death.

Injury becomes irreversible when the cell membrane or the organelles can no longer function.

Cell degeneration

Degeneration is a type of sublethal cell damage that generally occurs in the cytoplasm and doesn't affect the nucleus. Degeneration usually affects organs with metabolically active cells, such as the liver, heart, and kidneys. When changes in cells are identified, prompt health care can slow degeneration and prevent cell death. Unfortunately, many cell changes are unidentifiable, even with the use of a microscope, and early detection of disease is then impossible. Examples of reversible degenerative changes are cervical dysplasia and fatty changes in the liver. Examples of irreversible degenerative diseases include Huntington's chorea and amyotrophic lateral sclerosis.

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Cell aging

During the normal process of aging, cells lose both structure and function. Atrophy may reflect loss of cell structure, hypertrophy or hyperplasia, or lost function. Signs of aging occur in all body systems. Aging can proceed at different rates depending on the number and extent of injuries and the amount of wear and tear on the cell.

Cell death

Cell death may be caused by internal (intrinsic) factors that limit the cell's life span or external (extrinsic) factors that contribute to cell damage and aging. When stress 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. It can involve apoptosis or necrosis.

·   Apoptosis—genetically programmed cell death—accounts for the constant cell turnover in the skin's outer keratin layer and the lens of the eye. It's controlled by autodigestion.

There are five types of necrosis:

·   Liquefactive 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.

·   Caseous necrosis occurs when necrotic cells disintegrate but the cellular pieces remain undigested for months or years. Its name derives from the resulting tissue's crumbly, cheeselike (caseous) appearance. It commonly occurs in pulmonary tuberculosis.

·   Fat necrosis occurs when lipase enzymes 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.

·   Coagulative necrosis commonly follows interruption of blood supply to any organ—generally the kidneys, heart, or adrenal glands—except the brain. It inhibits activity of lysosomal lytic enzymes in the cells, so that the necrotic cells maintain their shape, at least temporarily.

·   Gangrenous necrosis, a form of coagulative necrosis, typically results from a lack of blood flow and is complicated by an overgrowth and invasion of bacteria. It commonly occurs in the lower limbs as a result of arteriosclerosis or in the GI tract. Gangrene can occur in one of three forms:

§  dry gangrene—occurs when bacterial invasion is minimal. It's marked by dry, wrinkled, dark brown or blackened tissue on an extremity.

§  moist (or wet) gangrene—is accompanied by liquefactive necrosis, which is extensive lytic activity from bacteria and WBCs that produces a liquid center in affected area. It can occur in the internal organs as well as the extremities.

§  gas gangrene—develops when anaerobic bacteria of the genus Clostridium infect tissue. It's more likely to follow severe trauma and may be fatal. The bacteria release toxins that kill nearby cells, and the gas gangrene rapidly spreads. Release of gas bubbles from affected muscle cells indicates that gas gangrene is present.

Cell death releases intracellular enzymes, which start to dissolve cellular components, and triggers an acute inflammatory reaction in which WBCs migrate to the necrotic area and begin to digest the dead cells.

Homeostasis: Maintaining balance

Every cell in the body participates in maintaining a dynamic, steady state of internal balance, called homeostasis. Pathophysiology results from changes or disruption in normal cellular function. Three structures in the brain are primarily responsible for maintaining homeostasis of the entire body:

·   medulla oblongata—the part of the brain stem associated with vital functions, such as respiration and circulation

·   pituitary gland—regulates the function of other glands and, thereby, the body's growth, maturation, and reproduction

·   reticular formation—a network of nerve cells and fibers in the brain stem and spinal cord that helps control vital reflexes, such as cardiovascular function and respiration.

Each structure that maintains homeostasis through selfregulating feedback mechanisms has three components:

·   sensors—cells that detect disruptions in homeostasis reflected by nerve impulses or changes in hormone levels

·   CNS control center—receives signals from the sensor and regulates the body's response to those disruptions by initiating the effector mechanism

·   effector—acts to restore homeostasis.

Feedback mechanisms exist in two varieties:

·   positive—moves the system away from homeostasis by enhancing a change in the system

·   negative—works to restore homeostasis by correcting a deficit in the system and producing adaptive responses.

Disease

Although disease and illness are often used interchangeably, they aren't synonyms. Disease occurs when homeostasis isn't maintained. Illness occurs when a person isn't in a state of perceived “normal” health. A person may have a disease but not be ill all the time because his body has adapted to the disease.

The cause of disease may be intrinsic or extrinsic. Genetic factors, age, gender, infectious agents, or behaviors (such as inactivity, smoking, or abusing illegal drugs) can all cause disease. Diseases that have no known cause are called idiopathic.

The way a disease develops is called its pathogenesis. A disease is usually detected when it causes a change in metabolism or cell division that causes signs and symptoms. How the cells respond to disease depends on the causative agent and the affected cells, tissues, and organs. Without intervention, resolution of the disease depends on many factors functioning over a period of time, such as extent of disease and the presence of other diseases. Manifestations of disease may include hypofunction, hyperfunction, or increased mechanical function.

Typically, diseases progress through these stages:

·   exposure or injury—target tissue exposed to a causative agent or injury

·   latency or incubation period—no signs or symptoms evident

·   prodromal period—signs and symptoms generally mild and nonspecific

·   acute phase—disease reaches full intensity, possibly with complications; called the subclinical acute phase if the patient can still function as though the disease weren't present

·   remission—a second latency phase that occurs in some diseases and is commonly followed by another acute phase

·   convalescence—patient progresses toward recovery

·   recovery—return of health or normal functioning; no signs or symptoms of disease remain.