Manifestations of Disease at the Cellular Level

Read Also

Adaptive Structural Changes

Within limits, most cells can adapt to environmental stresses by modifying their size/shape, pattern of growth, and/or metabolic activity (fig.3.) In the extreme, adaptive cellular changes are also markers for injury and disease. Common examples include:

• Atrophy. A decrease in individual cell size due to lower rates of metabolism and decreased protein synthesis. Atrophic cells have less structural proteins, fewer mitochondria, and less endoplasmic reticulum. Although atrophic cells have reduced functions, they are not dead. The reduced metabolic activity of atrophic cells makes them less vulnerable to injury. When a sufficient number of cells become atrophic, the whole tissue or organ diminishes in size. Occasionally the numbers of cells in atrophic tissues may also decrease. This is sometimes referred to as involution.

Causes of atrophy include: (1) Decreased workload (e.g., muscle atrophy in an injured limb immobilized in a plaster cast). (2) Loss of innervation (e.g., muscle atrophy in patients with spinal cord or peripheral nerve injuries). (3) Diminished blood supply (e.g., chronic stenosis [narrowing] of the renal artery may lead to kidney atrophy). (4) Inadequate nutrition (e.g., lack of protein in diet leads to muscle atrophy, vitamin B12 deficiency is associated with gastric atrophy). (5) Loss of endocrine stimulation (e.g., hypofunction of the pituitary gland can lead to atrophy of thyroid gland, adrenal glands, ovaries, and testes). Physiologic atrophy of the endometrium, vaginal epithelium, and breast occur with menopause and the loss of estrogen stimulation. (6) Aging is associated with cellular atrophy and involution - especially in the heart and brain.

• Hypertrophy - An increase in tissue mass resulting from an increase in cell size rather than cell numbers. The increase in cell size is due to accelerated synthesis of proteins and other structural components of the cell. Hypertrophied tissues and organs do not have greater numbers of cells, just larger cells. If atrophy is a kind of "cell hibernation" designed to reduce susceptibility to injury, hypertrophy is equivalent to "calling up the reserves" to shore up cell defenses.

Hypertrophy may be caused by: (1) Increased functional demand (e.g., increased skeletal muscle mass in response to exercise; increased heart size in response to the abnormal workload imposed by chronic hypertension or valvular heart disease). (2) Hormonal stimulation (e.g., estrogenic stimulation of uterine smooth muscle during pregnancy contributes to increased uterine size).

Physiologic hypertrophy, as an adaptive mechanism, has its limitations. As hypertrophy progresses, the increase in cell size eventually is no longer able to compensate for increased workload. This probably occurs because of the cell's inability to indefinitely provide oxygen and nutrients as cell size increases. For example, even though enlargement of the heart is an adaptive mechanism to chronic hypertension, ultimately the myocardium reaches its adaptive limits and is unable to continue providing adequate blood output to meet demand. Heart failure then ensues.

• Hyperplasia - Increase in tissue mass due to an increased rate of cell division and cellular proliferation. A hyperplastic organ is increased in size because it has more cells.

Hyperplasia may be physiologic or pathologic. (1) Physiologic hyperplasia can occur as a result of normal hormonal stimulation (e.g., female breast enlargement during puberty and pregnancy; or as a compensatory mechanism for loss of tissue (e.g., hyperplasia of skin cells during the healing of an abrasion). (2) Pathologic hyperplasia is the result of a noxious stimulus (e.g., callous formation on the hands of a manual laborer); or excessive hormonal stimulation (e.g., goiters and hyperthyroidism, prostate enlargement in response to chronic exposure to androgens).

Hyperplasia and hypertrophy are closely related. The two processes often occur together in injured tissues. Both are reversible if the stimulus is withdrawn. Pathologic hyperplasia is probably a step in the development of cancer (neoplasia). Thus hyperplastic changes in some tissues may be considered premalignant. For example, chronic hyperplasia of the uterine endometrium (as seen with estrogen replacement therapy) is associated with an increased risk for endometrial cancer.

• Metaplasia - A reversible change in cell structure from one fully differentiated form to another in response to a noxious stimulus. Metaplasia represents an attempt by tissue to replace a susceptible cell type with a more resistant one. For example, the cells lining the normal trachea and bronchioles are mucous secreting, ciliated columnar epithelium which is very sensitive to the chemicals in tobacco smoke. In smokers, these cells are eventually replaced by stratified squamous epithelium which are more resistant to smoke. Metaplasia is potentially reversible. If the abnormal stimulus is removed, the cells may revert to their original type. Smokers who quit may regain normal mucous secreting bronchial epithelium. However, if the stimulus producing metaplasia persists, it may induce malignant transformation. Thus, like hyperplasia, metaplasia is considered a pre-malignant change.

• Dysplasia - Disordered cellular morphology, organization, and function. Unlike atrophy, hypertrophy, and hyperplasia which may be physiologic adaptations as well as manifestations of disease, dysplasia (and probably metaplasia) is always associated with a pathologic process. Dysplastic tissues display abnormal variation in overall cell size and shape as well as nuclear structure. Cell numbers are typically increased in dysplastic tissue and normal tissue morphology is distorted.

Dysplasia is strongly implicated as a precursor to cancer. Dysplastic cellular changes are frequently found adjacent to areas of cancer. Dysplasia is distinguished from cancer by the important fact that dysplastic changes can be reversed if the abnormal stimulus is removed. Unlike cancer cells, dysplastic cells are not autonomous - they are still capable of responding to normal physiologic growth and differentiation controls.

Cell swelling. A common feature of almost all cell injuries. A form of reversible injury associated with the abnormal influx of sodium and water into the cell.

Intracellular accumulations - Another way cells can adapt to injury that disrupts metabolic pathways is to accumulate and store various substances in the cytoplasm. Intracellular accumulations may be substrates of biosynthetic processes or normal cellular constituents such as lipids, proteins, or carbohydrates - or pigments such as melanin and bilirubin. Lipofuschin (a lipid rich pigment derived from degraded cell membranes) is commonly found in aging or chronically injured tissues. This substance gives these tissues a characteristic yellow-brown color.

Intracellular accumulations are not usually harmful to the cell in themselves - they are simply markers indicating cellular dysfunction (e.g., lipid accumulation in hepatocytes with alcoholic liver disease). In some instances, however, intracellular accumulations can impair cell function and contribute to a disease process (e.g., iron overload and hemochromatosis, uric acid and gout, beta amyloid and Alzheimer's disease).

Calcification. Injury and cell death can cause the release of intracellular phosphate ions and fatty acids into the extracellular environment. These compounds react with calcium ions forming insoluble calcium salts which are precipitated in tissues. This type of calcification is particularly common in atherosclerosis and diseases associated with chronic inflammation. Abnormal calcifications can also occur in conditions associated with hypercalcemia - excess levels of calcium in the blood (e.g., hyperparathyroidism).

Enzyme leakage. Injury to cell membranes can also be associated with the leakage of normal intracellular enzymes into extracellular fluids. Elevated plasma levels of these enzymes are often used as indirect laboratory markers for cell injury. A common example is myocardial infarction which is associated with elevations of serum creatine kinase (CK) and cardiac troponins. Hepatobiliary disease is frequently accompanied by elevations of the enzymes AST, ALT, and alkaline phosphatase.