Cellular swelling attributable to accumulation of water, or hydropic swelling, is the first manifestation of most forms of reversible cell injury.1 Hydropic swelling results from malfunction of the sodium-potassium (Na⁺-K⁺) pumps that normally maintain ionic equilibrium of the cell. Failure of the Na⁺-K⁺ pump results in accumulation of sodium ions within the cell, creating an osmotic gradient for water entry. Because Na⁺-K⁺ pump function is dependent on the presence of cellular ATP, any injury that results in insufficient energy production also will result in hydropic swelling (Figure 4-1). Hydropic swelling is characterized by a large, pale cytoplasm, dilated endoplasmic reticulum, and swollen mitochondria. With severe hydropic swelling, the endoplasmic reticulum may rupture and form large water-filled vacuoles. Generalized swelling in the cells of a particular organ will cause the organ to increase in size and weight. Organ enlargement is indicated by the suffix -megaly (e.g., splenomegaly denotes an enlarged spleen, hepatomegaly denotes an enlarged liver).

Excess accumulations of substances in cells may result in cellular injury because the substances are toxic or provoke an immune response, or merely because they occupy space needed for cellular functions. In some cases, accumulations do not in themselves appear to be injurious but rather are indicators of cell injury. Intracellular accumulations may be categorized as (1) excessive amounts of normal intracellular substances such as fat, (2) accumulation of abnormal substances produced by the cell because of faulty metabolism or synthesis, and (3) accumulation of pigments and particles that the cell is unable to degrade (Figure 4-2).

A common site of intracellular lipid accumulation is the liver, where many fats are normally stored, metabolized, and synthesized. Fatty liver is often associated with excessive intake of alcohol.2 Mechanisms whereby alcohol causes fatty liver remain unclear, but it is thought to result from direct toxic effects as well as the preferential metabolism of alcohol instead of lipid (see Chapter 38 for a discussion of fatty liver). Lipids may also contribute to atherosclerotic diseases and accumulate in blood vessels, kidney, heart, and other organs. Fat-filled cells tend to compress cellular components to one side and cause the tissue to appear yellowish and greasy (Figure 4-3). In several genetic disorders, the enzymes needed to metabolize lipids are impaired; these include Tay-Sachs disease and Gaucher disease, in which lipids accumulate in neurologic tissue.

Like other disorders of accumulation, excessive glycogen storage can be the result of inborn errors of metabolism, but a common cause is diabetes mellitus.1 Diabetes mellitus is associated with impaired cellular uptake of glucose, which results in high serum and urine glucose levels. Cells of the renal tubules reabsorb the excess filtered glucose and store it intracellularly as glycogen. The renal tubule cells also are a common site for abnormal accumulations of proteins. Normally, very little protein escapes the bloodstream into the urine. However, with certain disorders, renal glomerular capillaries become leaky and allow proteins to pass through them. Renal tubule cells recapture some of the escaped proteins through endocytosis, resulting in abnormal accumulation.

Cellular stress may lead to accumulation and aggregation of denatured proteins. The abnormally folded intracellular proteins may cause serious cell dysfunction and death if they are allowed to persist in the cell. A family of stress proteins (also called chaperone or heat-shock proteins) is responsible for binding and refolding aberrant proteins back into their correct three-dimensional forms (Figure 4-4). If the chaperones are unsuccessful in correcting the defect, the abnormal proteins form complexes with another protein called ubiquitin. Ubiquitin targets the abnormal proteins to enter a proteosome complex, where they are digested into fragments that are less injurious to cells (see Figure 4-4). In some cases, the accumulated substances are not metabolized by normal intracellular enzymes. In diabetes, for instance, high serum glucose levels result in excessive glucose uptake by neuronal cells because they do not require insulin for glucose uptake.³ (Diabetes mellitus is discussed in Chapter 41.)

Finally, a variety of pigments and inorganic particles may be present in cells. Some pigment accumulations are normal, such as the accumulation of melanin in tanned skin, whereas others signify pathophysiologic processes. Pigments may be produced by the body (endogenous) or may be introduced from outside sources (exogenous). In addition to melanin, the iron-containing substances hemosiderin and bilirubin are endogenous pigments that, when present in excessive amounts, indicate disease processes. Hemosiderin and bilirubin are derived from hemoglobin. Excessive amounts may indicate abnormal breakdown of hemoglobin-containing red blood cells (RBCs), prolonged administration of iron, and the presence of hepatobiliary disorders. Inorganic particles that may accumulate include calcium, tar, and mineral dusts such as coal, silica, iron, lead, and silver. Mineral dusts generally are inhaled and accumulate in lung tissue (Figure 4-5). Inhaled dusts cause chronic inflammatory reactions in the lung, which generally result in destruction of pulmonary alveoli and capillaries and the formation of scar tissue. Over many years, the lung may become stiff and difficult to expand because of extensive scarring (see Chapter 23).

The biochemical pathways that result in cellular atrophy are imperfectly known; however, two pathways for protein degradation have been implicated. The first is the previously mentioned ubiquitin-proteosome system, which degrades targeted proteins into small fragments (see Figure 4-4). The second involves the lysosomes that may fuse with intracellular structures leading to hydrolytic degradation of the components. Certain substances apparently are resistant to degradation and remain in the lysosomal vesicles of atrophied cells. For example, lipofuscin is an age-related pigment that accumulates in residual vesicles in atrophied cells, giving them a yellow-brown appearance.

Hypertrophy is an increase in cell mass accompanied by an augmented functional capacity. Cells hypertrophy in response to increased physiologic or pathophysiologic demands. Cellular enlargement results primarily from a net increase in cellular protein content.4 Like the other adaptive responses, hypertrophy subsides when the increased demand is removed; however, the cell may not entirely return to normal because of persistent changes in connective tissue structures. Organ enlargement may be a result of both an increase in cell size (hypertrophy) and an increase in cell number (hyperplasia). For example, an increase in skeletal muscle mass and strength in response to repeated exercise is primarily the result of hypertrophy of individual muscle cells, although some increase in cell number is also possible because muscle stem cells (satellite cells) are able to divide. Physiologic hypertrophy occurs in response to a variety of trophic hormones in sex organs—the breast and uterus, for example. Certain pathophysiologic conditions may place undue stress on some tissues, causing them to hypertrophy. Liver enlargement in response to bodily toxins and cardiac muscle enlargement in response to high blood pressure (Figure 4-7) represent hyperplastic and hypertrophic adaptations to pathologic conditions. Hypertrophic adaptation is particularly important for cells, such as differentiated muscle cells, that are unable to undergo mitotic division.

Metaplasia is the replacement of one differentiated cell type with another. This most often occurs as an adaptation to persistent injury, with the replacement cell type better able to tolerate the injurious stimulation.1 Metaplasia is fully reversible when the injurious stimulus is removed. Metaplasia often involves the replacement of glandular epithelium with squamous epithelium. Chronic irritation of the bronchial mucosa by cigarette smoke, for example, leads to the conversion of ciliated columnar epithelium to stratified squamous epithelium. Metaplastic cells generally remain well differentiated and of the same tissue type, although cancerous transformations can occur. Some cancers of the lung, cervix, stomach, and bladder appear to derive from areas of metaplastic epithelium.

Dysplasia refers to the disorganized appearance of cells because of abnormal variations in size, shape, and arrangement. Dysplasia occurs most frequently in hyperplastic squamous epithelium, but it may also be seen in the mucosa of the intestine. Dysplasia probably represents an adaptive effort gone astray. Dysplastic cells have significant potential to transform into cancerous cells and are usually regarded as preneoplastic lesions. (See Chapter 7 for a discussion of cancer.) Dysplasia that is severe and involves the entire thickness of the epithelium is called carcinoma in situ. Mild forms of dysplasia may be reversible if the inciting cause is removed.

Necrotic cells demonstrate typical morphologic changes, including a shrunken (pyknotic) nucleus that is subsequently degraded (karyolysis), a swollen cell volume, dispersed ribosomes, and disrupted plasma and organelle membranes (Figure 4-8). The disruption of the permeability barrier of the plasma membrane appears to be a critical event in the death of the cell.⁵

Four different types of tissue necrosis have been described: coagulative, liquefactive, fat, and caseous (Figure 4-9). They differ primarily in the type of tissue affected. Coagulative necrosis is the most common. Manifestations of coagulative necrosis are the same, regardless of the cause of cell death. In general, the steps leading to coagulative necrosis may be summarized as follows: (1) ischemic cellular injury, leading to (2) loss of the plasma membrane’s ability to maintain electrochemical gradients, which results in (3) an influx of calcium ions and mitochondrial dysfunction, and (4) degradation of plasma membranes and nuclear structures (Figure 4-10). The area of coagulative necrosis is composed of denatured proteins and is relatively solid. The coagulated area is then slowly dissolved by proteolytic enzymes and the general tissue architecture is preserved for a relatively long time (weeks). This is in contrast to liquefactive necrosis.

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