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Regardless of the cause, reversible injuries and the early stages of irrevers- ible injuries often result in cellular swelling and the accumulation of excess substances within the cell. These changes reflect the cell’s inability to perform normal metabolic functions because of insufficient cellular energy in the form of adenosine triphosphate (ATP) or dysfunction of

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60 UNIT II Cellular Function

is often associated with excessive intake of alcohol. 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 (Fig. 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.

Glycosaminoglycans (mucopolysaccharides) are large carbohydrate complexes that normally compose the extracellular matrix of connective tissues. Connective tissue cells secrete most of the glycosaminoglycan into the extracellular space, but a small portion remains inside the cell and is normally degraded by lysosomal enzymes. The mucopolysaccharidoses are a group of genetic diseases in which the enzymatic degradation of these molecules is impaired and they collect within the cell. Mental disabilities and connective tissue disorders are common findings.

Like other disorders of accumulation, excessive glycogen storage can be the result of inborn errors of metabolism, but a common cause is diabetes mellitus. 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 (Fig. 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 Fig. 4.4).

Finally, a variety of pigments and inorganic particles may be present in cells. Some pigment accumulations are normal, such as the accumulation

associated metabolic enzymes. Once the acute stress or injury has been removed, by definition of a reversible injury, the cell returns to its preinjury state.

Hydropic Swelling Cellular swelling attributable to accumulation of water—called hydropic swelling or oncosis—is the first manifestation of most forms of reversible cell injury. 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 causes insufficient energy production will result in hydropic swelling (Fig. 4.1). Hydropic swelling is character- ized 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 may 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).

Intracellular Accumulations 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 (Fig. 4.2).

Normal intracellular substances that tend to accumulate in injured cells include lipids, carbohydrates, glycogen, and proteins. Faulty metabolism of these substances within the cell results in excessive intracellular storage. In some cases, the enzymes required for breaking down a particular substance are absent or abnormal as a result of a genetic defect. In other cases, altered metabolism may be due to excessive intake, toxins, or other disease processes.

A common site of intracellular lipid accumulation is the liver, where many fats are normally stored, metabolized, and synthesized. Fatty liver


FIG 4.1 Cellular swelling in kidney tubule epithelial cells. A, Normal kidney tubule with cuboidal cells. B, Early ischemic changes showing surface blebs and swelling of cells. (From Kumar V et al: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders, p 42. Photograph courtesy Drs. Neal Pinckard and M. A. Venkatachalam, University of Texas Health Sciences Center, San Antonio, TX.)



CHAPTER 4 Cell Injury, Aging, and Death 61

include calcium, tar, and mineral dusts such as coal, silica, iron, lead, and silver. Mineral dusts generally are inhaled and accumulate in lung tissue (Fig. 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).

Deposits of calcium salts occur in conditions of altered calcium intake, excretion, or metabolism. Impaired renal excretion of phosphate

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 red blood cells (RBCs), prolonged administration of iron, or the presence of hepatobiliary disorders. Inorganic particles that may accumulate