It is useful to describe the basic alterations that occur in damaged cells before discussing the biochemical mechanisms that bring about these changes. All stresses and noxious influences exert their effects first at the molecular or biochemical level. There is a time lag between the stress and the morphologic changes of cell injury or death; the duration of this delay may vary with the sensitivity of the methods used to detect these changes (Fig. 1). With histochemical or ultrastructural techniques, changes may be seen in minutes to hours after injury; however, it may take considerably longer (hours to days) before changes can be seen by light microscopy or on gross examination. As would be expected, the morphologic manifestations of necrosis take more time to develop than those of reversible damage. For example, in ischemia of the myocardium, cell swelling is a reversible morphologic change that may occur in a matter of minutes, and may progress to irreversibility within an hour or two. Unmistakable light microscopic changes of cell death, however, may not be seen until 4 to 12 hours after onset of ischemia.

Fig1. Sequential development of biochemical and morphologic changes in cell injury. Cells may become rapidly nonfunctional after the onset of injury, although they may still be viable, with potentially reversible damage; a longer duration of injury may lead to irreversible injury and cell death. Note that irreversible biochemical alterations may cause cell death, and typically this precedes ultrastructural, light microscopic, and grossly visible morphologic changes.

The sequential morphologic changes in cell injury progressing to cell death are illustrated in Figure 2. Reversible injury is characterized by generalized swelling of the cell and its organelles, blebbing of the plasma membrane, detachment of ribosomes from the ER, and clumping of nuclear chromatin. These morphologic changes are associated with decreased generation of ATP, loss of cell membrane integrity, defects in protein synthesis, cytoskeletal damage, and DNA damage. Within limits, the cell can repair these derangements and, if the injurious stimulus abates, will return to normalcy. Persistent or excessive injury, however, causes cells to pass the rather nebulous “point of no return” into irreversible injury and cell death. Different injurious stimuli may induce death by necrosis or apoptosis (Fig. 2 and Table 1). Severe mitochondrial damage with depletion of ATP and rupture of lysosomal and plasma membranes are typically associated with necrosis. Necrosis occurs in many commonly encountered injuries, such as those following ischemia, exposure to toxins, various infections, and trauma. Apoptosis has many unique features.

Fig2. Schematic illustration of the morphologic changes in cell injury culminating in necrosis or apoptosis.

Table1. Features of Necrosis and Apoptosis

Reversible Injury

Two features of reversible cell injury can be recognized under the light microscope: cellular swelling and fatty change. Cellular swelling appears whenever cells are incapable of maintaining ionic and fluid homeostasis and is the result of failure of energy-dependent ion pumps in the plasma membrane. Fatty change occurs in hypoxic injury and various forms of toxic or metabolic injury. It is manifested by the appearance of lipid vacuoles in the cytoplasm. It is seen mainly in cells involved in and dependent on fat metabolism, such as hepatocytes and myocardial cells. The mechanisms of fatty change are discussed later in the chapter.

Necrosis

The morphologic appearance of necrosis as well as necroptosis is the result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell. Necrotic cells are unable to maintain membrane integrity and their contents often leak out, a process that may elicit inflammation in the surrounding tissue. The enzymes that digest the necrotic cell are derived from the lysosomes of the dying cells themselves and from the lysosomes of leukocytes that are called in as part of the inflammatory reaction. Digestion of cellular contents and the host response may take hours to develop, and so there would be no detectable changes in cells if, for example, a myocardial infarct caused sudden death. The earliest histologic evidence of myocardial necrosis does not become apparent until 4 to 12 hours later. However, because of the loss of plasma membrane integrity, cardiac-specific enzymes and proteins are rapidly released from necrotic muscle and can be detected in the blood as early as 2 hours after myocardial cell necrosis.

Patterns of Tissue Necrosis

The discussion of necrosis has focused so far on changes in individual cells. When large numbers of cells die the tissue or organ is said to be necrotic; thus, a myocardial infarct is necrosis of a portion of the heart caused by death of many myocardial cells. Necrosis of tissues has several morphologically distinct patterns, which are important to recognize because they may provide clues about the underlying cause. Although the terms that describe these patterns are somewhat outdated, they are used often and their implications are understood by pathologists and clinicians.

Ultimately, in the living patient most necrotic cells and their contents disappear due to enzymatic digestion and phagocytosis of the debris by leukocytes. If necrotic cells and cellular debris are not promptly destroyed and reabsorbed, they provide a nidus for the deposition of calcium salts and other minerals and thus tend to become calcified. This phenomenon, called dystrophic calcification, is considered later in the chapter.

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