HEPATIC PATHOPHYSIOLOGY

Mechanisms of Cell Death

Death of hepatic parenchymal cells occurs in almost all forms of liver disease, but the mechanisms are often poorly understood. Hepatocellular degeneration and mechanisms of cell death are discussed in detail in the literature. ^{[143] [211] [231] [232]}

Necrosis

Hypoxia or anoxia is the most common cause of cellular death in humans. This is usually the result of a circulatory derangement that critically compromises oxygen delivery to tissues. The immediate effect is a decrease in intracellular ATP, which stimulates glycogenolysis and glycolysis, causes lactate to accumulate, and reduces intracellular pH. Precipitous decreases of high-energy phosphates induce subcellular events that lead inexorably to hepatocellular necrosis. The energy-dependent ion pumps that preserve intracellular fluid and electrolyte balance fail abruptly. The plasma membrane loses integrity; hepatocytes swell rapidly and rupture. Necrosis releases various substances into the surrounding tissues, including hepatocellular enzymes and macromolecular breakdown products such as lipid peroxides, aldehydes, and eicosanoids. Some of these molecules are chemoattractants for circulating neutrophils, recruiting them to engage in the hepatic inflammatory response.

Apoptosis

Unlike necrosis, apoptosis requires energy. This is a genetically programmed form of cell death that advances in an orderly sequence. Hepatic injuries from various causes (toxic, viral, immune) can trigger apoptosis by activating pro-apoptotic intracellular signaling pathways or pro-apoptotic cell surface receptors. These receptors include Fas, tumor necrosis factor receptor (TNFR), and other members of the TNFR superfamily.^{[233] [234] [235] [236] [237]}

Apoptosis produces the following characteristic ultrastructural features: (1) a shrunken cell and nucleus; (2) condensed, marginated nuclear chromatin; (3) blebs on plasma membrane; and (4) cellular fragmentation into membrane-bound bodies that contain intact organelles. Epithelial and mesenchymal cells engulf these apoptotic bodies, and lysosomes help to digest and recycle them. Thus, apoptosis conserves cellular fragments (intact mitochondria, nucleic acids) and minimizes the release of bioactive substances. In its purest form, apoptosis does not incite an inflammatory tissue reaction. The seeming dichotomy between apoptosis and necrosis probably represents the ends of a spectrum of overlapping morphologic and mechanistic cell death processes.^{[143] [233]}