Bacterial, Viral, and Immune Injury

Bacterial products such as endotoxins injure and kill hepatocytes. Endotoxins refer to lipopolysaccharide complexes that are integral to the outer membrane of Gram-negative bacteria. Bacterial lysis releases these endotoxins, which consist of two polysaccharide regions (a bacterial strain-specific O-antigen and more constant core R-antigen) and a common lipid part (lipid A). Lipid A binds to high-density lipoproteins in blood and to other tissues, and mediates the biologic reactions common to endotoxins. Endotoxins bind more extensively to Kupffer cells than to hepatocytes. Thus, endotoxins can damage hepatocytes both directly and indirectly. Indirect hepatocellular or cholestatic damage involves Kupffer cell stimulation. Activated Kupffer cells produce and release proinflammatory mediators, including cytokines and ecosanoids.^[280] Viruses may similarly cause hepatocellular injury through direct and indirect mechanisms. Viral infections can stimulate the production of cytokines that induce lymphocyte- or macrophage-dependent cytotoxicity, which is typical of hepatotropic viruses and certain herpesviruses. Antigens on hepatocellular membranes may be primary targets of cell-mediated injury. Antibodies to such antigens selectively increase in patients with autoimmune hepatitis and primary biliary cirrhosis. Other potential antigenic focuses for cell-mediated cytotoxicity include liver-specific lipoproteins and hepatic lectins, which may be important targets in hepatitis B and other liver diseases.