Widespread death of hepatocytes may produce confluent necrosis. This may be seen in acute toxic or ischemic injuries or in severe chronic viral or autoimmune hepatitis. Confluent necrosis begins as a zone of hepatocyte dropout around the central vein. With increasing severity necrosis “bridges” central veins and portal tracts or adjacent portal tracts.
Fig. 16.2 Hepatocytenecrosis.InthisPAS-D–stainedbiopsyfromapatientwithacutehepatitisB,clustersofpigmentedhepatocyteswitheosinophiliccytoplasmindicatefociofhepatocytesundergoingnecrosis.PAS-D, Periodicacid-Schiffstainafterdiastasedigestion.
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Fig. 16.3 Hepatocyteapoptosis.ThisbiopsyfromapatientwithlobularhepatitisduetochronichepatitisCshowsscatteredapoptotichepatocytes(“acidophilbodies”;single arrows)andapatchyinflammatoryinfiltrate(double arrows).
Regeneration of lost hepatocytes takes place primarily by mitotic replication of hepatocytes adjacent to those that have died. In more severe forms of acute liver injury hepatic stem cells located in a niche near the canal of Hering may also begin to divide, but the contribution of stem cells to the replenishment of hepatocytes in the setting of acute liver damage remains uncertain. In longstanding chronic liver diseases, however, there is clear evidence that stem cell proliferation and differentiation make significant contributions to parenchymal restoration, probably following the replicative senescence of preexisting hepatocytes. The differentiating progeny of these tissue stem cells produce duct-like structures, called ductular reactions, a morphologic marker of stem cell–mediated liver regeneration.
Scar formation may follow very severe acute injury, but occurs more often as a reaction to chronic injury. The principal cell type involved in scar deposition is the perisinusoidal hepatic stellate cell. Following liver injury, stellate cells may become activated and convert into highly fibrogenic myofibroblasts, which produce the fibrous scar. Stellate cell activation involves complex interactions between Kupffer cells, hepatocytes, and inflammatory cells. When there is severe injury that causes death of large number of hepatocytes and the drop out of liver cells, there may be collapse of the underlying reticulin, precluding orderly regeneration of hepatocytes. In such cases, there is activation of stellate cells, and the areas of liver cell loss are replaced by fibrous septae. Eventually, these fibrous septa encircle surviving, regenerating hepatocytes in late-stage chronic liver disease, many forms of which are described as cirrhosis.
Inflammation and immunologic reactions are involved in many forms of liver disease. Systemic inflammation alters the metabolic and biosynthetic activities of the liver, leading to increased secretion of acute-phase reactants such as C-reactive protein, serum amyloid A protein (a precursor of some forms of amyloid) and hepcidin, a key regulator of iron metabolism (Chapter 12). As we will discuss, adaptive immune cells play a critical role in viral hepatitis, with CD4+ and CD8+ T cells being particularly important in the eradication of virus-infected hepatocytes and, in chronic disease, liver injury.
The most severe clinical consequence of liver disease is liver failure. It primarily occurs in three clinical scenarios: acute, chronic, and acute-on-chronic liver failure.