Chronic liver disease is usually secondary to chronic alcohol abuse or chronic viral hepatitis. Alcoholic liver disease is most common and begins with the accumulation of fat vacuoles within hepatocytes and hepatic enlargement. There is a decrease in cytochrome P450 content per weight of tissue, but this is compensated for by the increase in liver size so that drug metabolism is not impaired (18). Alcoholic fatty liver may be accompanied or followed by alcoholic hepatitis, in which hepatocyte degeneration and necrosis become evident. In neither of these conditions is there significant diversion of blood flow past functioning hepato-cytes by functional or anatomic shunts.
Cirrhosis occurs most frequently in the setting of alcoholic liver disease and represents the final common pathway of a number of chronic liver diseases. The development of cirrhosis is characterized by the appearance of fibroblasts and collagen deposition. This is accompanied by a reduction in liver size and the formation of nodules of regenerated hepatocytes. As a result, total liver content of cytochrome P450 is reduced in these patients. Initially, fibroblasts deposit collagen fibrils in the sinusoidal space, including the space of Disse (18). Collagen deposition not only produces characteristic bands of connective scar tissue but also forms a basement membrane devoid of microvilli along the sinusoidal surface of the hepato-cyte. The collagen barrier between the hepatocyte and sinusoid, in conjunction with alterations in the sinusoidal membrane of the hepatocyte, results in functional shunting of blood past the remaining hepatocyte mass. This can interfere significantly with the hepatic uptake of oxygen, nutrients, and plasma constituents, including drugs and metabolites.
The deposition of fibrous bands also disrupts the normal hepatic vascular architecture and increases vascular resistance and portal venous pressure. This reduces portal venous flow that normally accounts for 70% of total liver blood flow (19). However, the decrease in portal venous flow is compensated for by an increase in hepatic artery flow, so that total blood flow reaching the liver is maintained at the normal value of 18 mL/min ■ kg in patients with either chronic viral hepatitis or cirrhosis (20). The increase in portal venous pressure also leads to the formation of extra-hepatic and intrahepatic shunts. Extrahepatic shunting occurs through the extensive collateral network that connects the portal and systemic circulations (19). Important examples include collaterals at the gastro-esophageal junction, which can dilate to form varices, and the umbilical vein. In a study of cirrhotic patients with bleeding esophageal varices, an average of 70% of mesenteric and 95% of splenic blood flow was found to be diverted through extrahepatic shunts (21). Intrahep-atic shunting results both from intrahepatic vascular anastamoses that bypass hepatic sinusoids and from the functional sinusoidal barrier caused by collagen deposition. Iwasa et al. (20) found that the combination of anatomic and functional intrahepatic shunting averaged 25% of total liver blood flow in normal subjects, but was increased to 33% in patients with chronic viral hepatitis and to 52% in cirrhotic patients.
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