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INTRODUCTION

The liver plays an essential role in metabolic homeostasis. Hepatic functions include the synthesis, storage, and breakdown of glycogen. In addition, the liver is important in the metabolism of lipids; the synthesis of albumin, clotting factors, and other important proteins; the synthesis of the bile acids necessary for absorption of lipids and lipid-soluble vitamins; and the metabolism of cholesterol. Hepatocytes facilitate the excretion of metals, most importantly iron, copper, zinc, manganese, mercury, and aluminum, as well as the detoxification of products of metabolism, such as bilirubin and ammonia.27,59 Generalized disruption of these important functions results in manifestations of liver failure: hyperbilirubinemia, coagulopathy, hypoalbuminemia, hyperammonemia, and hypoglycemia. Disturbances of more specific functions result in accumulation of lipids, metals, and bilirubin, and the development of lipid-soluble vitamin deficiencies.125

The liver is also the primary site of biotransformation and detoxification of xenobiotics. The interposition of the liver between the gastrointestinal tract and systemic circulation makes it the first-pass recipient of ingested xenobiotics. The liver receives blood from the systemic circulation and participates in the detoxification and elimination of xenobiotics that reach the bloodstream through other routes, such as inhalation or cutaneous absorption.112,125

Many xenobiotics are lipophilic and inert, requiring chemical modification followed by conjugation to make them sufficiently water-soluble to be eliminated. The liver is the primary organ responsible for this biotransformation, and contains the highest concentration of cytochrome P450 (CYP) enzymes involved in the first stage of detoxification for many lipophilic xenobiotics (Chap. 11). Although many of the xenobiotics that are detoxified in the liver are subsequently excreted in the urine, the biliary tract provides an additional route for their elimination.43 Although cytochrome P450 phase I activation of xenobiotics usually leads to detoxification, in some cases it can produce xenobiotics with increased toxicity and hepatocyte injury at the site of synthesis.112

MORPHOLOGY AND FUNCTION OF THE LIVER

Two pathologic concepts are used to describe the appearance and function of the liver: a structural one represented by the hepatic lobule, and a functional one represented by the acinus. The basic structural unit of the liver as characterized by light microscopy is the hepatic lobule, a hexagon with the hepatic vein at the center and the portal triads at the angles. The portal triad consists of the portal vein, the common bile duct, and the hepatic artery. Cords of hepatocytes are oriented radially around the central hepatic vein, forming sinusoids. In contrast, the acinus, or “metabolic lobule” is the functional unit of the liver. Located between 2 central hepatic veins, it is bisected by terminal branches of the hepatic artery and portal vein that extend from the bases of the acini toward hepatic venules at the apices. The acinus is subdivided into 3 metabolically distinct zones: Zone 1 lies near the portal triad, zone 3 lies near the central hepatic vein, and ...

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