Xenobiotic-Induced Hepatotoxicity: Mechanisms of Liver Injury and Methods of Monitoring Hepatic Function (Beckman Conference‪)‬

Many xenobiotics (drugs and environmental chemicals) are capable of causing some degree of liver injury. In the U5, xenobiotic-induced liver toxicity is implicated in 2-5% of hospitalizations for jaundice, an estimated 15-30% of the cases of fulminant liver failure, and ~40% of the acute hepatitis cases in individuals older than 50 [1, 2]. Fortunately, most drug-induced liver injuries resolve once the offending agent is withdrawn, but morbidity may be severe and prolonged as recovery ensues. The overall mortality rate for drug-induced liver injury is ~5% [3]. The liver is prone to xenobiotic-induced injury because of its central role in xenobiotic metabolism, its portal location within the circulation, and its anatomic and physiologic structure [4]. The liver is divided into multiple lobules, each centered around a terminal hepatic (central) venule and surrounded peripherally by six portal triads. Afferent blood is supplied by the portal venules and hepatic arterioles of the portal triads, flows through the hepatic venous sinusoids, and empties into the terminal hepatic venule. The regional pattern of hepatocellular necrosis observed with some xenobiotic-induced liver injuries can be understood by dividing the liver into functional subunits referred to as acini [4,5]. Each liver acinus is divided into three concentric zones of hepatocytes radiating from a portal triad and terminating at one or more adjacent terminal hepatic venules. Hepatocytes closest to the portal triad (zone one) receive blood most enriched with oxygen and other nutrients and are most resistant to injury. Hepatocytes more distal to the blood supply receive a lower concentration of essential nutrients, making them more susceptible to ischemic or nutritional damage. Most important for xenobiotic-induced hepatic damage, the centrilobular (zone three) hepatocytes are the primary sites of cytochrome P450 enzyme activity, which frequently makes them most susceptible to xenobiotic-induced liver injury [6], as discussed below.