Drugs and Toxins Effects on the Liver

Abstract

Drug induced hepatotoxicity can be defined as a liver injury caused by drug or herbal medicines leading to liver test abnormalities or to a liver dysfunction with a reasonable exclusion of the other competing aetiologies. The liver has a central function in the metabolism of the xenobiotics, and as a result it may be susceptible to its toxic or idiosyncratic effects. While the overall incidence of drug induced liver injury (DILI) is infrequent (1 in 10.000 to 100.000 persons exposed), the impact is significant in the general population, with broad implications for patients, physicians, pharmaceutical industries and governmental regulatory agencies. DILI is the principle reason for the termination in clinical trials and the most frequent adverse event leads to drug non approvals, withdrawals or to a restriction of prescription drug use after an initial approval and postmarketing regulatory decisions. DILI has been shown to have a dose-dependent component. However, most of the cases of DILI are due to idiosyncratic reactions: over 1000 drugs and herbal products have been associated with idiosyncratic hepatotoxicity. It is difficult to establish a diagnosis of DILI. In fact, there is no single pathognomonic test to establish that a given drug in a given subject is the cause of liver injury. Furthermore, the clinical presentation of DILI may considerably vary. It can mimic other known forms of acute and chronic liver diseases and the severity may range from asymptomatic elevations of hepatic enzymes to fulminant hepatic failure. Because of these factors, a diagnosis of DILI is frequently delayed or may be entirely missed. So, the study of DILI is confounded by the heterogeneity of its clinical presentation and by the course of the injury, the delay in establishing diagnosis as it requires exclusion of other causes of liver injury, the lack of standardized criteria or specific ‘gold standard’ diagnostic tests and underreporting of cases of DILI or their final outcomes. The aim of this chapter is to provide a review and an update of DILI.