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INTRODUCTION

  • Drug-induced liver injury (DILI) is a term used to describe the hepatotoxic adverse effect of prescribed and over-the-counter medications, as well as botanicals and herbal and dietary supplements (HDS).

  • It may be further divided into:

    • Intrinsic: dose-dependent hepatotoxicity, expected in all individuals where dose threshold is exceeded

    • Idiosyncratic: mostly dose-independent hepatotoxicity, rarely occurring in susceptible individuals

  • The sequelae of DILI can encompass the entire spectrum of liver disease, ranging from asymptomatic, self-limited acute hepatitis to fulminant liver failure and from chronic hepatitis to advanced fibrosis and cirrhosis.

EPIDEMIOLOGY

  • The incidence of idiosyncratic DILI is estimated at 14 to 19 per 100,000 people per year.1,2

  • The cases of frank jaundice attributed to DILI are rare (4% and only 0.7% nonacetaminophen related);3 on the other hand, it remains the major cause (52%) of acute liver failure (ALF) in the United States.4

  • The most frequent culprit medication classes and individual drugs include, in order of frequency, antimicrobials, HDS, central nervous system (CNS), cardiovascular agents, and analgesics (see Table 11-1).5 High daily dose,6 predominantly hepatic metabolism,7,8 and biliary excretion also portend hepatotoxicity risk.

  • In terms of patient characteristics, extremes of age, gender, pregnancy, and known concurrent chronic liver disease may confer increased susceptibility to DILI by specific agents;9 examples of this include the use of aspirin in children (Reye syndrome), nitrofurantoin in women and the elderly, and antiretroviral agents in HIV patients coinfected with hepatitis C virus (HCV) or hepatitis B virus (HBV). However, there is no established patient risk factor for “all-cause” DILI.

  • Associations with specific human leukocyte antigen (HLA) alleles and susceptibility to immune-mediated, drug-specific hepatotoxicity, as well as with genes encoding proteins relating to drug metabolism,10–12 have been explored; however, no allele conferring a generalized risk for DILI has been reliably identified so far.

TABLE 11-1The Most Commonly Implicated Drug Classes and Agents as Established by the DILIN Prospective Study*

PATHOPHYSIOLOGY

  • On a cellular level, the hepatotoxic effect of a drug may result in hepatocyte necrosis, apoptosis, or both.13 Necrosis is cell death due to loss of osmotic regulation, with swelling and subsequent lysis, eventually forming amorphous, granular material. Apoptosis, on the other hand, is the programmed death of damaged cells and functions as a homeostatic mechanism to allow replacement of those cells by mitosis.14 It is largely facilitated by specific proteases: the caspases; these act by cleaving crucial ...

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