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Drugs and the liver: Metabolism and mechanisms of injury

INTRODUCTION

Many drugs, both prescription and over-the-counter, herbal products, or toxins can cause hepatotoxicity through a variety of mechanisms [1,2]. A high index of suspicion is often necessary to expeditiously establish the diagnosis.

The hepatic metabolism of drugs and the mechanisms by which drugs might injure the liver will be reviewed here. The different clinical patterns of drug-induced hepatotoxicity and the use of medications in patients with liver disease are discussed separately. (See "Drug-induced liver injury" and "Overview of the management of chronic hepatitis C virus infection", section on 'Dose adjustments of medications' and "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'General management'.)

EPIDEMIOLOGY

Drug-induced liver injury (DILI) is a well-recognized problem. Over 1000 medications and herbal products have been implicated in the development of DILI [3,4]. DILI has an estimated annual incidence of between 10 and 15 per 10,000 to 100,000 persons exposed to prescription medications [5-12]. It accounts for up to 30 percent of cases of acute hepatitis, up to 10 percent of consultations by hepatologists, and is the most common cause of acute liver failure in the United States [13-19]. It is also the cause of acute jaundice in up to 50 percent of patients who present with new onset jaundice [8,9,13,20-25]. Finally, DILI is the most frequently cited reason for the withdrawal of medications from the marketplace and the list continues to grow [14,15,26,27].

Database of drugs, herbs, and supplements associated with hepatotoxicity — The National Institutes of Health (NIH) maintains a searchable database of drugs, herbal medications, and dietary supplements that have been associated with DILI [28].

ROLE OF THE LIVER IN DRUG METABOLISM

The liver is responsible for the selective uptake, concentration, metabolism, and excretion of the majority of drugs and toxins that are introduced into the body. While some parent drugs can directly cause hepatotoxicity, it is generally the metabolites of these compounds that lead to drug-induced liver injury (DILI). These compounds are processed by a variety of soluble and membrane-bound enzymes, especially those related to the hepatocyte endoplasmic reticulum. Each drug has its specific enzyme disposal pathway(s) of biotransformation involving one or more of these enzyme systems. Genetic variation in drug metabolism is increasingly being recognized as a factor in the development of DILI. Environmental factors (eg, alcohol use) may also alter the processing of drugs and toxins.

                   

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Literature review current through: Jul 2014. | This topic last updated: Feb 25, 2014.
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