Introduction

Drug-induced liver disease (DILD) is clearly common, although the exact incidence and prevalence are difficult to ascertain due to under-reporting. It is worth noting that hepatotoxicity is one of the most common reasons for termination of drug development programs or clinical trials. In addition, there are clearly genetic predispositions to some types of DILD, as well as gender and age effects. Pre-existing medical conditions may predispose to drug injury and the severity of that injury; studies have implicated diabetes mellitus and alcohol use. While most drug reactions are considered idiosyncratic, and therefore unpredictable and dose-independent, there may be a dose dependency for the most severe cases of DILD.

In a recent review, antimicrobials were reported to be the most common class of agents implicated in DILD, accounting for almost half of reported cases. Central nervous system agents were second; immunomodulatory drugs, analgesics, antineoplastic agents, antihypertensives, and lipid-lowering agents were among the other classes of drugs reported.

Acute liver injury is the typical pattern in DILD; however, a small proportion of patients may develop chronic disease.

Mechanisms of Drug-Induced Liver Injury

It is not surprising, given the wide variety of classes of drugs that can cause liver injury, that a variety of mechanisms leads to hepatotoxicity. One involves cell membrane disruption with subsequent cell death, due to covalent binding of drug to cell proteins, which triggers an immunologic response to newly created adducts. Another pathway of injury leads to cholestasis through interruption of bile transport pumps or alterations in actin microfilaments. A direct toxic effect on mitochondrial function, with subsequent lipid accumulation and steatosis/steatohepatitis, represents yet another mechanism of drug injury. These pathways and others are discussed in detail elsewhere.

Patterns of Drug Injury

It is often a help to look at DILD according to the pattern of injury produced, in an effort to narrow down the potential agents in patients who may be exposed to multiple medications with hepatotoxic potential. An hepatocellular pattern, reflecting hepatocyte necrosis, is characterized by much higher elevation in aminotransaminases (AST, ALT) when compared with cholestatic markers (bilirubin, ALP). The former is typical of acetaminophen toxicity, as well as antituberculous medications, valproic acid, ketoconazole, and non-steroidal anti-inflammatory drugs (Box 16.1). A cholestatic picture is more commonly seen with many antibiotic-related DILD (penicillin derivatives and erythromycin) as well as estrogen-based hormones (Box 16.2). There are many compounds, however, that produce a mixed picture, including sulfa drugs, phenytoin, angiotensin-converting enzyme (ACE)-inhibitors, and others (Box 16.3). Other DILD may be complicated by the cholestatic effect of the oral contraceptive pill. Drugs that induce fatty liver (amiodarone, tamoxifen, tetracycline) typically present with signs of more hepatocellular injury than cholestasis. Immunologically mediated injury, such as that seen with phenytoin, nitrofurantoin, or halothane, tends to present with the mixed pattern of abnormal liver biochemistry.

The timing of abnormal biochemistry with drug exposure may be helpful. Although there is some controversy regarding the true incidence of statin-induced hepatotoxicity, is it generally considered that a rise in aminotransaminases within a few weeks of use may be attributed to these agents. Extremely rapid onset of idiosyncratic DILD is rare, although seen with drugs in the erythromycin class and among the fluoroquinolones.

In contrast, methotrexate-induced hepatic injury is thought to be related to the cumulative dose of the medication, which means that it may take several years to appreciate the development of drug-related fibrosis and often simultaneous chronic alcohol consumption may have an additive effect.

It is also possible to classify DILD by the histologic findings seen on liver biopsy (Box 16.4), although it is usually unnecessary to obtain liver tissue in this situation. However, a patient may be receiving more than a single drug that can cause DILD, for example, and stopping the drugs to determine etiology may not be an option. Alternatively, underlying liver disease may make determination of the role of DILD in new biochemical abnormalities difficult, and biopsy may be helpful. Patients may be critically ill, with sepsis or hemodynamic disturbances that can affect liver biochemistry or liver function, and biopsy is more often required to determine the relative contributions of these various hepatotoxic possibilities.

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