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Drug-Induced Liver Injury
Drug-induced liver injury (DILI) is a frequent cause of liver injury. It is the most frequent reason for withdrawal from the market of an approved drug and accounts for one-third to one-half of the cases of acute liver failure in this country. It can mimic both acute and chronic forms of liver disease and often represents an important diagnostic and therapeutic challenge for the treating physician. Although more than 1100 drugs, including herbal, vitamin, dietary supplements, and prescription medications, are believed to have the potential to cause DILI, only a handful are associated with acute liver failure and resultant death or liver transplantation.
Epidemiology
DILI is a relatively underreported clinical entity, with a crude incidence ranging from 10 to 20 per 100,000 persons exposed. The true incidence remains unknown due to the lack of systemic reporting, controversy regarding the diagnosis in the context of polypharmacy, and the lack of a simple objective test to establish the diagnosis.
The Acute Liver Failure Study Group in the United States has reported the incidence of mortality or liver transplantation as 10% among a large group of 300 cases of DILI. Data from the national liver transplantation network in the United States suggest that DILI accounts for 15% of all cases requiring transplantation in patients who present with acute liver failure.
The low incidence of DILI makes it difficult to ascertain the type and severity of hepatotoxicity of new drugs during phase III clinical trials. Therefore the modified Hy's rule is used by the US Food and Drug Administration (FDA) to categorize the severity of hepatotoxicity. Drugs that can cause an alanine aminotransferase (ALT) level 3 or more times the upper limit of normal (ULN) with bilirubin levels 2 or more times ULN are historically associated with greater than 10% mortality and are considered at risk for life-threatening liver damage.
In general, drugs that cause liver injury can be divided into two categories: those that cause dose-dependent toxicity, such as acetaminophen or tetracycline, and the vast majority of others (>90% to 95%) that cause idiosyncratic reactions. For the former group, factors such as dose, blood level, and duration of intake play an important role in determining toxicity. For the latter group, host factors such as age, gender, concomitant diseases, and other drug exposure are important factors ( Fig. 130.1 ).
Age
Hepatic drug reactions are more common in the elderly (probably due to the presence of polypharmacy) and much less frequent among children. The exceptions include valproic acid, where hepatotoxicity is frequently seen among children younger than 3 years of age. Salicylic acid–induced Reye syndrome is also exclusively seen in children, although now rarely so due to widespread education and awareness.
Gender
Women seem to be particularly predisposed to drug-induced hepatotoxicity from medications such as minocycline, methyldopa, and nitrofurantoin in which the injury histologically resembles autoimmune hepatitis. Women also seem to be predisposed to the development of severe liver injury, as shown by a female preponderance in most studies of acute liver failure and liver transplantation related to DILI.
Concomitant Drugs
Recipients of polypharmacy are more likely to experience liver toxicity due to various mechanisms, including enhanced cytochrome P450 metabolism that results in accumulation of the toxic metabolite or delayed biliary excretion. Chronic alcohol ingestion can increase the severity of liver injury from certain agents, such as acetaminophen and isoniazid (INH), due to depletion of glutathione.
Concomitant Illnesses
In general, patients with preexisting liver disease, including cirrhosis, are not predisposed to DILI, but they are believed to be at higher risk for complicated courses and outcomes of DILI. Human immunodeficiency virus (HIV) infection increases the risk of sulfonamide toxicity, and renal transplantation is considered a risk factor for azathioprine-induced vascular injury. Most medications metabolized in the liver will demonstrate altered pharmacokinetics with elevated area under the curve (AUC), and clinical judgment should determine the safety of their use in patients with decompensated cirrhosis.
Genetics
Genetics play an important role in the susceptibility of an individual at multiple phases of the processing of a drug. A major role is played by genes encoding cytochrome P450 (CYP) isoenzymes responsible for drug metabolism. A common example is slow acetylator genotype responsible for isoniazid-related liver injury. Genetic mutations affecting the cytokeratin proteins on hepatocytes have also been implicated in the causation of severe DILI. In addition, immune-mediated pathogenesis for DILI has brought to light the susceptible human leukocyte antigen (HLA) haplotypes seen in some cases of DILI. This approach of genetic screening has shown promise in reducing the incidence of idiosyncratic reactions of drugs. A solid example is the HLA-B*5701 genotyping prior to institution of abacavir therapy, which has almost eliminated the incidence of a potentially severe hypersensitivity reaction to the drug.
Intrinsic Properties of the Drug
The most commonly implicated group of drugs are antimicrobials. The hepatotoxic potential of drugs dosed at more than 50 to 100 mg/day is higher than those dosed at under 20 mg daily. In addition, drugs with greater lipophilicity and predominantly hepatic metabolism are more prone to DILI. Interestingly, drugs used at higher doses have shorter latency to the onset of DILI.
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