Elsevier

Mayo Clinic Proceedings

Volume 89, Issue 1, January 2014, Pages 95-106
Mayo Clinic Proceedings

Review
Drug-Induced Liver Injury

https://doi.org/10.1016/j.mayocp.2013.09.016Get rights and content

Abstract

Drug hepatoxicity can be nonidiosyncratic (predictable), as in the case of acetaminophen, or idiosyncratic (unpredictable). This review article focuses primarily on idiosyncratic drug-induced liver injury (DILI). New epidemiologic data suggest that approximately 20 new cases of DILI per 100,000 persons occur each year. Idiosyncratic DILI accounts for 11% of the cases of acute liver failure in the United States. Risk factors for DILI include medication dose, drug lipophilicity, and extent of hepatic metabolism. There is mixed evidence to support the role of host factors such as age, sex, and chronic liver disease in the development of DILI. For specific drugs, a genetic predisposition appears to be a risk factor for DILI. Suspected cases of idiosyncratic DILI should be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase and alkaline phosphatase. A careful evaluation for other causes of liver disease should be performed, though a liver biopsy is rarely needed. There is evidence that some patients with DILI may actually have hepatitis E and this diagnosis should be considered. Amoxicillin/clavulanate isoniazid, and nonsteroidal anti-inflammatory drugs are among the most common causes of DILI. Drug discontinuation or dechallenge should lead to an improvement in liver biochemistries in most patients, though a bilirubin value of more than 3 g/dL is associated with mortality of at least 10%. New biomarkers for DILI using proteomics and micro RNA appear promising but require further study. New studies on drugs with potential for causing DILI are reviewed herein, including tumor necrosis factor-alpha antagonists, fluoroquinolones, tyrosine kinase inhibitors, statins, and supplements. PubMed was used with search terms of drug induced liver injury OR DILI with filter settings of “English language” and “humans” and custom date range of “January 1, 2000.” The authors also manually searched bibliographies from key references and included seminal references before the year 2000.

Section snippets

Classification

DILI is a broad term applied to any injury to the liver by a prescribed medication, over-the-counter medication, herb, or dietary supplement manifesting as a spectrum from asymptomatic liver test elevations to ALF. Epidemiologic studies and prospective registries use different, arbitrary liver biochemical thresholds to define what constitutes DILI. The first step in describing DILI is to differentiate idiosyncratic (unpredictable) DILI from intrinsic (predictable) DILI. The most common example

Risk Factors for DILI

Risk for DILI is complex and involves several interrelated factors. It has been suggested that DILI is more likely to occur in females, the elderly, and patients with chronic liver disease, HIV, and obesity. Many of these possibilities have come under scrutiny, and there is little empiric data available to support the validity of these factors.15 With the exception of the Icelandic and French epidemiologic studies, the study of risk factors for DILI is an imperfect science because the

Diagnosis

A patient with suspected DILI should have a careful evaluation for other forms of liver disease, especially viral hepatitides. Other forms of acute and chronic liver disease can be evaluated as outlined in the Figure. In most cases, the diagnostic steps are carried concurrently, especially if the suspected DILI is deemed to be severe. There are some important potential diagnostic pitfalls to consider when evaluating for other liver diseases. Nonalcoholic fatty liver disease is the most common

New Data on Individual Agents and Specific Formulations

In this section, we provide an update on individual agents that cause DILI. We would also like to direct the reader to a new website called LiverTox (www.livertox.nih.gov), which is sponsored by the National Institutes of Health and serves as a repository of information on drugs known to cause DILI. This database is searchable and is helpful when it is unclear as to whether an agent may be responsible for DILI or not. Other common drugs that can lead to DILI are listed in Table 2 with their

Treatment

Treatment for most forms of DILI is focused on supportive care and requires longitudinal monitoring of the patient and laboratory work. Discontinuation of the offending agent is the first step. Rechallenge is not recommended except under very rare scenarios with the input of a hepatologist. Once DILI has been diagnosed, it is important to list that drug as an “allergy” and to counsel the patient on the importance of avoiding that particular drug, and when appropriate, other drugs in its class.

Prognosis

For the vast majority of patients with DILI, full recovery is expected during the dechallenge. For patients with jaundice, this may take up to 30 to 40 days, and occasionally up to a year in those with severe cholestasis. In general, the hepatocellular injury phenotype carries a worse prognosis than do the cholestatic or mixed presentations. One of the oldest tools used for prognosis in DILI was developed by the famous hepatologist Hyman Zimmerman. His simple rule stated that a bilirubin level

Conclusion

The epidemiology of idiosyncratic DILI has become clearer with the addition of the Iceland study, demonstrating a crude annual incidence of 19 per 100,000 inhabitants. Idiosyncratic DILI is a serious problem, accounting for approximately 10% of the ALF cases in the United States. There is now a better understanding of drug-specific properties that result in the risk of DILI such as the interaction of drug dose and lipophilicity as well as the extent of hepatic metabolism. Specific host genetic

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