Important elements for the diagnosis of drug-induced liver injury

Abstract

Background & aims: Drug-induced liver disease is the leading cause of acute liver failure in the United States. Accurate reporting of drug-induced liver injury is essential for early detection of hepatotoxicity and for developing reliable, interpretable literature. We assessed the extent to which published case reports of drug-induced liver disease include sufficient clinical data for interpreting the cause of toxicity.

Methods: We developed a list of 42 predetermined, specific minimal elements necessary in evaluating causality of drug-induced liver injury. We then analyzed 97 published case reports or series studies of hepatotoxicity from 6 drugs (from 3 classes): amoxicillin/clavulanic acid (n = 35), troglitazone (n = 32), rosiglitazone (n = 10), pioglitazone (n = 8), zafirlukast (n = 8), and montelukast (n = 4).

Results: Patient age, sex, primary disease, and drug name were reported in most, if not all, published case reports. However, many elements were underreported; some publications did not mention initial bilirubin levels (12%), many did not provide initial alkaline phosphatase levels (58%), and others provided vague descriptions of how certain diagnoses were excluded, that is, tests for hepatitis A, B, and C were negative. Data on abnormal results from serial liver tests frequently were absent. Exclusions of competing viral etiologies were reported in less than 50% of the studies.

Conclusions: Reports of drug-induced liver diseases often do not provide the data needed to determine the causes of the adverse effects. Efforts to promote and include a list of essential diagnostic elements in research articles could increase the quality and clinical utility of published case reports of drug toxicity.

Figure 1. Exclusion of a Competing Viral Etiology

Among 97 published case reports of drug-induced liver disease related to specific drugs, fewer than half specified whether competing viral etiologies were excluded. “Viral Screen Negative” represents percent of cases for which results of tests for competing etiology were vaguely reported (for example, “tests for hepatitis A, B, and C were negative”). ALT, alanine aminotransferase; ANA, antinuclear antibody; AP, alkaline phosphatase; HAV, hepatitis A virus; HBc, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.

Figure 2. Minimal Elements Reported in Published Case Reports of Hepatotoxicity with Thiazolidinediones

Reports were regarding troglitazone (n= 32), rosiglitazone (n= 10), and pioglitazone (n= 8). “Re-challenge” refers to whether a re-challenge with the same medication was reported as being done or not. ALT, alanine aminotransferase; ANA, antinuclear antibody; AP, alkaline phosphatase; HAV, hepatitis A virus; HBc, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.

Figure 3. Minimal Elements Reported in Published Case Reports of Hepatotoxicity with Leukotriene Receptor Antagonists

Reports were regarding zafirlukast (n=8) and montelukast (n= 4). “Re-challenge” refers to whether a re-challenge with the same medication was reported as being done or not.

Figure 4. Minimal Elements Reported in Published Case Reports of Hepatotoxicity with Amoxicillin/Clavulanic Acid (n = 35)

“Re-challenge” refers to whether a re-challenge with the same medication was reported as being done or not.