Causality assessment for liver injury attributable to dietary supplements.

Abstract

Watch a video presentation of this article Watch the interview with the author Dietary supplements (DS) have been used by Americans with remarkable consistency over the past several decades. Data from the National Health and Nutrition Examination Survey 2003 to 2006 revealed that approximately 50% of all Americans and 70% of adults aged ≥71 years used DS during the reporting period.1 DS are nonprescribed products intended to supplement the diet. They include vitamins, minerals, amino acids, and other botanicals.2 Although the use of DS remains ubiquitous, their true impact, whether beneficial or deleterious, has been difficult to define. The potential for liver injury from DS is irrefutable; however, the accuracy of diagnosis of attributable liver injury is confounded by limitations in causality assessment. The incidence of drug-induced liver injury (DILI) caused by DS remains unknown. Population-based studies have attempted to address this issue. In 2013, a study based on the Icelandic population revealed an incidence of DILI of 19.1 per 100,000 inhabitants per year; DS was the second most common cause for DILI.3 The first US population-based estimate revealed an incidence rate of 2.7 DILI cases per 100,000 adults.4 This estimate was determined by a 2014 prospective surveillance program for DILI conducted through gastroenterologists practicing in the state of Delaware. Notably, Delaware has a demographic composition closely mirroring that of the overall US population. Given the limitation to subspecialists, the true incidence of DILI is likely higher. Supplements was the second most common cause for injury, corroborating findings from the Drug Induced Liver Injury Network (DILIN).5 Although there appears to be an association between DS and DILI, their ill effects are not limited solely to the liver. An estimated 23,000 emergency department visits in the United States each year are attributed to adverse events related to DS.6 Adverse events ranged from cardiac symptoms to pill-induced dysphagia, with weight-loss products implicated in more than half of adverse events among patients 20 to 34 years of age. DILI can be a difficult diagnosis to establish because it is largely a diagnosis of exclusion. However, assessment tools have been developed in an effort to evaluate objectively the likelihood that liver injury is due to a drug. These tools have also been applied to the assessment of liver injury caused by DS. The Roussel Uclaf Causality Assessment Model (RUCAM) is commonly used in research and serves as a validated causality algorithm (Table 1).7, 8 However, this approach is not without its limitations for DS, because it was originally developed for assessing injury caused by medications. In the United States, structured expert opinion has been widely regarded as the gold standard for assessing causality and arguably may be superior to the RUCAM when applied to DS. Specifically, three of the seven RUCAM domains can be confounded by nuances unique to DS. First, the RUCAM has a limited period of ascertainment of 90 days. It is possible that a culprit DS could have been consumed for a much longer period, but changed composition, thus leading to a more toxic ingredient or mixture. Second, the risk factors for liver injury caused by DS may be different from those for drugs. For example, the patterns of use or associated behaviors surrounding use of DS may contribute to toxicity. Third, previous information on hepatotoxicity may be limited. Thus, there may be limited recognition of a product's capacity for injury or a specific injury pattern. In addition, the RUCAM does not take into account the possibility that DS adulteration, contamination, or mislabeling could account for injury. In Hong Kong, a toxicology analysis of 26 weight-loss products that were associated with adverse events (liver failure requiring transplant in one patient) was performed.9 The majority of products (15) were adulterated with analogues of sibutramine and fenfluramine. Although a causal association between the unlabeled ingredients and injury is not firm, their presence and known toxic potential raise valid concern.10 The association between DILI and DS has now long been recognized. However, there are shortcomings to the RUCAM that confound the accuracy of causality assessment and in making the association more confident. Implicating a DS depends on determining the potential toxicity of individual ingredients, or combinations thereof. Therefore, further efforts must be made to develop an assessment approach that can include chemical analysis of products, followed by validation of its hepatotoxic potential.