Suspected herbal hepatotoxicity: requirements for appropriate causality assessment by the US Pharmacopeia.

The aim of this current opinion report is to discuss relevant issues of regulatory causality assessment methods related to initially suspected herb-induced liver injury (HILI). Herbal hepatotoxicity represents a major clinical, regulatory and public challenge since its diagnosis may be difficult to be established, requiring a sophisticated approach that includes a liver-specific and validated causality assessment method. In cases of primarily suspected HILI, however, problems emerged when the US Pharmacopeia (USP) published results with causality assessments of liver disease cases. In these studies, herbal drugs and herbal dietary supplements were considered as causative products based on causality attribution by a shortened version of the Naranjo scale. However, the Naranjo scale is not liver specific and not validated for liver toxicity, and these shortcomings also apply to its shortened and thereby modified version. Consequently, these results were questioned and considered invalid, requiring re-evaluation with a liver-specific causality assessment method validated for hepatotoxicity, such as the scale of the Council for International Organizations of Medical Sciences (CIOMS) or its validated update. In essence, the USP and other regulatory agencies should apply validated liver-specific causality assessment methods rather than liver unspecific and not validated assessment methods in suspected HILI cases.