Traditional Chinese Medicine (TCM) and Herbal Hepatotoxicity: RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs

Abstract

Background: Traditional Chinese Medicine (TCM) with its focus on herbal use is popular and appreciated worldwide with increased tendency, although its therapeutic efficacy is poorly established for most herbal TCM products. Treatment was perceived as fairly safe but discussions emerged more recently as to whether herb induced liver injury (HILI) from herbal TCM is a major issue; Methods: To analyze clinical and case characteristics of HILI caused by herbal TCM, we undertook a selective literature search in the PubMed database with the search items Traditional Chinese Medicine, TCM, alone and combined with the terms herbal hepatotoxicity or herb induced liver injury; Results: HILI caused by herbal TCM is rare and similarly to drugs can be caused by an unpredictable idiosyncratic or a predictable intrinsic reaction. Clinical features of liver injury from herbal TCM products are variable, and specific diagnostic biomarkers such as microsomal epoxide hydrolase, pyrrole-protein adducts, metabolomics, and microRNAs are available for only a few TCM herbs. The diagnosis is ascertained if alternative causes are validly excluded and causality levels of probable or highly probable are achieved applying the liver specific RUCAM (Roussel Uclaf Causality Assessment Method) as the most commonly used diagnostic tool worldwide. Case evaluation may be confounded by inappropriate or lacking causality assessment, poor herbal product quality, insufficiently documented cases, and failing to exclude alternative causes such as infections by hepatotropic viruses including hepatitis E virus infections; Conclusion: Suspected cases of liver injury from herbal TCM represent major challenges that deserve special clinical and regulatory attention to improve the quality of case evaluations and ascertain patients' safety and benefit.

Keywords: HLA; RUCAM; Traditional Chinese Medicine; diagnostic biomarkers; herbal TCM hepatotoxicity; metabolomics; microRNA; microsomal epoxide hydrolase; pyrrole-protein adducts; pyrrolizidine alkaloids.

Figure 1

Publications in PubMed reporting RCT (randomized controlled trial) studies of herbal TCM. Reports from 1990 to 2015 (search: “TCM herbs AND randomized controlled trial”, accessed on 26 April 2016).

Figure 2

Adulteration of Han Fan Ji for Guang Fang Ji in Belgium [45,46,47].

Figure 3

Case classification of liver injury due to herbal TCM, adapted from previous reports [50,60].

Figure 4

Classification of liver injury and its pattern. Adapted from a previous report, which provides additional information [51]. ALP: from hepatic origin. ALP, alkaline phosphatase; ALT, Alanine aminotransferase; N, Upper limit of normal; R, Ratio; RUCAM, Roussel Uclaf Causality Assessment Method.