Evidence chain-based causality identification in herb-induced liver injury: exemplification of a well-known liver-restorative herb Polygonum multiflorum

Abstract

Herbal medicines have recently been recognized as the second most common cause of drug-induced liver injury (DILI) in the United States. However, reliable methods to identify the DILI causality of some herbs, such as Heshouwu (dried root of Polygonum multiflorum), remain lacking. In this study, a total of 12 307 inpatients with liver dysfunction and 147 literature-reported cases of Heshouwu DILI were screened. A general algorithm indicated that only 22.5% (9/40) and 30.6% (45/147) of all hospitalization and literature case reports, respectively, demonstrate the high probability of DILI causality of Heshouwu. By contrast, 95% (19/20) of all cases prospectively investigated by pharmacognosy, phytochemistry, and metabolomic tests exhibited highly probable causality, including a patient who was previously incorrectly attributed and a case that was excluded from Heshouwu causality by pharmacognostic evidence. Toxin (heavy metals, pesticides, and mycotoxins) contamination was also excluded from Heshouwu DILI causality. The objectivity of these screening methods for Heshouwu DILI diagnosis addresses safety concerns regarding stilbene-containing herbal medicines and dietary supplements.

Metabolomic Study on Idiosyncratic Liver Injury Induced by Different Extracts of Polygonum multiflorum in Rats Integrated with Pattern Recognition and Enriched Pathways Analysis

“…Despite a significant increase of Heshouwu-induced hepaototoxity has been reported, they occur in a minority of patients in fact by means of the retrospective statistics of medicinal liver injury cases in 302 Hospital, so that they might be idiosyncratic liver injury based on integrated evidence chain-based identification of Chinese herbal medicine (Wang et al, 2015; Zhu et al, 2016). Whereas, the traditional toxicity evaluations showed that Heshouwu treatments caused hepatotoxicity requiring more than 50∼70 times of clinical equivalent dose with continuous administration for 4∼8 weeks (Wang T. et al, 2012; Li et al, 2013; Zhang et al, 2013), resulting in difficult evaluate the hepatotoxicity of herbal medicines.…”

A Case Report of Liver and Renal Function Changes in Stroke Patients Taking Long-term Herbal Medicine

“…Currently, Heshouwu has been widely used to prevent hair loss and graying, prevent aging, and extend lifespan, which also has potential for treatment of Parkinson's disease, liver injury, hyperlipidemia, and Alzheimer's disease. However, a typical example of DILI causality determination of Heshouwu was presented by Wang et al [15]. The major active ingredient might be 2,3,5,4 -tetrahydroxy trans-stilbene-2-O--glucoside (TSG), and it was found to expand the lifespan of model organisms by activating Sirtuin 1 (Sirt1) [20,21] and cause autophagy stimulation [22].…”

“…Based on the general RUCAM assessment, Wang et al established a model for assessing HILI causality that combines translational laboratory tests with pharmacognosy, phytochemistry, and metabolomics [15,[20][21][22][23] (Figure 1). This model might improve our capability for the diagnosis and causality assessment of HILI.…”

“…Exogenous harmful substances: herbal drugs may be contaminated during growth, processing, storage, transportation, and other courses, resulting in seriously high level of herbal pesticide residues, heavy metals, and microbial toxins, which causes liver damage [38,39]. Meanwhile, inadequate processing could augment the toxic risk of the clinical usage of Radix Polygonum [15].…”

“…Overdosed drug, unconventional dosing or treatment, and improper drug compatibility may increase risk of liver damage [40]. For example, not as other well-known hepatotoxic herbs, the potential risk of Heshouwu was not fully clarified in the clinical community and therefore the hepatotoxic risk among herbs should be paid attention to in clinical practice and by regulatory administration [15]. Patients with different physical conditions, for instance, underlying chronic diseases, genetic differences, and other factors, may also have increased risk of liver damage [41].…”