Drug-induced liver injury associated with Complementary and Alternative Medicine: a review of adverse event reports in an Asian community from 2009 to 2014

AERs were submitted to the VCB of the HSA through the “Suspected Adverse Drug Reactions” form. The form contains multiple fields for entry by the health care professional or company reporting the adverse event, such as the patient’s demographic information, reporter’s details, details of the AE or ADR, management of the adverse event, as well as other relevant information. These reports were submitted by e-mail, facsimile, postal mail, or electronically through the Critical Medical Information Store (CMIS) component of the Electronic Medical Record Exchange (EMRX).

Submitted forms were reviewed by regulatory specialists of the VCB. These reports were examined for causality of the suspected drug or herb. Any information that was lacking or unclear were clarified with the reporters, and documented accordingly. All related materials and documents to each report were stored within the Pharmaceutical Regulatory Information System (PRISM) database. The information was also used in aggregate analysis. As a member of the World Health Organisation (WHO) International Drug Monitoring Programme, these reports are submitted to the Uppsala Monitoring Centre (UMC) in Sweden for collation into WHO’s VigiLyze [33].

Adverse event(s) in each report were categorised using the WHO Adverse Reaction Terminology (WHO-ART). Filters were used to obtain the desired reports for the review. The System Organ Class chosen was “Liver and Biliary System Disorders”. “Complementary Medicines”, “CPM”, and “Health Supplements” were selected as the type of product involved, and the inclusion period was from 1st January 2009 to 31st December 2014 based on the date of receipt of the AER by the VCB. The WHO-UMC organisation system for standardised case causality assessment was also used. Only reports with the causality terms “certain”, “probable” or “possible”, as assessed by the VCB, were included for analysis. Reports that were associated with adulterated CAM products, assessed by the VCB as “unlikely” or “unconfirmed”, or had missing critical information such as ingredient lists or names of products, were excluded from the study. The statuses of all reports are updated as of 31st Jan 2015.

The following information were extracted from the reports and compiled into a Microsoft^® Excel spreadsheet: (1) Demographic information (i.e. age, gender, and ethnicity); (2) Date of onset and time to onset for the adverse event; (3) Hospitalisation status of the patient; (4) Outcome of the adverse event; (5) Type of hepatotoxicity involved; (6) Ingredients of all CAM products used, and the TDD of each ingredient; (7) Details of any concurrent western medicines; and (8) Profession of the reporter.

Hospitalisation status of the patients were categorised as “hospitalised”, “not hospitalised” and “already hospitalised”. The term “already hospitalised” describes patients who have been admitted for other co-morbidities prior to the adverse event. The outcomes of the events were classified into “recovered”, “not yet recovered”, “uncertain outcome” and “death”. The type of hepatotoxicity in the cases were classified according to the phenotypes of DILI, as described in the LiverTox database by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [34]. A brief description of the different phenotypes is shown in Table 1. Western medicines that were consumed by the patient at the same time or within 3 months before the date of receipt of AER were considered as concomitant medications. To ascertain the likelihood of DILI in the cases for review, only CAM products that were used within the 3-month period prior to the date of receipt of AER were considered for analysis. The variables collected from the AERs were analysed using descriptive statistics.

Amongst the CAM ingredients compiled, those suspected to be associated with hepatotoxicity, either through expert opinion from the VCB or from previous documented reports in established databases such as LiverTox and the China Food and Drug Administration (CFDA), were further examined in detail. References to tertiary literature such as the Chinese Pharmacopoeia and textbooks on complementary medicines were also made. The RUCAM [27, 28] was employed to review the likelihood of these ingredients causing hepatotoxicity in the patients. The updated version of RUCAM was used to calculate the scores of the case reports [35, 36]. For cases with concomitant western medicines reported, the RUCAM was also used to evaluate the causality of those medicines with documented evidence of hepatotoxicity in the literature.

There was no difference in the gender distribution of the AERs. This is opposed to previous findings that women were more likely to be affected by adverse reactions to drug treatment [39, 54, 55]. Differences in endogenous and exogenous hormones, body size and fat compositions, and also liver metabolism were cited as possible reasons for the gender differences. A woman’s reproductive function may also increase the need for medications at an earlier age than men, increasing the likelihood of adverse drug reactions [55]. In this study, the small sample size of 57 reports may be insufficient to conclude whether there are any gender differences predisposing to hepatotoxicity. Furthermore, only one patient used CAM to regulate menstruation, and none for contraceptive or reproductive purposes.

Majority (73.7 %) of the patients were above 40 years of age, and there was no significant differences (p = 0.755) in the gender distribution in this age group (19 males, 23 females). Age has been cited as a risk factor for hepatotoxicity due to the increased likelihood of comorbid conditions and deteriorating organ function, especially the liver [41, 56]. Therefore it is not unexpected that a large proportion of cases involved patients above 40 years old. Nonetheless, under-reporting of DILI is still a prevalent phenomenon in many countries [57, 58] and the demographic characteristics of patients in this study may not accurately reflect those found in prospective cohort studies of DILI.

The proportions of different types of CAM used were similar to other studies conducted in Singapore [17, 59, 60]. TCM accounted for the majority of CAM usage, followed by health supplements, regardless of ethnicity.

TCM, was implicated in 61.4 % of the adverse events. The major affected ethnic group was the Chinese (82.5 %). These findings are congruent with the earlier review of AERs associated with complementary medicines and health supplements [21]. The study found that CPMs and Chinese patients were more commonly implicated in adverse events than other CAMs and ethnic groups. The reason for these similar findings could be attributed to the widespread availability and relatively easy accessibility of TCM products in Singapore where the population is 80 % of Chinese ethnicity.

Among the 35 cases involving TCM products, RUCAM scores were calculated for 29 (82.9 %), with a median score of 4 and range of 1 to 8. Only Chinese herbal ingredients that were previously reported in the literature as possibly risky for liver injury (Table 5) were assessed for causality. The range of scores indicates causalities of unlikely, possible or probable. None of these cases had a score of 0 or less, which suggests that the likelihood of hepatotoxicity for these TCM cannot be entirely ruled out. Notwithstanding the range of scores obtained for these 29 cases, a proper evaluation of causality for these DILI cases was challenging and hard to ascertain.

In addition, most of the patients used at least ten different ingredients, and the duration of use ranged from a few months to 3 years. The use of multiple products over an extended period of time could have produced a heavy metabolic burden on the liver. This could predispose the patients to acute liver injuries, regardless of the presence of potentially hepatotoxic ingredients.

Chinese herbal ingredients taken at recommended doses by the Chinese Pharmacopoeia typically do not present harm to the liver, though it is unclear whether prolonged use or abrupt changes in the dosage can precipitate hepatotoxicity. In this study, most of the TCM ingredients were used within their recommended dose ranges. There were two patients that used a number of ingredients beyond their recommended daily doses; some examples were Dang Gui (Radix angelicae sinensis), Dang Shen (Radix codonopsis) and Chai Hu (Radix bupleuri). Among these ingredients, only Chai Hu was previously reported in the literature as potentially hepatotoxic [37, 43, 47, 61]. However, due to the advanced age of both patients (70 and 83 years old), coupled with the use of numerous herbal products over a prolonged period, it was hard to pinpoint specific agents that could have caused DILI.

Accurate naming of the correct plant species and specific plant part is also crucial for an appropriate assessment. Unfortunately, AERs rarely provide sufficient details on the plant family, subfamily, species, subspecies or variety used. This specification is necessary as hepatotoxic chemicals may be distributed unevenly throughout some plants [62]. For example, if rhizomes of a plant are prescribed, additional clarification is needed on whether the peeled or unpeeled rhizome was used, the extent of peeling, as well as whether any adjacent parts were included in the herbal product. The degree of processing may also influence the toxicity of a plant species, such as He Shou Wu (Radi polygoni multiflori), where the processed form (Zhi He Shou Wu [Radix polygoni multiflori praeparata]) would be less hepatotoxic and higher daily doses could be recommended. Variations in these aspects could have affected the toxicity potential of different formulations, and in turn influence the outcome of causality assessments [44].

With the regulation of CPMs in Singapore, many of these factors influencing the accuracy of herbal hepatotoxicity assessments can be mitigated to a certain extent. The processes of listing CPM products for regulatory approval ensures manufacturers and importers accurately report the specific ingredients and amounts within each product [63]. Requirements on labelling, prohibited claims, types of test reports, quality parameters are needed before a CPM can be listed.

As no CPM is 100 % safe, DILI can occur with no plausible explanations. For example, the Chinese herbal plant Chai Hu (Radix bupleuri) is traditionally used to treat liver-related conditions such as jaundice, and is said to disperse liver ‘qi’ stagnation and reduce dampness. However, Chai Hu had been implicated in multiple cases of acute hepatitis both as an ingredient alone and within a particular formulation “Xiao Chai Hu Tang” (also known as Syo-Saiko-To in Japanese) [37, 43, 47, 61]. The incidences had been linked to the consumption of Chai Hu for prolonged periods of time, even at therapeutic doses, and evaluated as possible to probable causality. Additionally, the mentioned reports ruled out other possible causes of liver injury, as well as any quality and manufacture issues of the Chai Hu-containing products. In this study, 11 cases with Chai Hu as one of the suspected ingredients were identified. The mean TDD was 18.0 ± 33.5 g, which was more than the Chinese Pharmacopoeia recommended range of 3 to 10 g. However, there was a large variability in the TDD among the 11 cases, with minimum and maximum daily doses of 0.2 g and 100 g respectively. Differences in the clinical course and presence of confounders in the cases could have complicated the evaluation process and made it difficult to establish a general observation. Therefore, the likelihood of hepatotoxicity with Chai Hu could not be adequately addressed.

Another patient, where a causality assessment of “certain” was assigned, experienced abdominal pain, poor appetite, dark coloured urine and malaise for about 10 days, after taking TCM for about 1 month. She was advised to discontinue the TCM products because of the possibility of DILI. About 6 months later, she took TCM once again and developed liver injury after 3 days of consumption. Investigations did not establish any abnormal aetiology and the hepatitis resolved after supportive treatment. The temporal relationship on multiple occasions, along with the exclusion of other possible causes, gave a strong indication of possible TCM-induced DILI. However, due to the wide range of herbal ingredients which the patient was taking, it was difficult to pinpoint any exact causative agents, making any conclusive assessment highly challenging.

DILI remains poorly understood and are often neglected. The limited body of knowledge presents a major clinical and regulatory challenge for appropriate assessment of causal factors. Although expert opinion from clinicians and regulatory authorities remain the mainstay for conducting evaluations, more objective methods such as probability scales and mathematical models may be necessary to supplement causality evaluation [24]. A recent review of systematic reviews involving DILI associated with CAM had shown the importance of including case reports and series in these reviews, in order to obtain a more holistic interpretation of the available evidence [64].

It was necessary to rule out the influence of western pharmaceuticals with reported hepatotoxicity in the literature. Sixteen out of the 57 cases were reviewed for confounding effects by western medicines. The RUCAM was used for 10 of these 16 cases, and the median score was 1 (range: 0 to 5). RUCAM scores were not computable for the remaining 6 cases due to a lack of information. Among the 10 cases, there was only one case with a score of 5, while the scores for the other 9 were from 0 to 2. This means that for most of the cases, causality for the western medicines were either excluded or unlikely. From these observations, it was unlikely that the western medicines used attributed to the adverse reactions reported.