Albrecht Wolff

Herbal hepatotoxicity: a tabular compilation of reported cases

Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide.

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.

Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved.

Black cohosh hepatotoxicity: quantitative causality evaluation in nine suspected cases.

Objective: Black cohosh (BC), synonym for Actaea racemosa and Cimicifuga racemosa, is a herbal remedy for the treatment of menopausal symptoms. Recently, worldwide discussions have emerged as to whether its use may be associated with the risk of rare hepatotoxicity in a few susceptible women. Methods: We have evaluated the causal relationship in nine cases with suspected hepatotoxicity by the use of BC. The updated Council for International Organizations of Medical Sciences scale was used to quantitatively assess the causality for BC. Results: In eight of nine patients with liver disease, causality for BC ± comedication was excluded (n = 4) or unlikely (n = 4). The failure to ascribe causality in these cases was mainly due to alternative diagnosis, missing temporal association and dechallenge, and presentation of low quality data. In only one case, causality was possible for a BC preparation of an unknown brand taken for 2 months with an unknown daily dose. Confounding factors in this case include symptomatic cholelithiasis and fatty liver. Comedication with synthetic drugs and herbal or other dietary supplements was reported in five of nine patients. Conclusions: In nine cases of patients with liver disease, causality for BC ± comedication was possible (n = 1), unlikely (n = 4), or excluded (n = 4). Due to this lack of significant circumstantial evidence, the present study shows little, if any, hepatotoxic risks by the use of BC in the analyzed cases.

Traditional Chinese Medicine and herbal hepatotoxicity: a tabular compilation of reported cases

Traditional Chinese Medicine (TCM) with its focus on herbal use became popular worldwide. Treatment was perceived as safe, with neglect of rare adverse reactions including liver injury. To compile worldwide cases of liver injury by herbal TCM, we undertook a selective literature search in the PubMed database and searched for the items Traditional Chinese Medicine, TCM, Traditional Asian Medicine, and Traditional Oriental Medicine, also combined with the terms herbal hepatotoxicity or herb induced liver injury. The search focused primarily on English-language case reports, case series, and clinical reviews. We identified reported hepatotoxicity cases in 77 relevant publications with 57 different herbs and herbal mixtures of TCM, which were further analyzed for causality by the Council for International Organizations of Medical Sciences (CIOMS) scale, positive reexposure test results, or both. Causality was established for 28/57 different herbs or herbal mixtures, Bai Xian Pi, Bo He, Ci Wu Jia, Chuan Lian Zi, Da Huang, Gan Cao, Ge Gen, Ho Shou Wu, Huang Qin, Hwang Geun Cho, Ji Gu Cao, Ji Xue Cao, Jin Bu Huan, Jue Ming Zi, Jiguja, Kudzu, Ling Yang Qing Fei Keli, Lu Cha, Rhen Shen, Ma Huang, Shou Wu Pian, Shan Chi, Shen Min, Syo Saiko To, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, and Zhen Chu Cao. In conclusion, this compilation of liver injury cases establishes causality for 28/57 different TCM herbs and herbal mixtures, aiding diagnosis for physicians who care for patients with liver disease possibly related to herbal TCM.

Herbal traditional Chinese medicine and its evidence base in gastrointestinal disorders

Herbal traditional Chinese medicine (TCM) is used to treat several ailments, but its efficiency is poorly documented and hence debated, as opposed to modern medicine commonly providing effective therapies. The aim of this review article is to present a practical reference guide on the role of herbal TCM in managing gastrointestinal disorders, supported by systematic reviews and evidence based trials. A literature search using herbal TCM combined with terms for gastrointestinal disorders in PubMed and the Cochrane database identified publications of herbal TCM trials. Results were analyzed for study type, inclusion criteria, and outcome parameters. Quality of placebo controlled, randomized, double-blind clinical trials was poor, mostly neglecting stringent evidence based diagnostic and therapeutic criteria. Accordingly, appropriate Cochrane reviews and meta-analyses were limited and failed to support valid, clinically relevant evidence based efficiency of herbal TCM in gastrointestinal diseases, including gastroesophageal reflux disease, gastric or duodenal ulcer, dyspepsia, irritable bowel syndrome, ulcerative colitis, and Crohns disease. In conclusion, the use of herbal TCM to treat various diseases has an interesting philosophical background with a long history, but it received increasing skepticism due to the lack of evidence based efficiency as shown by high quality trials; this has now been summarized for gastrointestinal disorders, with TCM not recommended for most gastrointestinal diseases. Future studies should focus on placebo controlled, randomized, double-blind clinical trials, herbal product quality and standard criteria for diagnosis, treatment, outcome, and assessment of adverse herb reactions. This approach will provide figures of risk/benefit profiles that hopefully are positive for at least some treatment modalities of herbal TCM. Proponents of modern herbal TCM best face these promising challenges of pragmatic modern medicine by bridging the gap between the two medicinal cultures.

The mystery of the Hawaii liver disease cluster in summer 2013: A pragmatic and clinical approach to solve the problem.

BACKGROUND AND AIM In the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis. MATERIAL AND METHODS To further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions. RESULTS We noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster. CONCLUSIONS Thus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP.BACKGROUND AND AIM In the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis. MATERIAL AND METHODS To further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions. RESULTS We noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster. CONCLUSIONS Thus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP.

USP suspected herbal hepatotoxicity: Quality of causality assessment is more important than quantity of counted cases, not vice versa

Dear Editor, We appreciate the actual commentary by Prof. Mahady and her colleagues1 from the US Pharmacopeia (USP) regarding our report2 because they hereby confirm that the scale of the Council for International Organizations of Medical Sciences (CIOMS) is better suited than the Naranjo scale for assessing reports of liver damage1. Their respective statements and adjustments are indeed a real breakthrough in the longstanding discussion around the use of the appropriate causality assessment method. They now support the views of others who dismissed before the preferential use of the Naranjo scale by USP2–9 regarding black cohosh (BC)10 and green tea extract.11 In future, we therefore prefer causality assessments performed by USP and other pharmacovigilance centers with the scale of the original CIOMS,12 or better the updated CIOMS,13 rather than the Naranjo scale.2,8 Nevertheless, their six-point commentary contains several procedural errors and flaws in the course of their other considerations.

Rare statin hepatotoxicity: Convincing evidence based on breakthrough case study

unlikely to apply to statin hepatotoxicity since prerequisites such as short duration of exposure of 1–5 weeks, features of overt hypersensitivity, and prompt response to re-exposure with 1–2 doses [5] are not apparent in the reported cases [1]. However, the metabolic subtype with items of variable duration of exposure of one week up to 12 months, the absence of clinical features of hypersensitivity such as rash, fever, and eosinophilia, and the delayed response to rechallenge of many days or weeks [5] best fit with cases of idiosyncratic statin hepatotoxicity [1]. The diagnosis of liver injury by drugs and herbs is often cumbersome to establish, because surrogate markers are lacking [6] and new sophisticated diagnostic approaches have not yet reached the clinical area [7,8]. This is why alternative diagnoses were found and were described in details in numerous hepatotoxicity studies upon thorough causality assessment, as summarized previously [6,9]. In the present study [1], however, primarily missed alternative diagnoses were not mentioned and should have been provided, because this information is helpful also as a reminder to clinicians to evaluate the various differential diagnoses that may otherwise easily be overlooked. For reasons of transparency, also listed details of individual CIOMS items for each case with a highly probable or probable causality for statins would have been appreciated. These few suggestions should not detract from the excellent quality of this highly appreciated statin hepatotoxicity report [1], as will not by no means the associated and somewhat irritating editorial comment that tries to justify ex post own previous unsustainable confusing statements and detracts from the actual topic of statin hepatotoxicity existence [10]. Essentially, this breakthrough case study provides convincing evidence for the existence of rare statin hepatotoxicity and will certainly facilitate assessments of patients with primarily suspected toxic liver injury associated with the use of statins. Statin hepatotoxicity is due to idiosyncrasy of the metabolic subtype, occurs unpredictably and independently of the dose, and is not preventable. Early recognition and statin discontinuation are mandatory for risk management to improve overall prognosis.

Is obesity rather than the dietary supplement used for weight reduction the cause of liver injury?: Obesity and liver injury

Acute liver injury has been attributed to dietary supplements (DS) used for weight loss, but their causal role was much questioned, and obesity as an alternative cause of the liver injury remained unclear. A comprehensive search of the Medline database was conducted with terms that included “DS,” “liver injury,” “obesity,” “obesity‐related liver diseases,” and “nonalcoholic steatohepatitis.” For each term, we focused on the first 50 publications. We undertook a manual search to identify additional reports. Underlying liver diseases and other health issues are common in patients taking DS for weight reduction. These include obesity or morbid obesity, as well as complex metabolic disorders complicated by excess morbidity and mortality due to associated liver diseases. Among these are nonalcoholic fatty liver disease with potential progression to nonalcoholic steatohepatitis and cirrhosis, often classified as cryptogenic with a rare risk of hepatocellular carcinoma. With the exception of hepatocellular carcinoma, these obesity‐related liver diseases were observed to varying degrees in patients, and some even required a liver transplant. This raises the question whether the liver injury that occurred in these patients is due to DS consumed for weight loss or to the underlying obesity‐related liver diseases. This analysis showed that, in many instances, the causal role of obesity has been neglected. Obesity‐associated liver diseases should be considered as differential diagnosis of liver injury in obese patients using DS.

Liver Injury from Herbs and “Dietary Supplements”: Highlights of a Literature Review from 2015 to 2017

Purpose of the ReviewTo present highlights of recent liver injury from herbs and “dietary supplements,” based on a literature review from 2015 to 2017.Recent findingsChallenging are quality issues of herb and dietary supplements (HDS) products, influenced by the circadian clock system in plants that controls many important metabolic pathways including photosynthesis and molecular processes of gene expression. Important also is plant stress, caused by pathogen attacks, heavy UV radiation, draft, soil contamination by salts or heavy metals, involving oxidative stress through generation of free radicals including reactive oxygen species (ROS), damaging the plant’s integrity. Finally, expectations are high if physicians publish case reports of HDS liver injury using the Roussel Uclaf Causality Assessment Method (RUCAM), but intentional overscoring of causality gradings must be resisted. In critical situations, reevaluation of original case data was a good approach clarifying divergencies.SummaryPlant stress impairs the quality of herbs, requiring better understanding of plant physiology, and clinical liver injury cases need better causality assessment using RUCAM.