Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

AIM: To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. METHODS: We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase(ALT) < 5 upper limit of normal (N) before reexposure, with Nas the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. RESULTS: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables in- cluded low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Short-comings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis Evirus infection was considered in one single patient and found positive, infections by herpes simplexvirus and varicella zoster virus were excluded in none. CONCLUSION: Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.     

Herbal hepatotoxicity:Challenges and pitfalls of causality assessment methods

The diagnosis of herbal hepatotoxicity or herb induced liver injury(HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation.At the day HILI is suspected in a patient,physicians should start assessing the quality of the used herbal product,optimizing the clinical data for completeness,and applying the Council for International Organizations of Medical Sciences(CIOMS) scale for initial causality assessment.This scale is structured,quantitative,liver specific,and validated for hepatotoxicity cases.Its items provide individual scores,which together yield causality levels of highly probable,probable,possible,unlikely,and excluded.After completion by additional information including raw data,this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation.The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases,compared to numerous other causality assessment methods,which are inferior on various grounds.Among these disputed methods are the Maria and Victorino scale,an insufficiently qualified,shortened version of the CIOMS scale,as well as various liver unspecific methods such as thead hoc causality approach,the Naranjo scale,the World Health Organization(WHO) method,and the Karch and Lasagna method.An expert panel is required for the Drug Induced Liver Injury Network method,the WHO method,and other approaches based on expert opinion,which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician.In conclusion,HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale,avoiding pitfalls commonly observed with other approaches.     

Drug and herb induced liver injury: Council for International Organizations ofMedical Sciences scale for causality assessment简

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.     

Traditional Chinese Medicine Induced Liver Injury

Traditional Chinese Medicine (TCM) is popular around the world and encompasses many different practices with particular emphasis on herbal TCM. Using the PubMed database, a literature search was undertaken to assess the extent herbal TCM products exert rare hepatotoxicity. Analysis of reported cases revealed numerous specified herbal TCM products with potential hepatotoxicity. Among these were An Shu Ling, Bai Fang, Bai Xian Pi, Ban Tu Wan, Bo He, Bo Ye Qing Niu Dan, Bofu Tsu Sho San, Boh Gol Zhee, Cang Er Zi, Chai Hu, Chaso, Chi R Yun, Chuan Lian Zi, Ci Wu Jia, Da Chai Hu Tang, Da Huang, Du Huo, Gan Cao, Ge Gen, Ho Shou Wu, Hu Bohe You, Hu Zhang, Huang Qin, Huang Yao Zi, Hwang Geun Cho, Ji Gu Cao, Ji Ji, Ji Xue Cao, Jiguja, Jin Bu Huan, Jue Ming Zi, Kamishoyosan, Kudzu, Lei Gong Teng, Long Dan Xie Gan Tang, Lu Cha, Ma Huang, Mao Guo Tian Jie Cai, Onshido, Polygonum multiflorum, Qian Li Guang, Ren Shen, Sairei To, Shan Chi, Shen Min, Shi Can, Shi Liu Pi, Shou Wu Pian, Tian Hua Fen, White flood, Wu Bei Zi, Xi Shu, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, Zhen Chu Cao, and various unclassified Chinese herbal mixtures. Causality was firmly established for a number of herbal TCM products by a positive reexposure test result, the liver specific scale of CIOMS (Council for International Organizations of Medical Sciences), or both. Otherwise, the quality of case data was mixed, especially regarding analysis of the herb ingredients because of adulteration with synthetic drugs, contamination with heavy metals, and misidentification. In addition, non-herbal TCM elements derived from Agaricus blazei, Agkistrodon, Antelope, Bombyx, Carp, Fish gallbladder, Phellinus, Scolopendra, Scorpio, and Zaocys are also known or potential hepatotoxins. For some patients, the clinical course was severe, with risks for acute liver failure, liver transplantation requirement, and lethality. In conclusion, the use of few herbal TCM products may rarely be associated with hepatotoxicity in some susceptible individuals, necessitating a stringent pretreatment evaluation of the risk/benefit ratio, based on results of multicenter, randomized, double-blind, placebo-controlled clinical trials.     

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. 2014 Baishideng Publishing Group Co., Limited. All rights     

Kava hepatotoxicity: pathogenetic aspects and prospective considerations

Kava hepatotoxicity is a well‐defined herb‐induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava‐induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ± comedication, confounding factors include non‐adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs–kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P‐glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent.     

Liver Injury from Herbal,Dietary, and Weight Loss Supplements: a Review

Herbal and dietary supplement usage has increased steadily over the past several years in the United States. Among the non-bodybuilding herbal and dietary supplements, weight loss supplements were among the most common type of HDS implicated in liver injury. While drug induced liver injury is rare, its consequences are significant and on the rise. The purpose of this review is to highlight case reports of weight loss products such as Hydroxycut and OxyElite Pro as one form of HDS that have hepatotoxic potential and to characterize its clinical effects as well as pattern of liver injury. We also propose future strategies in the identification and study of potentially hepatotoxic compounds in an effort to outline a diagnostic approach for identifying any drug induced liver injury.     

Drug- and Herb-Induced Liver Injury in Clinical and Translational Hepatology: Causality Assessment Methods,Quo Vadis?

Drug-induced liver injury (DILI) and herb-induced liver injury (HILI) are typical diseases of clinical and translational hepatology. Their diagnosis is complex and requires an experienced clinician to translate basic science into clinical judgment and identify a valid causality algorithm. To prospectively assess causality starting on the day DILI or HILI is suspected, the best approach for physicians is to use the Council for International Organizations of Medical Sciences (CIOMS) scale in its original or preferably its updated version. The CIOMS scale is validated, liver-specific, structured, and quantitative, providing final causality grades based on scores of specific items for individual patients. These items include latency period, decline in liver values after treatment cessation, risk factors, co-medication, alternative diagnoses, hepatotoxicity track record of the suspected product, and unintentional re-exposure. Provided causality is established as probable or highly probable, data of the CIOMS scale with all individual items, a short clinical report, and complete raw data should be transmitted to the regulatory agencies, manufacturers, expert panels, and possibly to the scientific community for further refinement of the causality evaluation in a setting of retrospective expert opinion. Good-quality case data combined with thorough CIOMS-based assessment as a standardized approach should avert subsequent necessity for other complex causality assessment methods that may have inter-rater problems because of poor-quality data. In the future, the CIOMS scale will continue to be the preferred tool to assess causality of DILI and HILI cases and should be used consistently, both prospectively by physicians, and retrospectively for subsequent expert opinion if needed. For comparability and international harmonization, all parties assessing causality in DILI and HILI cases should attempt this standardized approach using the updated CIOMS scale.     

Clinical and histologic features of Azathioprine-induced hepatotoxicity

Background: Hepatoxicity is a relative uncommon complication related with Azathioprine, however most studies were performed in inflammatory bowel diseases patients. The aim of this study is to report the clinical profile of patients with Azathioprine-induced hepatotoxicity.

Methods: All medical records of patients received Azathioprine from 2010 to 2015 were retrospectively reviewed. Hepatotoxicity was defined as serum alanine aminotransferase (ALT) or aspatate aminotransferase (AST) or total bilirubin >2 times upper limit normal. Other causes of liver diseases were excluded. All subjects were followed until the resolution of liver injury.

Results: Two-hundred and ninety-three patients receiving Azathioprine were retrospectively reviewed. Eight patients (2.7%) were diagnosed with Azathioprine-induced hepatotoxicity. The median age was 45 year with female preponderance. The latency to onset of liver injury ranged from 7 to 236 d, and 4 patients were symptomatic. Median peak levels were ALT 295?U/L, alkaline phosphatase 169?U/L, and total bilirubin 1?mg/dl. According to R-ratio, mixed pattern (50%) was more frequent than cholestatic (37.5%) and hepatocellular pattern (12.5%). Liver biopsies were performed in 2 patients, and showed hepatocellular and canalicular cholestasis with mild portal and peri-portal inflammation. All patients recovered fully with a median time of 41.3 days. Two patients developed prolonged cholestasis >2 months, hence none had liver failure or required liver transplantation.

Conclusion: Hepatotoxicity is relative uncommon in patients receiving Azathioprine, and predominantly is mixed hepatocellular and cholestatic in nature. Even though all patients recover fully after drug withdrawal, severe cholestasis can occur.     

231例药物性肝损伤临床分析

目的对近4年多我院收治的药物性肝损伤(DILI)患者进行回顾性分析,以提高临床医师对此病的认识。方法对2003年1月至2007年6月期间在我院就诊的231例诊断为药物性肝病的患者进行回顾性分析,并根据Maria药物性肝损伤评分标准进行评价。结果231例患者中,Maria评分≥14分者69例,10～13分119例,6～9分43例,其中抗结核药物引起的肝损伤患者依次为24例(34.78%)、72例(60.50%)及14例(32.56%)。涉及药物频率由高至低,主要为抗结核药47.62%(110/231),中草药18.61(43/231),其他抗生素7.36%(17/231),其他药物26.41%(61/231)。临床分型:肝细胞损伤型84.42%(195/231),胆汁淤积型6.49%(15/231),混合型9.10%(21/231)。结论Maria评分表在对抗结核药物引起的肝损伤进行评估时,其分值相对较低。抗结核药及中草药引起的肝损伤最为常见,应引起临床医生重视。     

Hepatotoxicity of NONI juice： Report of two cases

NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses. No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice. A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acute hepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice.     

抗结核药物所致肝损伤患者血浆MiRNA-4284水平及其临床意义探讨*

目的 探讨抗结核药物导致的肝损伤（ATDH）患者血浆微小RNA(miRNA）-4284水平变化及其临床意义。方法 在初治的200例肺结核患者,采用 WHO 推荐的标准6个月短程化学方案抗结核治疗,采用高通量实时荧光定量PCR技术检测血浆miRNA-4284水平。绘制血浆miRNA-4284水平诊断ATDH的ROC曲线,评估其诊断ATDH的效能。结果 经过6个月抗结核治疗后,发生肝功能损伤70例（35.0%）,其中肝细胞型24例,胆汁淤积型20例,混合型26例;ATDH组血浆miRNA-4284水平为（1.9±1.6）,显著高于非ATDH组的 【（0.9±0.6）,P< 0.05】;以血浆miRNA-4284水平=1.15为诊断ATDH的最佳截断点,其曲线下面积为0.71（95%CI：0.43~1.45）,诊断ATDH的敏感度为70.0%,特异度为69.9%,阳性预测值为77.8%,阴性预测值为67.4%,正确性为68.0%;经护肝治疗3个月,70例ATDH患者血清肝功能指标恢复至正常水平,而血浆miRNA-4284水平也降至（0.8±0.5）。结论 ATDH患者血浆miRNA-4284水平显著升高,在诊断ATDH和评估抗痨疗效方面具有一定的临床指导意义。     

Corticosteroid therapy in drug‐induced liver injury: Pros and cons

Drug‐induced liver injury (DILI) is a liver toxicity induced by a drug or its metabolite. The incidence of DILI continues to increase and it has been an enormous challenge worldwide, while the prognosis is not optimistic. Currently, the most effective treatment for DILI is to suspend the offending drug(s) and to avoid re‐exposure, with no definitive therapy available for idiosyncratic DILI with or without acute liver failure. Given the anti‐inflammatory effects of corticosteroids, they have been widely used in DILI in clinical practice, although their efficacy remains controversial. Several studies have shown their beneficial effects but a few reports have refuted the efficacy of corticosteroids in treating patients with DILI. In this review, we summarized the history and current status of corticosteroid use in liver diseases and the pros and cons of corticosteroid treatment in DILI, and we explored the DILI candidates who may benefit from corticosteroid therapy, the administration route and dosage, and the adverse effects related to corticosteroid use.     

Guideline review: Guideline review: EASL clinical practice guidelines: drug-induced liver injury (DILI)

The European Association for the Study of the Liver has produced extensive guidelines for the investigation and management of drug-induced liver injury. Here, we provide a commentary and overview of some of the principle disease investigations and management that arise from these guideline recommendations.