Original Article
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World J Hepatol. Jul 27, 2013; 5(7): 353-363
Published online Jul 27, 2013. doi: 10.4254/wjh.v5.i7.353
Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests
Rolf Teschke, Christian Frenzel, Johannes Schulze, Alexander Schwarzenboeck, Axel Eickhoff
Rolf Teschke, Alexander Schwarzenboeck, Axel Eickhoff, Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/Main, D-63450 Hanau, Germany
Christian Frenzel, Department of Medicine I, University Medical Center Hamburg Eppendorf, D-20246 Hamburg, Germany
Johannes Schulze, Institute of Industrial, Environmental and Social Medicine, Medical Faculty of the Goethe University Frankfurt/Main, D-60590 Frankfurt/Main, Germany
Author contributions: Teschke R and Eickhoff A provided substantial contributions to conception and design; Frenzel C contributed to acquisition of data; Frenzel C, Schulze J and Schwarzenboeck A contributed to analysis and interpretation of data; Teschke R and Eickhoff A contributed to drafting the article; Frenzel C, Schulze J and Schwarzenboeck A contributed to revising it critically for important intellectual content; and Teschke R, Frenzel C, Schulze J, Schwarzenboeck A and Eickhoff A contributed to final approval of the version to be published.
Correspondence to: Rolf Teschke, Professor, Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University of Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany. rolf.teschke@gmx.de
Telephone: +49-6181-21859 Fax: +49-6181-2964211
Received: January 9, 2013
Revised: June 3, 2013
Accepted: June 19, 2013
Published online: July 27, 2013
Processing time: 196 Days and 12.9 Hours
Abstract

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 N as 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 included 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. Shortcomings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis E virus infection was considered in one single patient and found positive, infections by herpes simplex virus 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.

Keywords: Herbalife hepatotoxicity; Herbalife induced liver injury; Herbal hepatotoxicity; Herb induced liver injury; Herbs

Core tip: Our analysis focuses on published cases of suspected Herbalife hepatotoxicity with positive reexposure tests and high causality gradings. Problems included poorly fulfilled test criteria, numerous confounding variables, and the use of liver unspecific, obsolete causality assessment methods. Submitting the case data to well established criteria for positive reexposure tests, the test was positive in 1/8 cases and negative or uninterpretable in the other cases. Using the liver specific Council for International Organizations of Medical Sciences scale, causality was probable in 1 case, unlikely and excluded in the other cases. Thus, causality levels were much lower than hitherto proposed.