Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

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 ORIGINAL ARTICLE

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

“…In other spontaneous case collections, initial ALT values were available in 5/24 cases (21%) [35] , 19/22 cases (86%) [37] , 12/15 cases (80%) [38] , and 7/13 cases (54%) [39] . The corresponding figures for ALT in published case reports of HILI were 16/16 cases (100%) [35] , 21/21 cases (100%) [32] , and 5/8 cases (63%) [33] . ALT values were included in DILI reports for amoxicillin/clavulanic acid, troglitazone, pioglitazone and montelukast in 11% to 88% of the cases, which were not further scored for causality by the Drug Induced Liver Injury Network (DILIN) [6] .…”

“…Assessment is best started on the day of suspecting DILI or HILI, with a continuous update of the required data and a change in the diagnostic and therapeutic concept if needed. Finally, a complete data set for presentation to regulatory agencies, expert panels and eventually for publication is obtained [24,[30][31][32][33] , including a checklist with additional data helpful in overall case evaluation and causality assessment (Table 3). Therefore, the CIOMS scale should be considered as a standard for causality assessment of DILI and HILI, both for the attending physician and later evaluation stages.…”

“…Hepatobiliary sonography was supplemented by color Doppler sonography, including assessments of the liver vessels, endosonography, computed tomography (CT) and magnetic resonance cholangiography (MRC), if these tests were indicated clinically (Tables 1 and 2). For comparison and method validation, causality has been evaluated in 101 hepatotoxicity cases by both the original and updated CIOMS scales, with identical causality results published in 6 studies [32,33,[36][37][38][39] . Therefore, the updated CIOMS scale was validated and there is no need for further validation of the updated CIOMS scale versus the original CIOMS scale.…”

Critical Evaluation for Alternative Causes of Drug Induced and Herbal Induced (DILI/HILI) Hepatotoxicity

“…Certain events also appear to have been more likely associated with pre-existing etiologies amongst these cases (e.g. use of known hepatotoxic medications, viral hepatitis, and alcoholism) [2] [3].…”

Considerations regarding the alleged association between Herbalife products and cases of hepatotoxicity: a rebuttal

“…Regarding the case series from Israel, Switzerland, Spain, Argentina and Iceland, Teschke et al [5] have addressed a number of the relevant issues concerning the problem of causality assessment and rechallenge. In our review, published before these articles were available, we referred only to the already reported cases identified by widely used causality assessment scores as probable, avoiding a discussion of their reliability.…”