Hepatitis associated Hepatol ; Causality assessment of adverse reactions to drugs-I. Physical examination showed a conscious and oriented patient with no neurological impairment. Camellia sinensis dried etanolic extract. Hepatotoxicity of herbal remedies. To conclude, knowing that J.
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All rights reserved. This article has been cited by other articles in PMC. 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.
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 virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. 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.
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. 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. These reports created safety concerns and led to editorials[ 11 - 13 ], commentaries[ 14 - 16 ], and critical Letters to the Editor[ 17 - 27 ], all addressing relevant issues[ 11 - 27 ].
Speculations about bacterial contamination with Bacillus subtilis in Herbalife products emerged[ 8 , 12 ], and potentially hepatotoxic ingredients such as green tea extracts, ephedra sinica, aloe, or vitamin A overdose have been proposed as culprits[ 2 - 4 , 10 ]. In addition, overall case data quality was mixed due to confounding variables, missing firm exclusion of alternative explanations, and the use of problematic causality attribution methods[ 1 - 10 ].
When adjusted for case duplications, Herbalife hepatotoxicity was suspected in 53 cases[ 1 - 10 ]. Among these were eight cases with high causality gradings for Herbalife products because of positive unintentional reexposure tests, though criteria to evaluate reexposure tests were not presented[ 1 - 5 ].
A positive reexposure test is commonly considered as gold standard to establish causality for hepatotoxicity[ 1 - 5 , 31 - 35 ], provided specific and well established criteria are fulfilled[ 31 - 34 ].
In this study, case data with assumed Herbalife hepatotoxicity and a positive unintentional reexposure test were reevaluated for fulfilment of specific and well established reexposure criteria and for liver specific causality assessments.
Details were provided in case reports and case series of hepatotoxicity with assumed causal relationship to Herbalife products. In eight patients, a positive reexposure test with Herbalife was reported[ 1 - 5 ] with causality levels of highly probable[ 1 ], certain[ 2 , 3 ], likely and certain[ 4 ], and definite and probable[ 5 ]. These eight cases represented the study group. Methods All data sets of the eight patients with suspected Herbalife hepatotoxicity and positive reexposure tests were analyzed for specific criteria to establish a positive test result according to the conclusions of an international consensus meeting[ 31 ].
Some prerequisites are necessary to ensure transparency and reproducibility of this method. Second, during reexposure the ALT value must be at least doubled as compared to the baseline ALT value before reexposure. Only when both criteria are met, a positive reexposure test can be assumed, otherwise the test is negative; the test is uninterpretable, if required information is not presented.
Causality assessment methods as reported in the eight Herbalife cases were evaluated in detail. Subsequently, causality was reevaluated using the quantitative, liver specific and structured CIOMS scale validated for hepatotoxicity[ 32 ] and its update as algorithm for hepatotoxicity causality assessment[ 34 ]. To differentiate between the hepatocellular, cholestatic or mixed hepatocellular-cholestatic type of hepatotoxicity, serum ALT and ALP values are to be evaluated on the day the diagnosis of Herbalife hepatotoxicity was suspected.
The female: male ratio was Two patients originated from Switzerland cases 1 and 5 , three patients from Israel cases , one patient from Iceland case 6 , and two patients from Spain cases 7 and 8. Outcome was favourable in all patients. Table 1 Clinical data of all eight patients with liver disease and a reported positive reexposure test by Herbalife products Patient Specific information for each individual patient 1 Hoffmann et al[ 1 ], 63 yr female Herbalife product of unknown daily dose for several weeks.
BMI Intended weight loss of 14 kg within the past 3 mo. Loss of appetite, nausea, vomiting, and abdominal crampy pains for 2 wk prior to first presentation with increasing jaundice, pale stool and dark urine, transient urticarial exanthema. Pancreatitis not excluded. Difficult assessment conditions: abdominal ultrasound showed cholecystolithiasis, but number of stones and exclusion of cholecystitis and bile duct obstruction not reported, and magnetic resonance cholangiography not performed.
Liver histology with acute cholestatic hepatitis, inflammatory biliary lesions, confluent necroses, and eosinophilic infiltration. For the first clinical episode, therefore, synthetic drugs, Herbalife, symptomatic cholecystolithiasis with crampy abdominal pains and possible transient choledocholithiasis, or an incipient overlap syndrome may have been responsible; for the second episode, Herbalife, the biliary disease, and an incipient overlap syndrome remain as culprits.
For Herbalife, CIOMS 7 points Final diagnosis: Probable Herbalife hepatotoxicity, symptomatic biliary stone disease, or incipient overlap syndrome as less probable alternatives 2 Elinav et al[ 2 ], their case 1, 55 yr female Herbalife products of unknown daily dose for 6 mo. Comedication: aspirin, metformin for non-insulin dependent diabetes mellitus, statins for hyperlipidemia.
Following first exposure, medications and Herbalife were stopped, resulting in complete recovery without any described details. One month after Herbalife reuse, a second flare of hepatitis was reported without any details, except that steroid treatment was initiated, which modulated the natural course.
Together with Herbalife cessation, this resulted in complete recovery. Normal abdominal ultrasound. Comedication: alpha adrenergic blocker for hypertension of unknown daily dose and treatment duration.
Resolving hepatitis following Herbalife cessation, but missing supportive data. A month after discharge reuse of Herbalife with a second episode, but liver values or further details not communicated. Liver histology: hepatocellular hepatitis. Comedication: biphosphonates and aspirin of unknown daily dose and duration, background illness psoriasis and non insulin dependent diabetes mellitus. A second hepatitis flare developed after Herbalife reuse, but details not provided except that the hepatitis was unresolved at the time of manuscript submission.
Painless jaundice as symptom. Data for abdominal ultrasound not reported. Patient recovered from the first episode, but details of ALT values not provided and Herbalife cessation not communicated. At a second episode of jaundice, positive hepatitis E IgG antibodies.
Liver histology showed acute hepatitis with dense neutrophilic and lymphocytic infiltration, multiple apoptotic bodies, and discrete endophlebitis of central veins. The pathologist considered these findings compatible with hepatitis E.
Histology at a third episode showed also fibrosis and incomplete cirrhosis. Only after this third episode, the patient was advised to stop his intake of Herbalife products. Between the three episodes and around a fourth episode, normalization of ALT has never been documented, nor a real reexposition after a period of Herbalife cessation.
Thus, chronic hepatitis E with incomplete cirrhosis and undulating liver values is the more likely diagnosis rather than Herbalife hepatotoxicity.
BMI unknown. Abdominal pain and jaundice as symptoms with a latency period of mo. Comedication: bupropion of unknown daily dose for 20 d.
After stopping Herbalife and bupropion, normal liver values reported but details and time course not presented. Following Herbalife reuse, rise in liver values without any further details and normalization after 2 mo.
Tests did not indicate any other liver disease, but no details described. Poorly documented case. Unknown BMI. No comedication. Hepatitis improved after Herbalife cessation, but details of ALT values and time course not reported. Shortly after Herbalife rechallenge, recurrent increase of ALT with normalization after Herbalife withdrawal, but actual ALT values and time course not presented.
No viral serology, no abdominal ultrasound. Insufficiently documented case. Comedication: Bach flowers. Negative viral serology reported, but no details presented. Abdominal ultrasound data not reported and obviously not done. For Herbalife, CIOMS 0 points Final diagnosis: Excluded Herbalife hepatotoxicity Open in a separate window Details are presented for eight patients with liver disease and a published positive reexposure test to Herbalife products.
Most quality problems with missing data occurred in retrospective case series, and uncertainties to exclude or verify alternative causes remained from nonspecific parameters used. Though exact start and end dates of Herbalife intake and onset of symptoms or increased liver values were missing in all cases, time on Herbalife and time to onset was available. Table 2 Overview of known information of eight cases with suspected Herbalife hepatotoxicity and positive reexposure tests Presented information.
Estudos associam consumo de Herbalife® a lesões no fígado
Meztikora Toxicidad hepatica por t e verde camellia sinensis revision. Hospital General de Valencia: Hepatitis aguda asociada al consumo de Copalchi. In Spain, Manso et al. Herbalife Injuries and toxicity cases. In the re- hepayica, probable or definite were included in the data- maining subjects the problem was identified upon hy- base. Med Clin Barc ; The evolution of the patient was torpid and laboratory parameters did not improve as shown in table I. It is difficult to determine whether the etiology of the liver failure was only related to the use of one of these substances or its combination.
Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests
Fenrizil Ann Epidemiol ; A study in between drug administration or toxic exposure onset our country pointed out that one in five patients on and liver disease, and between suspect agent discontin- drug therapy also used herbal remedies concomitantly uation and liver function improvement or recovery; ex- 4. Toxicol Lett ; J Hepatol ; Three patients underwent liver a 2-fold increase in alanine aminotransferase ALT or biopsy, and results were consistent with toxic hepatitis conjugated bilirubin levels above the upper limit of in all three Table I. Herbzlife Drug Saf ; Acute liver failure induced by green tea extracts: So far, there are seven cases described in the literature of liver toxicity related to Noni 4,5with one of them presenting as an acute liver toxixidad that required liver transplantation 4. Gastroenterol Jpn ; Within the framework of alternative medi- liver toxicity cases that was founded in and is co- cine, the use of plant products has grown most during ordinated by two of the present authors R.