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©2013 Baishideng Publishing Group Co.
World J Hepatol. Jul 27, 2013; 5(7): 353-363
Published online Jul 27, 2013. doi: 10.4254/wjh.v5.i7.353
Published online Jul 27, 2013. doi: 10.4254/wjh.v5.i7.353
Table 1 Clinical data of all eight patients with liver disease and a reported positive reexposure test by Herbalife products
| Patient | Identification | Specific information for each individual patient |
| 1 | Hoffmann et al[1], 63 yr female | Herbalife product of unknown daily dose for several weeks. BMI 30. 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. Comedication: hydrochlorothiazide/amiloride for hypertension since 2 yr and celecoxib temporarily for relapsing vertebral pain syndrome. ALT 1897 U/L, AST 2098 U/L, ALP 248 U/L. Upon discontinuation of all drugs and Herbalife, ALT 35 U/L within 2 mo. Four weeks later, recurrent ALT increase with peak ALT 758 U/L under Herbalife reexposure, but duration of use not communicated and clear temporal association not evaluable. Exclusion of acute infection by HAV, HBV, HCV, CMV, and EBV reported, but details of parameters not communicated. HEV, HSV, and VZV not excluded. Pancreatitis not excluded. Slightly increased ANA and AMA. 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. BMI 33. Comedication: aspirin, metformin for non-insulin dependent diabetes mellitus, statins for hyperlipidemia. Lack of reported symptoms and actual data of ALT, AST, and ALP values initially and later on. 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. Serology of HAV, HBV, HCV, CMV, and EBV was negative but not further specified and no reported serology for HEV, HSV, and VZV. Normal abdominal ultrasound. For Herbalife, CIOMS 2 points |
| Final diagnosis: Unlikely Herbalife hepatotoxicity | ||
| 3 | Elinav et al[2], their case 2, 48 yr female | Herbalife products of unknown daily dose for 9 mo. BMI 32. Comedication: alpha adrenergic blocker for hypertension of unknown daily dose and treatment duration. Symptoms and actual values of ALT, AST, and ALP not reported. 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. Serology of HAV, HBV, HCV, CMV, and EBV was negative but not further specified and no reported serology for HEV, HSV, and EBV. Normal abdominal ultrasound. Liver histology: hepatocellular hepatitis. For Herbalife CIOMS 1 point |
| Final diagnosis: Unlikely Herbalife hepatotoxicity | ||
| 4 | Elinav et al[2], their case 12, 78 yr female | Herbalife products of unknown daily dose for 12 mo. BMI 27. Comedication: biphosphonates and aspirin of unknown daily dose and duration, background illness psoriasis and non insulin dependent diabetes mellitus. Lack of reported symptoms and of ALT, AST, and ALP initially and later on. Serology of HAV, HBV, HCV, CMV, and EBV was negative but not further specified and no reported serology for HEV, HSV, and VZV. Normal abdominal ultrasound. A second hepatitis flare developed after Herbalife reuse, but details not provided except that the hepatitis was unresolved at the time of manuscript submission. For Herbalife, CIOMS 2 points Final diagnosis: Unlikely Herbalife hepatotoxicity |
| 5 | Schoepfer et al[3], their case 1, 30 yr male | Herbalife products for 26 mo according to the manufacturer’s recommended dose (exact daily dose not communicated). BMI 33. Painless jaundice as symptom. Reported initial liver enzymes as fold upper limit of normal: ALT 50, AST 19, and ALP 1.8, but lack of actual values in the subsequent course. Lack of any specific parameters and data on HAV, HBV, HCV, CMV, EBV, HSV, and VZV. 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. For Herbalife, CIOMS -1 point |
| Final diagnosis: Chronic hepatitis E, excluded Herbalife hepatotoxicity | ||
| 6 | Jóhannsson et al[4], their case 4, 44 yr female | Herbalife products of unknown daily dose for 5-6 mo. BMI unknown. Abdominal pain and jaundice as symptoms with a latency period of 4-5 mo. Comedication: bupropion of unknown daily dose for 20 d. ALT 2637 U/L, ALP 231 U/L. 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. For Herbalife, CIOMS -2 points Final diagnosis: Excluded Herbalife hepatotoxicity |
| 7 | Manso et al[5], their case 12, 39 yr female | Herbalife products of unknown daily dose for 60 d. Unknown BMI. No comedication. ALT 1200 U/L, AST 394 U/L, and ALP 454 U/L. 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. For Herbalife, CIOMS 1 point Final diagnosis: Unlikely Herbalife hepatotoxicity |
| 8 | Manso et al[5], their case 20, 49 yr female | Herbalife products of unknown daily dose for 2 yr. Unknown BMI. Comedication: Bach flowers. ALT 922 U/L, AST 702 U/L, ALP 201 U/L. Upon cessation of Herbalife and Bach flowers, ALT 793 U/L within 21 d. Eight days after Herbalife reintroduction, ALT 1500 U/L with lack of ALT normalization following Herbalife recessation. Negative viral serology reported, but no details presented. Abdominal ultrasound data not reported and obviously not done. Insufficiently documented case. For Herbalife, CIOMS 0 points Final diagnosis: Excluded Herbalife hepatotoxicity |
Table 2 Overview of known information of eight cases with suspected Herbalife hepatotoxicity and positive reexposure tests
| Presented information | Cases | Individual cases |
| Daily dose | 0/8 | - |
| Exact date of Herbalife start | 0/8 | - |
| Exact date of Herbalife end | 0/8 | - |
| Exact date of symptoms | 0/8 | - |
| Time on Herbalife | 8/8 | 1, 2, 3, 4, 5, 6, 7, 8 |
| Time to onset | 8/8 | 1, 2, 3, 4, 5, 6, 7, 8 |
| Temporal association | 7/8 | 1, 2, 3, 4, 6, 7, 8 |
| Specific symptoms | 3/8 | 1, 5, 6 |
| ALT value | 5/8 | 1, 5, 6, 7, 8 |
| AST value | 4/8 | 1, 5, 7, 8 |
| ALP value | 5/8 | 1, 5, 6, 7, 8 |
| ALT dechallenge | 3/8 | 1, 7, 8 |
| ALT normalization | 1/8 | 1 |
| Hepatobiliary tract imaging | 5/8 | 1, 2, 3, 4, 5 |
| HAV | 5/8 | 1, 2, 3, 4, 5 |
| HBV | 5/8 | 1, 2, 3, 4, 5 |
| HCV | 5/8 | 1, 2, 3, 4, 5 |
| HEV | 1/8 | 5 |
| CMV | 4/8 | 1, 2, 3, 4 |
| EBV | 4/8 | 1, 2, 3, 4 |
| HSV | 0/8 | - |
| VZV | 0/8 | - |
| Drug comedication | 5/8 | 1, 2, 3, 4, 6 |
| Herbal comedication | 2/8 | 6, 8 |
| Liver histology | 3/8 | 1, 3, 5 |
Table 3 Criteria of a positive reexposure test in herb induced liver injury cases
| Test result | ALTb | ALTr |
| Positive | < 5 N | ≥ 2 ALTb |
| Negative | < 5 N | < 2 ALTb |
| Negative | ≥ 5 N | ≥ 2 ALTb |
| Negative | ≥ 5 N | < 2 ALTb |
| Negative | ≥ 5 N | N/A |
| Uninterpretable | < 5 N | N/A |
| Uninterpretable | N/A | N/A |
Table 4 Analysis of positive reexposure tests in cases with suspected Herbalife hepatotoxicity
| Cases with initially suggested positive reexposure tests |
| Case 1 |
| The 63-yr old woman used a Herbalife product and experienced a positive reexposure test that was fairly well documented, but duration of product reuse was insufficiently communicated[1]. Upon first challenge, ALT was 1897 U/L and declined to 35 U/L after product discontinuation. Rechallenge increased ALT 758 U/L. Since ALTb is < 5 N and ALTr ≥ 2 ALTb, this ascertains the positive reexposure test |
| Case 2 |
| The 55-yr old woman consumed Herbalife products. Liver disease by not further specified liver values as well as a positive reexposure test was described[2]. Individual ALT values were not presented, hence data required for criteria of ALTb < 5 N and ALTr ≥ 2 ALTb are not available. The data are uninterpretable regarding the claimed positive reexposure test |
| Case 3 |
| The 48-yr old woman was on Herbalife products, when hepatocellular hepatitis was diagnosed associated with a positive reexposure test[2]. Lack of any specific ALT values prevented establishing criteria of ALTb < 5 N and ALTr ≥ 2 ALTb. The case is uninterpretable with respect to the reexposure test |
| Case 4 |
| The 78-yr old woman used Herbalife products and was diagnosed with hepatocellular liver injury based on liver values[2]. A positive reexposure test was described, but details of the test and individual ALT values were not provided. Therefore, criteria of ALTb < 5 N and ALTr ≥ 2 ALTb cannot be ascertained. The case is uninterpretable due to lacking test criteria. |
| Case 5 |
| The 30-yr old man consumed Herbalife products and experienced a biopsy proven liver disease[3]. A positive reexposure test was described, but details were not provided. An initial ALT value was reported with lack of ALT data in the further course including the reexposure test, preventing the confirmation of the essential criteria ALTb < 5 N and ALTr ≥ 2 ALTb. Lack of these criteria leads to uninterpretable data of the test |
| Case 6 |
| The 44-yr old woman used Herbalife products, experienced jaundice with increased ALT 2637 U/L[4]. Following product cessation, normalization of liver values reported, but actual ALT values were not presented. After Herbalife reuse, rise of liver values was communicated, but no details of actual ALT values given. ALTb is probably < 5 N, but ALTr is unknown. Currently, this case is uninterpretable regarding the reexposure test |
| Case 7 |
| The 39-yr old woman was on Herbalife products and experienced a hepatitis, which improved after product cessation, but actual ALT values before reexposure are not communicated[5]. Recurrent increase of ALT was reported, but actual values not presented. Since ALTb and ALTr are unknown, the reexposure test is uninterpretable |
| Case 8 |
| The 49-yr old woman used Herbalife products and experienced an ALT of 922 U/L, which dropped after product cessation to 793 U/L and rose to 1500 U/L after reintroduction[5]. ALTb is ≥ 5 N and ALTr < 2 ALTb, the test is negative |
| Cases with initially questionable positive reexposure tests |
| The 60-yr old man was reported with use of Herbalife products, a histology proven liver disease, and a questionable positive rechallenge[3]. When an increase of liver values was again observed, the patient denied Herbalife consumption. Thus, no evidence for a positive reexposure test exists |
| The 41-yr old woman was on a Herbalife product and suffered from fulminant hepatic failure requiring liver transplantation[3]. A questionable positive reexposure test with slightly elevated liver enzymes lacking actual ALT values was described for the transplanted liver one year after transplantation, when the patient was vague about Herbalife use. Therefore, clear evidence for a positive reexposure test is missing |
Table 5 Causality assessment of all eight patients with primarily suspected Herbalife hepatotoxicity and an initially assumed positive reexposure test
| Items for hepatocellular type of injury | Score | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 1 Time to onset from the beginning of Herbalife | |||||||||
| 5-90 d (rechallenge: 1-15 d) | +2 | +2 | |||||||
| < 5 or > 90 d (rechallenge: > 15 d) | +1 | +1 | +1 | +1 | +1 | +1 | +1 | +1 | |
| Alternative: Time to onset from cessation of Herbalife | |||||||||
| ≤ 15 d (except for slowly metabolized chemicals: > 15 d) | +1 | ||||||||
| 2 Course of ALT after cessation of Herbalife | |||||||||
| Percentage difference between ALT peak and N | |||||||||
| Decrease ≥ 50% within 8 d | +3 | ||||||||
| Decrease ≥ 50% within 30 d | +2 | +2 | |||||||
| No information | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Decrease ≥ 50% after the 30th d | 0 | ||||||||
| Decrease < 50% after the 30th d or recurrent increase | -2 | ||||||||
| 3 Risk factors | |||||||||
| Alcohol use (drinks/d: > 2 for woman, > 3 for men) | +1 | ||||||||
| Alcohol use (drinks/d: ≤ 2 for woman, ≤ 3 for men) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Age ≥ 55 yr | +1 | +1 | +1 | +1 | |||||
| Age < 55 yr | 0 | 0 | 0 | 0 | 0 | 0 | |||
| 4 Concomitant drug(s) | |||||||||
| None or no information | 0 | 0 | 0 | ||||||
| Concomitant drug with incompatible time to onset | 0 | 0 | |||||||
| Concomitant drug with compatible or suggestive time to onset | -1 | ||||||||
| Concomitant drug known as hepatotoxin and with compatible or suggestive time to onset | -2 | -2 | -2 | -2 | -2 | -2 | |||
| Concomitant drug with evidence for is role in this case (positive rechallenge or validated test) | -3 | ||||||||
| 5 Search for non Herbalife causes | |||||||||
| Group I (6 causes) | |||||||||
| Anti-HAV-IgM | - | - | - | - | - | ||||
| Anti-HBc-IgM/HBV-DNA | - | - | - | - | - | ||||
| Anti-HCV/HCV-RNA | - | - | - | - | - | ||||
| Hepato-biliary sonography/colour Doppler sonography of liver vessels/endosonography/CT/MRC | + | - | - | - | - | ||||
| Alcoholism (AST/ALT ≥ 2) | - | - | - | - | - | - | - | ||
| Acute recent hypotension history (particularly if underlying heart disease) | - | - | - | - | - | - | |||
| Group II (6 causes) | |||||||||
| Complications of underlying disease(s), such as sepsis, autoimmune hepatitis, chronic hepatitis B or C, primary biliary cirrhosis or sclerosing cholangitis, genetic liver diseases | - | - | - | - | - | ||||
| Infection suggested by PCR and titer change for | |||||||||
| CMV (Anti-CMV-IgM/IgG) | - | - | - | - | |||||
| EBV (Anti-EBV-IgM/IgG) | - | - | - | - | |||||
| HEV (Anti-HEV-IgM/IgG) | + | ||||||||
| HSV (Anti-HSV-IgM/IgG) | |||||||||
| VZV (Anti-VZV-IgM/IgG) | |||||||||
| Evaluation of group I and II | |||||||||
| All causes - group I and II - reasonably ruled out | +2 | ||||||||
| The 6 causes of group I ruled out | +1 | +1 | +1 | +1 | +1 | ||||
| 5 or 4 causes of group I ruled out | 0 | ||||||||
| Less than 4 causes of group I ruled out | -2 | -2 | -2 | -2 | |||||
| Non Herbalife cause highly probable | -3 | -3 | |||||||
| 6 Previous information on hepatotoxicity of Herbalife | |||||||||
| Reaction labelled in the product characteristics | +2 | ||||||||
| Reaction published but unlabelled | +1 | +1 | +1 | +1 | +1 | +1 | +1 | +1 | +1 |
| Reaction unknown | 0 | ||||||||
| 7 Response to readministration | |||||||||
| Doubling of ALT with Herbalife alone, provided ALT below 5 N before reexposure | +3 | +3 | |||||||
| Doubling of ALT with Herbalife and herb(s) or drug(s) already given at the time of first reaction | +1 | ||||||||
| Increase of ALT but less than N in the same conditions as for the first administration | |||||||||
| Other situations | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Total points for patients | +07 | +02 | +01 | +02 | -01 | -02 | +01 | 0 |
- Citation: Teschke R, Frenzel C, Schulze J, Schwarzenboeck A, Eickhoff A. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests. World J Hepatol 2013; 5(7): 353-363
- URL: https://www.wjgnet.com/1948-5182/full/v5/i7/353.htm
- DOI: https://dx.doi.org/10.4254/wjh.v5.i7.353