Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

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

Details are presented for eight patients with liver disease and a published positive reexposure test to Herbalife products. ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AMA: Antimitochondrial antibodies; ANA: Antinuclear antibodies; AST: Aspartate aminotransferase; BMI: Body mass index in kg/m²; CIOMS: Council for International Organizations of Medical Sciences; CMV: Cytomegalovirus; EBV: Epstein Barr virus; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; HSV: Herpes simplex virus; VZV: Varicella zoster virus.