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 |
In all eight patients with initially suspected Herbalife hepatotoxicity (Tables 1 and 4), causality assessment for Herbalife was performed with the updated CIOMS scale for the hepatocellular type of liver injury. The symbol “-” denotes that the obtained result was negative and that of “+” was positive, whereas lack of a symbol indicates missing data. Regarding risk factor of alcohol use, 1 drink commonly contains about 10 g ethanol. Total points provide causality levels: ≤ 0, excluded; 1-2, unlikely; 3-5, possible; 6-8, probable; ≥ 9, highly probable. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CIOMS: Council for International Organizations of Medical Sciences; CMV: Cytomegalovirus; CT: Computer tomography; EBV: Epstein Barr virus; HAV: Hepatitis A virus; HBc: Hepatitis B core; HBsAg: Hepatitis B antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; HILI: Herb induced liver injury; HSV: Herpes simplex virus; MRC: Magnetic resonance cholangiography; N: Upper limit of normal; VZV: Varicella zoster virus.