Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

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.