Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

Table 5 Updated Council for International Organizations of Medical Sciences scale for the hepatocellular type of injury with items required for causality assessment in herb induced liver injury cases

Items for hepatocellular injury	Possible score	Patient’s score
Time to onset from the beginning of the herb
5-90 d (rechallenge: 1-15 d)	+2
< 5 or > 90 d (rechallenge: > 15 d)	+1
Alternative: Time to onset from cessation of the herb
≤ 15 d (except for slowly metabolized herbal chemicals: > 15 d)	+1
Course of ALT after cessation of the herb
Percentage difference between ALT peak and N
Decrease ≥ 50% within 8 d	+3
Decrease ≥ 50% within 30 d	+2
No information or continued herbal use	0
Decrease ≥ 50% after the 30th day	0
Decrease < 50% after the 30th day or recurrent increase	-2
Risk factors
Alcohol use (drinks/d: > 2 for women, > 3 for men)	+1
No alcohol use (drinks/d: ≤ 2 for women, ≤ 3 for men)	0
Age ≥ 55 yr	+1
Age < 55 yr	0
Concomitant herbs(s) and drug(s)
None or no information	0
Concomitant herb or drug with incompatible time to onset	0
Concomitant herb or drug with compatible or suggestive time to onset	-1
Concomitant herb or drug known as hepatotoxin and with compatible or suggestive time to onset	-2
Concomitant herb or drug with evidence for its role in this case (positive rechallenge or validated test)	-3
Search for non drug causes
Group I (6 causes)
Anti-HAV-IgM
HBsAg, anti-HBc-IgM, HBV-DNA
Anti-HCV, HCV-RNA
Hepatobiliary sonography/colour Doppler sonography of liver vessels/endosonography/CT/MRC
Alcoholism (AST/ALT ≥ 2 IU/L)
Acute recent hypotension history (particularly if underlying heart disease)
Group II (6 causes)
Complications of underlying disease(s)
Infection suggested by PCR and titre change for
CMV (anti-CMV-IgM, anti-CMV-IgG)
EBV (anti-EBV-IgM, anti-EBV-IgG)
HEV (anti-HEV-IgM, anti-HEV-IgG)
HSV (anti-HSV-IgM, anti-HSV-IgG)
VZV (anti-VZV-IgM, anti-VZV-IgG)
Evaluation of group I and II
All causes-groups I and II- reasonably ruled out	+2
The 6 causes of group I ruled out	+1
5 or 4 causes of group I ruled out	0
Less than 4 causes of group I ruled out	-2
Non herb cause highly probable	-3
Previous information on hepatotoxicity of the herb
Reaction labelled in the product characteristics	+2
Reaction published but unlabelled	+1
Reaction unknown	0
Response to readministration
Doubling of ALT with the herb alone, provided ALT below 5N before reexposure	+3
Doubling of ALT with the herb(s) and 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	-2
Other situations	0
Total score for patient

The compilation of the individual items is adapted from the updated version of the Council for International Organizations of Medical Sciences (CIOMS) scale[62] and the original CIOMS scale[60]. The above items refer to the hepatocellular type of injury, whereas items for the cholestatic (± hepatocellular) type are presented in Table 6. Regarding risk factor of alcohol use, 1 drink commonly contains about 10 g ethanol[2,3,90]. Total score and resulting causality grading: ≤ 0, excluded; 1-2, unlikely; 3-5, possible; 6-8, probable; ≥ 9, highly probable. HAV: Hepatitis A virus; IgM: Immunoglobulin M; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CMV: Cytomegalovirus; CT: Computer tomography; EBV: Epstein Barr virus; HBc: Hepatitis B core; HBsAg: Hepatitis B antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E; HILI: Herb induced liver injury; HSV: Herpes simplex virus; MRC: Magnetic resonance cholangiography; N: Upper limit of the normal range; VZV: Varicella zoster virus.