Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

Table 6 Updated Council for International Organizations of Medical Sciences scale for the cholestatic (± hepatocellular) type of injury with items required for causality assessment in herb induced liver injury cases

Items for cholestatic (± hepatocellular) injury	Possible score	Patient’s score
Time to onset from the beginning of the herb
5-90 d (rechallenge: 1-90 d)	+2
< 5 or > 90 d (rechallenge: > 90 d)	+1
Alternative: Time to onset from cessation of the herb
≤ 30 d (except for slowly metabolized herbal chemicals: > 30 d)	+1
Course of ALP after cessation of the herb
Percentage difference between ALP peak and N
Decrease ≥ 50% within 180 d	+2
Decrease < 50% within 180 d	+1
No information, persistence, increase, or continued herbal use	0
Risk factors
Alcohol use (drinks/d: > 2 for women, > 3 for men) and pregnancy	+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 ALP with the herb alone, provided ALP below 5N before reexposure	+3
Doubling of ALP with the herb(s) and drug(s) already given at the time of first reaction	+1
Increase of ALP but less than N in the same conditions as for the first administration	-2
Other situations	0
Total score for patient

The compilation of 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 cholestatic (± hepatocellular) type of injury, whereas items for the hepatocellular type are presented in Table 5. 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. ALP: Alkaline phosphatase; N: upper limit of the normal range; HAV: Hepatitis A virus; IgM: Immunoglobulin M; HBsAg: Hepatitis B antigen; HBc: Hepatitis B core; HBV: Hepatitis B virus; HCV: Hepatitis C virus; CT: Computer tomography; MRC: Magnetic resonance cholangiography; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PCR: Polymerase chain reaction; CMV: Cytomegalovirus; EBV: Epstein Barr virus; HEV: Hepatitis E virus; HSV: Herpes simplex virus; IgG: Immunoglobulin G; VZV: Varicella zoster virus.