Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

Table 7 Council for International Organizations of Medical Sciences scale as an example with items required for causality assessment in a patient with herb induced liver injury by four Indian Ayurvedic herbs

Items for hepatocellular injury	Possible score	Psoralea corylifolia	Acacia catechu	Eclipta alba	Vetivexia zizaniodis
Time to onset from the beginning of the herb
5-90 d (rechallenge: 1-15 d)	+2
< 5 d or > 90 d (rechallenge: > 15 d)	+1	+1	+1	+1	+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	+3	+3	+3	+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	0	0	0	0
Age ≥ 55 yr	+1	+1	+1	+1	+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	-1
Concomitant herb or drug known as hepatotoxin and with compatible or suggestive time to onset	-2		-2	-2	-2
Concomitant herb or drug with evidence for its role in this case (positive rechallenge or validated test)	-3
Search for non herb 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	+2	+2	+2	+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	+1
Reaction unknown	0		0	0	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 each individual herb used by the patient		+7	+5	+5	+5

The data of the patient with severe hepatotoxicity by four different Indian Ayurvedic herbs are derived from a published report[58], using the updated Council for International Organizations of Medical Sciences scale for the hepatocellular type of liver injury (Table 5). The symbol - signifies that this particular item has been evaluated and no abnormality was found. Regarding risk factor of alcohol use, 1 drink commonly contains about 10 g ethanol[2,3,90]. For the four herbs, the total score was either 5 (possible causality) or 7 (probable causality). ALT: Alanine aminotransferase; N: Upper limit of the normal range; HBsAg: Hepatitis B antigen; HBc: Hepatitis B core; HAV: Hepatitis A virus; IgM: Immunoglobulin M; HBV: Hepatitis B virus; HCV: Hepatitis C virus; CT: Computer tomography; MRC: Magnetic resonance cholangiography; AST: Aspartate aminotransferase; PCR: Polymerase chain reaction; CMV: Cytomegalovirus; EBV: Epstein Barr virus; HEV: Hepatitis E virus; HSV: Herpes simplex virus; VZV: Varicella zoster virus.