Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

Table 1 Council for International Organizations of Medical Sciences scale for the hepatocellular type of injury and cholestatic or mixed type of injury in drug induced liver injury and herb induced liver injury cases

Items for hepatocellular injury	Score	Result
1 Time to onset from the beginning of the drug/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 drug/herb
≤ 15 d (except for slowly metabolized chemicals: > 15 d)	1	-
2 Course of ALT after cessation of the drug/herb
Percentage difference between ALT peak and N
Decrease ≥ 50 % within 8 d	3	-
Decrease ≥ 50 % within 30 d	2	-
No information or continued drug/herb use	0	-
Decrease ≥ 50 % after the 30th day	0	-
Decrease < 50 % after the 30th day or recurrent increase	-2	-
3 Risk factors
Alcohol use (drinks/d: > 2 for women, > 3 for men)	1	-
Alcohol use (drinks/d: ≤ 2 for women, ≤ 3 for men)	0	-
Age ≥ 55 yr	1	-
Age < 55 yr	0	-
4 Concomitant drug(s) or herbs(s)
None or no information	0	-
Concomitant drug or herb with incompatible time to onset	0	-
Concomitant drug or herb with compatible or suggestive time to onset	-1	-
Concomitant drug or herb known as hepatotoxin and with compatible or suggestive time to onset	-2	-
Concomitant drug or herb with evidence for its role in this case (positive rechallenge or validated test)	-3	-
5 Search for non drug/herb causes	Tick if negative	-
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)	□	-
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, 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 drug or herb cause highly probable	-3	-
6 Previous information on hepatotoxicity of the drug/herb
Reaction labelled in the product characteristics	2	-
Reaction published but unlabelled	1	-
Reaction unknown	0	-
7 Response to unintentional readministration
Doubling of ALT with the drug/herb alone, provided ALT below 5N before reexposure	3	-
Doubling of ALT with the drug(s) and herb(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 CIOMS scale is based on the original CIOMS scale[21] and was adapted from previous modifications[4,14,23,24,44,45]. The above items specifically refer to the hepatocellular type of injury rather than to the cholestatic or mixed type (shown in Table 2). Regarding risk factor of alcohol use, 1 drink commonly contains about 10 g ethanol and details were discussed recently[14,44,45]. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CIOMS: Council for International Organizations of Medical Sciences; CMV: Cytomegalovirus; CT: Computer tomography; DILI: Drug induced liver injury; 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 the normal range; VZV: Varicella zoster virus. Total score and resulting causality grading: ≤ 0: Excluded; 1-2: Unlikely; 3-5: Possible; 6-8: Probable; ≥ 9: Highly probable.

Table 2 Council for International Organizations of Medical Sciences scale for the cholestatic or mixed type of injury and cholestatic or mixed type of injury in drug induced liver injury and herb induced liver injury cases

Items for cholestatic or mixed injury	Score	Result
1 Time to onset from the beginning of the drug/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 drug/herb
≤ 30 d (except for slowly metabolized chemicals: > 30 d)	1	-
2 Course of ALP after cessation of the drug/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 drug/herb use	0	-
3 Risk factors
Alcohol use (drinks/d: > 2 for women, > 3 for men) or pregnancy	1	-
Alcohol use (drinks/d: ≤ 2 for women, ≤ 3 for men)	0	-
Age ≥ 55 yr	1	-
Age < 55 yr	0	-
4 Concomitant drug(s) or herbs(s)
None or no information	0	-
Concomitant drug or herb with incompatible time to onset	0	-
Concomitant drug or herb with compatible or suggestive time to onset	-1	-
Concomitant drug or herb known as hepatotoxin and with compatible or suggestive time to onset	-2	-
Concomitant drug or herb with evidence for its role in this case (positive rechallenge or validated test)	-3	-
5 Search for non drug/herb causes	Tick if negative	-
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)	□	-
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, 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 drug or herb cause highly probable	-3	-
6 Previous information on hepatotoxicity of the drug/herb
Reaction labelled in the product characteristics	2	-
Reaction published but unlabelled	1	-
Reaction unknown	0	-
7 Response to unintentional readministration
Doubling of ALP with the drug/herb alone, provided ALP below 5N before reexposure	3	-
Doubling of ALP with the drug(s) and herb(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 CIOMS scale presented in this table is designed specifically for the cholestatic or mixed type of liver injury rather than for the hepatocellular type, which differs in a few items and is presented separately in Table 1. Additional details and abbreviations are provided in the legend of Table 1. Abbreviation: ALP, Alkaline phosphatase. Total score with resulting causality grading: ≤ 0, excluded; 1-2, unlikely; 3-5, possible; 6-8, probable; ≥ 9, highly probable.

Table 3 Data checklist for drug induced liver injury and herb induced liver injury diagnosis assessment

Items to be assessed	Information obtained			Individual result
	Yes	No	Partial
Brand name with batch number and expiration date	□	□	□	-
Indication of drug/herb use	□	□	□	-
Begin of symptoms leading to drug/herb treatment	□	□	□	-
Daily dose	□	□	□	-
Application form of drug/herb product	□	□	□	-
Exact date of drug/herb start	□	□	□	-
Exact date of drug/herb end	□	□	□	-
Exact dates of emerging new symptoms after drug/herb start in chronological order	□	□	□	-
Exact date of initially increased liver values	□	□	□	-
Time frame of challenge	□	□	□	-
Time frame of latency period	□	□	□	-
Time frame of dechallenge	□	□	□	-
Verification of temporal association	□	□	□	-
Exclusion of temporal association	□	□	□	-
Gender, age, body weight, height, BMI	□	□	□	-
Ethnicity, profession	□	□	□	-
Preexisting general diseases with past medical history and actual assessment	□	□	□	-
Preexisting liver diseases with past medical history and actual assessment regarding	□	□	□	-
Risk factors such as age and alcohol	□	□	□	-
Alcohol use with quantification	□	□	□	-
Comedication by synthetic drugs, herbal drugs, herbal and other dietary supplements with all details of product, daily dose, exact dates of start and end of use, indication	□	□	□	-
ALT value initially including exact date and normal range	□	□	□	-
ALT values during dechallenge at least on days 8 and 30, and later on, with exact dates	□	□	□	-
ALT values during dechallenge to exclude a second peak, with exact dates	□	□	□	-
ALT normalization with exact date and actual value	□	□	□
ALP value initially including exact date and normal range	□	□	□	-
ALP values during dechallenge at least on days 8 and 30, and later on, with exact dates	□	□	□	-
ALP values during dechallenge to exclude a second peak, with exact dates	□	□	□	-
ALP normalization with exact date and actual value	□	□	□	-
AST value initially including normal range	□	□	□	-
Laboratory criteria for hepatotoxicity	□	□	□	-
Laboratory criteria for injury pattern	□	□	□	-
Liver and biliary tract imaging including hepatobiliary sonography, CT, MRT, MRC	□	□	□	-
Color Doppler sonography of liver vessels	□	□	□	-
Unintended reexposure	□	□	□	-
Known hepatotoxicity caused by the drug/herb	□	□	□	-
Other possible causes, consideration and exclusion	□	□	□	-
Hepatitis A - Anti-HAV-IgM	□	□	□	-
Hepatitis B - HBsAg, anti-HBc-IgM, HBV-DNA	□	□	□	-
Hepatitis C - Anti-HCV, HCV-RNA	□	□	□	-
Hepatitis E - Anti-HEV-IgM, anti-HEV-IgG, HEV-RNA	□	□	□	-
Cytomegalovirus (CMV) - CMV-PCR, titer change for anti-CMV-IgM and anti-CMV-IgG	□	□	□	-
Epstein Barr virus (EBV) - EBV-PCR, titer change for anti-EBV-IgM and anti-EBV-IgG	□	□	□	-
Herpes simplex virus (HSV) - HSV-PCR, titer change for anti-HSV-IgM and anti-HSV-IgG	□	□	□	-
Varicella zoster virus (VZV) - VZV-PCR, titer change for anti-VZV-IgM and anti-VZV-IgG	□	□	□	-
Other virus infections - specific serology of Adenovirus, coxsackie-B-Virus, echovirus, measles virus, rubella virus, flavivirus, arenavirus, filovirus, parvovirus, HIV, and others	□	□	□	-
Other infectious diseases - specific assessment of bacteria (such as campylobacter, coxiella, leptospirosis, listeria, salmonella, treponema pallidum), fungi, parasites, worms, tropical diseases, and others	□	□	□	-
Autoimmune hepatitis (AIH) type I - Gamma globulins, ANA, SMA, AAA, SLA/LP	□	□	□	-
Autoimmune hepatitis (AIH) type II - Gamma globulins, anti-LKM-1 (CYP 2D6), anti-LKM-2 (CYP 2C9), anti-LKM-3	□	□	□	-
Primary biliary cirrhosis (PBC) - AMA, anti PDH-E2	□	□	□	-
Primary sclerosing cholangitis (PSC) - p-ANCA, MRC	□	□	□	-
Autoimmune cholangitis (AIC) - ANA, SMA	□	□	□	-
Overlap syndromes - see AIH, PBC, PSC, and AIC	□	□	□	-
Non alcoholic steatohepatitis (NASH) - BMI, insulin resistance, hepatomegaly, echogenicity of the liver	□	□	□	-
Alcoholic liver disease (ALD) - patient’s history, clinical and laboratory assessment, sonography	□	□	□	-
Drug/herb induced liver injury - patient’s history, clinical and laboratory assessment, sonography, use of the CIOMS scale	□	□	□	-
Toxin Screening - cocaine, ecstasy and other amphetamines	□	□	□	-
Rare intoxications - toxin screening for household and occupational toxins	□	□	□	-
Hereditary hemochromatosis - serum ferritin, total iron-binding capacity, genotyping for C2824 and H63D mutation, hepatic iron content	□	□	□	-
Wilson’s disease - copper excretion (24 h urine), ceruloplasmin in serum, free copper in serum, coombs-negative hemolytic anemia, hepatic copper content, Kayser-Fleischer-Ring, neurologic-psychiatric work-up, genotyping	□	□	□	-
Porphyria - corphobilinogen in urine, total porphyrines in urine	□	□	□	-
α1 - antitrypsin deficiency - α1- Antitrypsin in serum	□	□	□	-
Biliary diseases - clinical and laboratory assessment, hepatobiliary sonography, endosonography, CT, MRT, MRC	□	□	□	-
Pancreatic diseases - clinical and laboratory assessment, sonography, CT, MRT	□	□	□	-
Celiac disease - TTG antibodies, endomysium antibodies, duodenal biopsy	□	□	□	-
Anorexia nervosa - clinical context	□	□	□	-
Parenteral nutrition - clinical context	□	□	□	-
Cardiopulmonary diseases with shock liver (cardiac hepatopathy, ischemic hepatitis) - cardiopulmonary assessment of congestive heart disease, myocardial infarction, cardiomyopathy, cardiac valvular dysfunction, pulmonary embolism, pericardial diseases, arrhythmia, hemorrhagic shock, and various other conditions	□	□	□	-
Addison’s disease - plasma cortisol	□	□	□	-
Thyroid diseases - TSH basal, T4, T3	□	□	□	-
Grand mal seizures - clinical context of epileptic seizure (duration > 30 min)	□	□	□	-
Heat stroke - shock, hyperthermia	□	□	□	-
Polytrauma - shock, liver injury	□	□	□	-
Systemic diseases - specific assessment of M. Boeck, amyloidosis, lymphoma, other malignant tumors, sepsis, and others	□	□	□	-
Graft vs host disease - clinical context	□	□	□	-
Other diseases - clinical context	□	□	□	-

This checklist is far from complete and considered as a reminder for the physician. Some listed liver diseases like AIH require a liver biopsy to establish the diagnosis. Few elements are not directed to causality assessment but are important for overall case evaluation. AAA: Anti-actin antibodies; AMA: Antimitochondrial antibodies; ANA: Antinuclear antibodies; BMI: Body mass index; CT: Computed tomography; CYP: Cytochrome P450; 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; HIV: Human immunodeficiency virus; LKM: Liver kidney microsomes; LP: Liver-pancreas antigen; MRC: Magnetic resonance cholangiography; MRT: Magnetic resonance tomography; p-ANCA: Perinuclear antineutrophil cytoplasmatic antibodies; PDH: Pyruvate dehydrogenase; PCR: Polymerase chain reaction; SLA: Soluble liver antigen; SMA: Smooth muscle antibodies; TSH: Thyroid stimulating hormone; TTG: Tissue transglutaminase.

Table 4 Conditions of unintentional reexposure tests in drug induced liver injury and herb induced liver injury cases

Reexposure test result	Hepatocellular type of liver injury		Cholestatic or mixed type of liver injury
	ALTb	ALTr	ALPb	ALPr
Positive	< 5N	≥ 2ALTb	< 5N	≥ 2ALPb
Negative	< 5N	< 2ALTb	< 5N	< 2ALPb
Negative	≥ 5N	≥ 2ALTb	≥ 5N	≥ 2ALPb
Negative	≥ 5N	< 2ALTb	≥ 5N	< 2ALPb
Negative	≥ 5N	NA	≥ 5N	NA
Uninterpretable	< 5N	NA	< 5N	NA
Uninterpretable	NA	NA	NA	NA

Conditions and criteria for an unintentional reexposure test are described in previous reports[4,21,22,24,26,27]. Accordingly, required data for the hepatocellular type of liver injury are the ALT levels just before reexposure, designed as baseline ALT or ALTb, and the ALT levels during reexposure, designed as ALTr. Response to reexposure is positive, if both criteria are met: first, ALTb is below 5N with N as the upper limit of the normal value, and second ALTr ≥ 2ALTb. Other variations lead to negative or uninterpretable results. For the cholestatic or mixed type of liver injury, corresponding values of ALP are to be used rather than of ALT. ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; NA: Not available.

Table 5 Frequency of risk factors of alcohol and age among herb induced liver injury patients

HILI study cohort	Total study cases (n)	Cases scored with risk factors (n)			Total cases scored with risk factors n (%)	Cases with references
		Alcohol	Age	Alcohol + Age
Kava	26	0	6	1	7 (26.9)	Cases 2, 4, 10, 17, 20, 24, 26[12]
Kava	5	0	3	0	3 (60.0)	Cases 1-3[46]
Ayurvedic herbs	1	0	1	0	1 (100.0)	Case 1[30]
Black cohosh	4	2	1	0	3 (75.0)	Cases 2, 3, 4[47]
Black cohosh	9	1	1	0	2 (22.2)	Cases 4, 9[48]
Black cohosh	22	4	2	0	6 (27.3)	Cases 2, 8, 10, 16, 17, 21[36]
Greater Celandine	22	1	9	0	10 (45.5)	Cases 3, 5, 8, 11, 14-18, 21[37]
Greater Celandine	21	0	7	0	7 (33.5)	Cases 4,9, 11, 16-18, 20[32]
Pelargonium sidoides	15	0	3	0	3 (20.0)	Cases 1, 7, 14[38]
Pelargonium sidoides	13	0	7	0	7 (53.9)	Cases 2, 3, 5, 8, 9, 11, 13[39]
Herbalife	8	0	3	0	3 (37.5)	Cases 1, 2, 4[33]
Total	146	8	43	1	52 (35.6)

The study cohort consisted of 146 herb induced liver injury patients patients assessed for the frequency of the risk factors alcohol and age ≥ 55 years. In 52/146 cases (35.6%), risk factors were evident.

Table 6 Changes of the Council for International Organizations of Medical Sciences gradings with considering the risk factors

HILI study	Scored risk		CIOMS assessment with RF	CIOMS assessment without RF	Grading change	Cases with references
	Alcohol	Age	Score/grading	Score/grading
Kava	0	+	+1/Unlikely	0/Excluded	↓	Case 2[12]
Kava	+	+	-1/Excluded	-3/Excluded	0	Case 4[12]
Kava	0	+	+1/Unlikely	0/Excluded	↓	Case 10[12]
Kava	0	+	-1/Excluded	-2/Excluded	0	Case 17[12]
Kava	0	+	+8/Probable	+7/Probable	0	Case 20[12]
Kava	0	+	-1/Excluded	-2/Excluded	0	Case 24[12]
Kava	0	+	-1/Excluded	-2/Excluded	0	Case 26[12]
Kava	0	+	+5/Possible	+4/Possible	0	Case 1[46]
Kava	0	+	+6/Probable	+5/Possible	↓	Case 2[46]
Kava	0	+	+8/Probable	+7/Probable	0	Case 3[46]
Ayurvedic herbs	0	+	+8/Probable	+7/Probable	0	Case 1[30]
Black cohosh	0	+	-2/Excluded	-3/Excluded	0	Case 1[47]
Black cohosh	+	0	-2/Excluded	-3/Excluded	0	Case 2[47]
Black cohosh	+	0	-3/Excluded	-4/Excluded	0	Case 3[47]
Black cohosh	0	+	+1/Unlikely	0/Excluded	↓	Cases 4[48]
Black cohosh	+	0	+1/Unlikely	0/Excluded	↓	Case 9[48]
Black cohosh	+	0	-1/Excluded	2/Excluded	0	Case 2[36]
Black cohosh	0	+	-1/Excluded	-2/Excluded	0	Case 8[36]
Black cohosh	0	+	-1/Excluded	-2/Excluded	0	Case 10[36]
Black cohosh	+	0	0/Excluded	-1/Excluded	0	Case 16[36]
Black cohosh	+	0	0/Excluded	-1/Excluded	0	Case 17[36]
Black cohosh	+	0	-2/Excluded	-3/Excluded	0	Case 21[36]
Greater Celandine	0	+	+9/Highly probable	+8/Probable	↓	Case 2[37]
Greater Celandine	0	+	+10/Highly probable	+9/Highly probable	0	Case 5[37]
Greater Celandine	0	+	+6/Probable	+5/Possible	↓	Case 8[37]
Greater Celandine	0	+	+5/Possible	+4/Possible	0	Case 11[37]
Greater Celandine	0	+	+8/Probable	+7/Probable	0	Case 14[37]
Greater Celandine	0	+	+5/Possible	+4/Possible	0	Case 15[37]
Greater Celandine	0	+	-1/Excluded	-2/Excluded	0	Case 16[37]
Greater Celandine	0	+	+8/Probable	+7/Probable	0	Case 17[37]
Greater Celandine	0	+	0/Excluded	-1/Excluded	0	Case 18[37]
Greater Celandine	+	0	+4/Possible	+3/Possible	0	Case 21[37]
Greater Celandine	0	+	+5/Possible	+4/Possible	0	Case 4[32]
Greater Celandine	0	+	+6/Probable	+5/Possible	↓	Case 9[32]
Greater Celandine	0	+	+3/Possible	+2/Possible	0	Case 11[32]
Greater Celandine	0	+	+7/Probable	+6/Probable	0	Case 16[32]
Greater Celandine	0	+	+7/Probable	+6/Probable	0	Case 17[32]
Greater Celandine	0	+	+5/Possible	+4/Possible	0	Case 18[32]
Greater Celandine	0	+	+7/Probable	+6/Probable	0	Case 20[32]
Pelargonium sidoides	0	+	0/Excluded	-1/Excluded	0	Case 1[38]
Pelargonium sidoides	0	+	+2/Unlikely	+1/Unlikely	0	Case 7[38]
Pelargonium sidoides	0	+	+1/Unlikely	0/Excluded	↓	Case 14[38]
Pelargonium sidoides	0	+	+1/Unlikely	0/Excluded	↓	Case 2[39]
Pelargonium sidoides	0	+	+4/Possible	+3/Possible	0	Case 3[39]
Pelargonium sidoides	0	+	0/Excluded	-1/Excluded	0	Case 5[39]
Pelargonium sidoides	0	+	0/Excluded	-1/Excluded	0	Case 8[39]
Pelargonium sidoides	0	+	+2/Unlikely	+1/Unlikely	0	Case 9[39]
Pelargonium sidoides	0	+	+2/Unlikely	+1/Unlikely	0	Case 11[39]
Pelargonium sidoides	0	+	0/Excluded	-1/Excluded	0	Case 13[39]
Herbalife	0	+	+7/Probable	+6/Probable	0	Case 1[33]
Herbalife	0	+	+2/Unlikely	+1/Unlikely	0	Case 2[33]
Herbalife	0	+	+2/Unlikely	+1/Unlikely	0	Case 4[33]

Based on details described in Table 5, in all 52 patients with evident risks factors of alcohol, age ≥ 55 years, or both, scores and Council for International Organizations of Medical Sciences (CIOMS) gradings with risk factors were compared with conditions without risk factor consideration. In 9 patients, there was a CIOMS downgrading when risk factors would not have been considered. RF: Risk factor.

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 different Indian Ayurvedic herbs

Items for hepatocellular injury	Possible score	Psoralea corylifolia	Acacia catechu	Eclipta alba	Vetivexia zizaniodis
1 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	1	1	1	1
Alternative: Time to onset from cessation of the herb
≤ 15 d (except for slowly metabolized herbal chemicals: > 15 d)	1
2 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
3 Risk factors
Alcohol use (drinks/d: > 2 for women, > 3 for men)	1
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
4 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
5 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)		-	-	-	-
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 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
6 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
7 Response to unintentional 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[30], using the CIOMS scale for the hepatocellular type of liver injury (Table 1). The symbol of - signifies that this particular item has been evaluated and no abnormality was found. For the four herbs, the total score was either +7 (probable causality) or +5 (possible causality). Abbreviations see legend to Table 1.

Table 8 Compilation of causality assessment methods used in suspected herb induced liver injury cases

Herbs/Herbal products	Ad hoc (n)	WHO (n)	CIOMS (n)	Naranjo (n)	DILIN (n)	KL (n)	Ref.
Kava	20						BfArM[58]
Kava		30					Denham et al[59]
Kava	20						Teschke et al[60]
Kava			36				Stickel et al[61]
Kava		80					Schmidt et al[62]
Greater Celandine	23						BfArM[63]
Black cohosh			31				EMA[54]
Herbalife products		12					Elinav et al[64]
Herbalife products		12					Schoepfer et al[65]
Kava			26				Teschke et al[12]
Black cohosh				30			Mahady et al[42]
Green tea				34			Sarma et al[43]
Black cohosh			4				Teschke et al[47]
Black cohosh			9				Teschke et al[48]
Kava			31				Teschke[34]
Hydroxycut					17		Fong et al[66]
Black cohosh			22				Teschke et al[36]
Greater Celandine			22				Teschke et al[37]
Herbalife products						20	Manso et al[67]
Various herbs			45				Chau et al[57]
Greater Celandine			21				Teschke et al[32]
Pelargonium sidoides			15				Teschke et al[38]
Pelargonium sidoides			13				Teschke et al[39]
Sum (n)	63	134	275	64	17	20
Sum (percent)	11.00%	23.40%	48.00%	11.20%	3.00%	3.40%

The data are derived from a study evaluating alternative causes in suspected HILI cases (n = 573) comprising the study cohort[5]. For the 275 CIOMS cases, causality assessment was performed with the updated CIOMS scale the original CIOMS scale, or both. Ad hoc: ad hoc approach; CIOMS: Council for International Organizations of Medical Sciences scale; DILIN: Drug Induced Liver Injury Network method; KL: Karch and Lasagna method; Naranjo: Naranjo scale; WHO: World Health Organization method.