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

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.