Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

Table 2 Check list for herb induced liver injury diagnosis

Items to be assessed	Information obtained
	Yes	No	Partial
Brand name with batch number and expiration date	□	□	□
Indication of herbal use	□	□	□
Dates of symptoms leading to herbal treatment	□	□	□
Daily dose	□	□	□
Application form of herbal product	□	□	□
Exact date of herb start	□	□	□
Exact date of herb end	□	□	□
Accurate dates of emerging new symptoms after herb start in chronological order	□	□	□
Accurate 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	□	□	□
Past medical history and actual assessment regarding preexisting general diseases	□	□	□
Past medical history and actual assessment regarding preexisting liver diseases	□	□	□
Risk factors such as age and alcohol	□	□	□
Quantification of alcohol and drug use	□	□	□
Comedicated 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 up to 180 d, 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 definition of 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 herb	□	□	□
Consideration and exclusion of other possible causes	□	□	□
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
CMV	□	□	□
CMV-PCR, titer change for anti-CMV-IgM and anti-CMV-IgG
EBV	□	□	□
EBV-PCR, titer change for anti-EBV-IgM and anti-EBV-IgG
HSV	□	□	□
HSV-PCR, titer change for anti-HSV-IgM and anti-HSV- IgG
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, fungi, parasites, worms, and others
AIH type I	□	□	□
Gamma globulins, ANA, SMA, AAA, SLA/LP, anti-LSP, anti-ASGPR
AIH type II	□	□	□
Gamma globulins, anti-LKM-1 (CYP 2D6), anti-LKM-2 (CYP 2C9), anti-LKM-3
PBC	□	□	□
AMA, anti-PDH-E2
PSC	□	□	□
p-ANCA, MRC
AIC	□	□	□
ANA, SMA
Overlap syndromes	□	□	□
See AIH, PBC, PSC, and AIC
NASH	□	□	□
BMI, insulin resistance, hepatomegaly, echogenicity of the liver
ALD	□	□	□
Patient’s history, clinical and laboratory assessment, sonography
DILI	□	□	□
Patient’s history, clinical and laboratory assessment, sonography, use of the CIOMS scale
Cocaine, ecstasy and other amphetamines	□	□	□
Toxin screening
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	□	□	□
Porphobilinogen 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	□	□	□
Other diseases
Clinical context	□	□	□

For each listed item, detailed results obtained for the individual patient are to be supplemented within the checklist. BMI: Body mass index; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; CT: Computer tomography; MRT: Magnetic resonance tomography; MRC: Magnetic resonance cholangiography; HAV: Hepatitis A virus; IgM: Immunoglobulin M; HBsAg: Hepatitis B antigen; HBc: Hepatitis B core; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; IgG: Immunoglobulin G; HIV: Human immunodeficiency virus; CMV: Cytomegalovirus; PCR: Polymerase chain reaction; EBV: Epstein Barr virus; HSV: Herpes simplex virus; VZV: Varicella zoster virus; AIH: Autoimmune hepatitis; ANA: Antinuclear antibodies; SMA: Smooth muscle antibodies; AAA: Anti-actin antibodies; SLA: Soluble liver antigen; LP: Liver-pancreas antigen; LSP: Liver specific protein; ASGPR: Asialo-glycoprotein-receptor; LKM: Liver kidney microsomes; CYP: Cytochrome P450; PBC: Primary biliary cirrhosis; AMA: Antimitochondrial antibodies; PDH: Pyruvate dehydrogenase; PSC: Primary sclerosing cholangitis; p-ANCA: Perinuclear antineutrophil cytoplasmatic antibodies; AIC: Autoimmune cholangitis; NASH: Non alcoholic steatohepatitis; ALD: Alcoholic liver disease; DILI: Drug induced liver injury; CIOMS: Council for International Organizations of Medical Sciences; TSH: Thyroid stimulating hormone.