Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

Table 1 Essential steps of herbal hepatotoxicity assessments

Quality specifications
Herbal product quality
Good agricultural practices
Good manufacturing practices
Definition of plant family, subfamily, species, subspecies, and variety
Definition of plant part
Definition of solvents and solubilizers
Lack of impurities, adulterants, and misidentifications
Minimum of batch and product variability
Lack of variety to variety variability
Clinical assessment quality
Brand name with details of ingredients, plant parts, batch number, and expiration date
Identification as herbal drug or herbal supplement
Herb as an ingredient of a polyherbal product or an undetermined herbal product
Manufacturer with address
Indication of herbal use with dates of symptoms leading to herbal treatment
Daily dose with details of the application form
Exact date of herb start and herb end
Accurate dates of emerging new symptoms after herb start in chronological order
Accurate date of initially increased liver values
Timeframes of challenge, latency period, and dechallenge
Verification or exclusion of a temporal association
Provided temporal association is verified, evaluation of a causal relationship
Gender, age, body weight, height, body mass index
Ethnicity, profession
Past medical history regarding general diseases and specifically liver diseases
ALT value initially including normal range
ALT values during dechallenge at least on days 8 and 30, as well as later on
ALT values during dechallenge to exclude a second peak
ALT normalization with exact date and actual value
ALP value initially including normal range
ALP values during dechallenge up to 180 d, as well as later on
ALP values during dechallenge to exclude a second peak
ALP normalization with exact date and actual value
AST value initially including normal range
Laboratory criteria for definition of hepatotoxicity and its pattern
Definition of risk factors such as age and alcohol
Alcohol and drug use
Statement regarding actual treatment including steroids or ursodesoxycholic acid
Assessment of preexisting and coexisting liver unrelated diseases
Assessment of preexisting and coexisting liver diseases
Consideration of the several hundreds of other possible liver diseases
Providing details to exclude alternative diagnoses
Assessment and exclusion of hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, cytomegalovirus, Epstein-Barr virus, HSV, VZV
Liver and biliary tract imaging including color Doppler sonography of liver vessels
Specific evaluation of alcoholic, cardiac, autoimmune, and genetic liver diseases
Individual quantitative score of each alternative diagnosis
Comedicated synthetic drugs, herbal drugs, herbal and other dietary supplements
Definition of and search for accidental, unintended reexposure
Assessing of unintended reexposure
Search for evidence of prior known hepatotoxicity of the suspected herb
Assessing of known hepatotoxicity caused by the herb
Qualified data acquisition and documentation of complete data
Transparent presentation of all data
Causality assessment quality
Prospective assessment by the physician suspecting herb induced liver injury
Structured and quantitative method
Liver specific causality assessment method validated for hepatotoxicity
Use of the CIOMS scale
Gathering of all data required for the CIOMS scale item by item
Presentation of individual CIOMS items and of scores to regulatory agency
Gathering all clinical data and presentation to regulatory agency
Excluding all alternative causes and presentation to regulatory agency
Regulatory case assessment by skilled hepatologist with clinical experience
Regulatory assessment with assistance of external experts
Transparent presentation of regulatory verified causality assessment results

Required quality specifications of herbal products refer to herbs, herbal drugs, and herbal supplements including herbal mixtures. ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; CIOMS: Council for International Organizations of Medical Sciences; HSV: Herpes simplex virus; VZV: Varicella zoster virus.