Black cohosh and suspected hepatotoxicity: inconsistencies, confounding variables, and prospective use of a diagnostic causality algorithm. A critical review

Objective: The data of 69 cases of initially suspected black cohosh (BC)-induced liver disease were reviewed and analyzed to clarify whether BC hepatotoxicity really exists as a disease entity in these cases comparable to toxic liver disease being caused by various drugs and dietary supplements. Methods: The cases comprised 11 published case reports and 58 spontaneous reports to national regulatory agencies. The analysis includes assessment of causality for BC, data quality of the presented cases, and their inconsistencies and confounding variables. Results: The assessed data raise serious doubts on the initial claims of causality for BC in these cases and provide clear evidence of their poor quality, especially when spontaneous reports are considered. There are major inconsistencies for the same patient regarding reported data. Moreover, the analysis of all cases disclosed confounding variables. These include poor case data quality, uncertainty of BC product, quality, and identification, undisclosed indication, insufficient adverse event definition, lack of temporal association and dechallenge, missing or inadequate evaluation of alcohol use, comedication, comorbidity, reexposure test, and alternative diagnoses. Conclusions: The presented data do not support the concept of hepatotoxicity in a primarily suspected causal relationship to the use of BC and failure to provide a signal of safety concern, but further efforts have to be undertaken to dismiss or to substantiate the existence of BC hepatotoxicity as a special disease entity. The future strategy should be focused on prospective causality evaluations in patients diagnosed with suspected BC hepatotoxicity, using a structured, quantitative, and hepatotoxicity-specific causality assessment method.