Fatal fulminant hepatic failure induced by a natural therapy containing kava

To the Editor: Gow and colleagues recently attributed fulminant hepatic failure in an Australian patient to an over-the-counter herbal product containing kava (Piper methysticum) that is extensively used in the community.1 We are not convinced that kava caused this patient’s liver failure. The hepatotoxicity could have been due to other unidentified contaminants of the herbal preparation or to chromium (from the mineral supplements also taken by the patient).

We tested a sample of the product Kava 1800 Plus (Eagle Pharmaceuticals, Batch No. 10711) by thin layer chromatography (TLC) and high pressure liquid chromatography (HPLC) methods, and assessed it against defined standards. Kavalactones were identified and quantified by normal-phase HPLC. Kava was positively identified, with a content of about 47 mg of kavalactones per tablet (the product label specifies 60 mg per tablet). However, flavonoids from Scutellaria lateriflora, analysed by reverse-phase HPLC, could not be found. Passiflora incarnata, analysed by TLC, was also not found, with none of the typical flavonoid bands being detectable.

The absence of two ingredients listed on the product label, P. incarnata and S. lateriflora, raises a new concern that there may be batch variations, as well as the possibility of unknown adulterants or contaminants being present. The possibilities of contaminants and batch variation were not excluded in the case report by Gow and colleagues.1 The Therapeutic Goods Administration established that Kava 1800 Plus did not contain common germander (Teucrium chaemaedrys), a known adulterant for S. lateriflora. However, Teucrium species are known to have hepatotoxic effects and there are about 100 species, any one of which could have been a contaminant.

Gow et al refer to 68 international case reports of suspected hepatotoxicity with the use of kava.1 An independent analysis of these 68 cases concluded that only two were probable kava-associated hepatotoxicities.2 An incidence calculation from these case reports indicates that hepatotoxicity from kava occurs in 0.008 cases per million daily doses,2 which represents an extremely low risk of adverse reactions associated with kava.

Recently, a study on the potential hepatotoxicity of kava found that the aqueous extract of kava does not affect results of liver function tests in rats. Extracts were administered in daily dosages of 200 or 500 mg of active kavalactones per kilogram of bodyweight for 2 or 4 weeks. Sera were assayed for four enzymes that are markers of liver toxicity, and liver homogenates were assayed for malondialdehyde formation, which indicates changes in lipid peroxidation. Kava did not elevate malondialdehyde or the enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase or lactate dehydrogenase. In fact, in certain instances, these enzymes were significantly reduced, suggesting a lack of toxic effect of kava on the liver.3 TLC analyses have shown that there is no qualitative difference between aqueous, acetone or ethanol extracts of kava.4

We propose, given that patients can consume other over-the-counter products such as chromium (shown to have hepatotoxicity at high concentrations),5 that all products consumed by patients must be evaluated before causality can be attributed to a particular herb. Reports of case records associated with hepatic failure due to kava require proper verification and documentation of all the findings.