In this issue of the Journal, Gow and colleagues (page 442) report the first Australian case of fulminant hepatic failure attributed to a herbal product containing kava,1 while Moulds and Malani (page 451) note the cultural and economic importance of kava for Pacific island nations, and provide a balanced overview on kava safety and availability.2 For centuries kava has been widely consumed in Pacific island countries as a ceremonial beverage and for its mood-altering and stress-relieving properties. It is prepared as an aqueous emulsion of the crushed fresh or dried roots or lower stems of the kava shrub Piper methysticum ("intoxicating pepper").3 Pharmacological properties, such as anxiolytic activity, are attributed to a poorly characterised group of compounds termed kavalactones.3,4

In 1982, kava was introduced to some Arnhem Land Aboriginal communities from Pacific island countries, in part to reduce the harmful effects of alcohol.5 Kava use continued to rise during the 1980s and 1990s, supplied by a lucrative black market. Concerns about adverse health, social and economic effects of widespread heavy consumption resulted in the Northern Territory Kava Management Act in May 1998, which made the possession of more than 2 kg of kava illegal unless in accordance with a licence. However, an illegal trade continued, with profiteering by those distributing kava imported from several Pacific island countries. In October 2000, the Kava Management Act was amended to incorporate harm reduction objectives and a system of licensed kava supply, controlled by local Aboriginal community organisations.

Over the last decade, there has been an expanding global market for herbal preparations made in Western countries and containing kava extracts.4 These products have been marketed for the treatment of anxiety, insomnia, premenstrual syndrome and stress, and sold over the counter as complementary medicines or dietary supplements.6 Since 1999, cases of severe hepatic toxicity in people using kava-containing herbal products have been reported from Europe and the United States.6,7 Subsequently, kava-based herbal products have been banned in some European countries, including the United Kingdom. In Australia, a practitioner alert and consumer advice were issued in February 2002 by the Therapeutic Goods Administration (TGA) concerning hepatotoxicity possibly related to kava-containing products. By late 2002, eight cases of liver transplantation after hepatic failure associated with use of kava-containing products had been reported from Europe, and two from the United States.6 The patient reported by Gow et al died soon after liver transplantation.1 As a result of this case, the TGA initiated a voluntary recall of all complementary medicines containing kava extracts on 15 August 2002.8 The TGA has 87 products containing kava on its Australian Register of Therapeutic Goods.8

Although details are sketchy for many of the at least 68 cases of suspected kava hepatotoxicity,4 with the herbal products sometimes containing additional ingredients, the increasing number of well documented cases1,6,7 make it likely that kava extracts are responsible for occasional severe progressive hepatotoxicity. However, the mechanism of this toxicity remains to be determined. Histological examination has shown portal inflammation with lymphocytes and eosinophils,6,7,9 and an idiosyncratic immune response to a reactive metabolite has been suggested as a possible cause.9 In two patients, phenotyping of the activity of cytochrome P450 isoform CYP2D6 showed that they were "poor metabolisers", and it was postulated that genetic differences in liver metabolism of kavalactones may be important.9

Moulds and Malani discuss the paradox that fulminant hepatic failure has not been documented with traditional kava use in Pacific countries.2 Kavalactones in herbal products are usually extracted with ethanol or acetone,6 and may differ critically from the aqueously extracted kavalactones used in Pacific countries and Aboriginal communities.

Of note is an early study of the health effects of kava use in Aboriginal communities, which documented consistent abnormalities in liver function tests in heavy kava drinkers.5 A recent study in Arnhem Land has confirmed these findings, with abnormal serum levels of γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) in 61% and 50% of kava users, respectively.10 However, serum levels of alanine aminotransferase (ALT) were not raised in any kava drinkers. Furthermore, the abnormalities in liver function usually return to normal within 1–2 months of stopping kava use.10 The raised GGT and ALP levels combined with normal ALT levels in Aboriginal kava users do not suggest acute inflammation and are not consistent with the changes documented in the cases of hepatotoxicity associated with herbal products, where aminotransferase levels are especially high.1,6,7 Clinical surveillance in the Northern Territory over 20 years has not documented any cases of fulminant hepatic failure attributable to kava use. This is despite Aboriginal kava drinkers consuming kavalactones in doses estimated to be 10–50 times the recommended therapeutic doses for herbal products.3 However, the recent study confirmed adverse effects of kava, such as kava dermopathy and lymphocytopenia,10 which were documented in the 1980s.5

Although a rigorous systematic review found kava to be an effective symptomatic treatment option for anxiety,4 herbal preparations should not be used until the mechanism for hepatic toxicity is clearly ascertained. The abnormal but reversible GGT and ALP levels seen in heavy kava drinkers does not reflect the same pathological process. Whether the apparently idiosyncratic fulminant hepatic failure documented with herbal kava preparations can also occur with traditional aqueous extracts requires further surveillance. Close monitoring for this and other potential adverse effects of kava use in Aboriginal communities and Pacific countries is recommended, in addition to initiatives encouraging moderation in consumption.