INTRODUCTION
	1. Total Listed Cases
	2. Duplicate Entries
	3. Side Effects With No Relationship to the Ingestion of Kava
	4. Causal relationship with concomitant medication probable
	5. Doubtful Causality
	6. Causal relationship cannot be evaluated due to information status
	7. Causal relationship probable at monograph-conforming dosage
	8. Probable cause relationship related to overdosage of kava extract
	9. Literature

Analysis of Kava Side Effects Reports Concerning the Liver

Translation to English by Lindenmaier M and Brinckmann J
31. December 2001

Analysis of hepatotoxic reactions listed by the BfArM (German Federal Institute for Drugs and Medical Devices)

7. Causal relationship probable at monograph-conforming dosage From the original 32 suspected cases, there are only 4 cases with probable causality to kava that remain after substraction of the double entries, the cases unrelated to kava as well as the improbable or doubtful ones. Of these 4 cases, only one is related to a monograph-conforming dosage regimen (Strahl et al. 1998). The remaining 3 cases should be therefore classified as usages associated with overdosages. In the only kava side effect case associated with recommended use and a somewhat causal certainty, there seems to be an existing relationship to an immunoligical condition in combination with a congentical cytochrom P450-2D6 deficency. A comparable cause could also possibly be related to one case associated with overdosage (IKS-Nr. 2000-0014; see below). In principle, drug sensitization cannot be excluded. In both cases where such a sensitization had been reported, the patients suffered from complications related to enzyme defects of the hepatic metabolism. Such case reports associated with sensitization could be expected from other drug substances which are metabolized by the same enzyme system. Such kind of incidences occur only very rarely, possibly because the combination of a poor metabolism and sensitization to kava-metabolites has only a low probabilty of occurring. 7.1 Literature case: Strahl et al. (1998) The case described by Strahl et al. (1998) (36) was the first relatively well-documented case of a serious hepatic side effect related to kava. The evaluation of the incidence was complicated by the fact that the kava preparation could not be identified with certainty. Based on the information by the authors, an ethanol extract with 60 mg kavalactones per unit was used. Communications with the German product manufacturers revealed that none of the companies had received any information about this case. Obviously, the authors did not notice the mandatory reporting procedures for adverse drug effects. However, doubts regarding the intake of a kava product were, in this case, unfounded. Later, other parties involved provided further details, which could indicate a possible causal relationship (30;31). Patient female, 39 years Date of entry: Unknown Reported adverse effects: Acute necrotic hepatitis Preparation: Unknown (60 mg kavalactones, ethanol extract), 60 mg kavalactones/day over 6 months Co-medication: Antidepressive drug: 20 mg paroxetin. Side effects: transient elevation of liver values Occasional use of St. John's wort. No known liver effects. Contraceptive (0.15 mg desogestrel + 0.02 mg ethinylestradiol) for 6 years Listed side effects: cholestasis, anicteric hepatitis, cholestatic icterus The patient was admitted to the hospital in order to investigate the elevated liver values. The hepatitis serology was negative; the sonography results were inconspicuous. The histological image was consistent with a diffuse and nectrotizing hepatitis, suggesting a viral or toxic genesis. After discontinuation of the medications, the liver values continued to rise for a week and then returned to normal values. Six months later, a new increase in transaminases could be observed. Anamnestically, a renewed kava intake was observed without further co-medication. The clinical image raised the suspicion of an exogenic-toxic, hepatopathic genesis. The serological tests could exclude hepatitis A, B and C, CMV, EBV, toxoplasmosis and leptospirosis. The sonographic image revealed a past hepatitis episode. The histopathological findings were consistent with an acute, necrotizing hepatitis. An autoimmune hepatits could not be excluded with certainty. After 4 weeks, the liver values improved, reaching normal levels after 4 months. Based on the positive re-exposure to kava, the lymphocyte transformation test was not performed. The shortened latency period, however, points towards an immunological sensitization on initial intake. Based on the positive re-exposure reaction and the negative virus serology, one can assume that this case has indeed a causal relationship to kava. Russmann et al. (2001) (31) suspect a relationship to a cytochrome P450-2D6 deficiency: they investigated the metabolic pattern of the patient and found a congenital deficiency for this enzyme system. This incidence could, therefore, have been caused by an immunological event based on the sensitization to a reactive kava metabolite. This explanation is supported by a positive re-exposure reaction and the shortened latency period in the second incidence. Allergic reactions to plant-derived drug substances have to be considered and, in the case of kava, are indicated on the label in the package insert.

www.mauikava.com
cliff@mauikava.com
©2009