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)

8. Probable cause relationship related to overdosage of kava extract In addition to the above mentioned case related to recommended usage (Strahl et al.), there are three cases with a possible causality to kava, associated with non-recommended dosages. One such case can be classified as drug abuse (Kraft et al. 2001). In one case, a contributing immunological reaction and a concurrent cytochrom-P450-2D6 deficiency could be detected (IKS-case 2000-0014). The official justification for a causal relationship in another case (IKS-case 2000-3052) is based on erroneous correlations and should therefore be classified as doubtful. 8.1 IKS-Case number 2000-0014, Liver transplant This Swiss case has been described in the medical literature, several times, in detail (30;31;35). Patient: female, 33 years Date of entry: March 21, 2000 Adverse effects reported: Jaundice, cholestatic hepatitis Preparation: Laitan (70 mg kavalactones, acetone extract), 210 mg/day orally for 2-3 months. Co-medication: Analgesic drug: 125 mg propyphenazone + 0.5 mg dihydroergotamine-mesylate+ 40 mg caffeine, taken once due to alcohol intake the evening before (see below). No known liver effects. Analgesic drug: 250 mg paracetamol (acetaminophen) + 150 mg propyphenazone + 50 mg caffeine, last date of intake: 02-13-2001 No known liver effects for propyphenazone. The hepatotoxic effects of paracetamol (acetaminophen) have been mentioned previously. Homeopathic combination product: Acidum silicicum D12 + Arnica montana D6 + Carbo vegetabilis D12 + Echinacea angustifolia D3 + Graphites D6 + Myristica sebifera D6 + Sulfuris iodidum D6, start of intake: 02-05-2000, last date of intake: 02-20-2000. No known liver effects. Extreme alcohol use on February 12, 2000, otherwise little alcohol consumption. The complaints started on February 13, first as a hang-over from alcohol, which led to the use of the pain medications listed above. After the hangover, the patient suffered increasingly from inappetence, fatigue, epigastric pressure and severe weight loss. On February 20, she noticed a dark coloration of the urine, had orthostatic complaints and dyspnea when active. Laitan was discontinued. The virus serology for hepatitis A-C was negative, and there was only one weak positive EBV-reaction which could indicate a reactivation of the previous infection. Obstruction of the biliferous ducts and autoimmune disease could be excluded. The transaminases were extremely elevated. The liver biopsy pointed towards a drug-induced, toxic genesis and, despite the extreme alcohol intake on February 12, an ethanolic genesis could be excluded. The patient had fully recovered by May 4, 2000. In addendum, a lymphocyte-transformation test was performed, which turned out positive for Laitan but negative for the homeopathic combination product. Based on the evaluation by the IKS, a causal relationship to kava was classified as „probable“; in light of the existing documentation, this conclusion by the IKS should be accepted. Subsequently, a cytochrome P450-2D6 deficiency could be detected in the patient. Considering the positive outcome of the lymphocyte transformation test, Russmann et al. (2001) (30;31) point towards an immuno-allergic reaction, as in the case published by Strahl et al. (1998) (36). 8.2 IKS-Case number 2000-3502, Liver transplant The case was reported by a hospital and is described several times, in detail, in the medical literature (14;30;35). Patient: male, 50 years Date of entry: Unknown Reported adverse effects: Acute subfulminant hepatitis with liver transplant Preparation: Laitan (70 mg kavalactones, acetone extract), 210-280 mg kavalactones, orally for 1.5 months Co-medication: Paracetamol (acetaminophen) 500-1000 mg, shortly before transplant (not related to the cause of this case; see below). Occasional intake of Evening Primrose Oil but not in October and November 1999. Yeast preparation. Kava was taken from the end of October to December 7. At the end of November, the patient noticed a dark coloration of the skin, similar to a sun tan. On December 5, an icteric condition developed, which led to the doctor's visit. The liver values, determined on December 7, were extremely elevated. Subsequently, the kava preparation was discontinued. The virus serology for hepatitis A,B,C and E was negative, as well as HIV and CMV. The serology indicated signs of a previous EBV infection. The results, however, are not consistent with a reactivation. An obstruction of the biliferous ducts could be exluded based on the sonographic examination. Later, ascites developed quickly as well as signs of hepatic encephalopathy; the patient was intubated on 12-13-1999. A liver transplant was considered. Even before the liver transplant, the patient developed fever, a skin rash and serious symptoms of liver failure. The patient received 500–100 mg paracetamol (acetaminophen) for fever reduction. The following toxicological blood tests indicated residual levels of paracetamol (acetaminophen) below the norm of the corresponding last dosage as well as traces of lidocain, caffeine, atracurium and metoclopramide in the urine. The liver transplant was performed on December 16, 1999. The biopsy results showed extreme signs of toxic-necrotic hepatitis. The IKS evaluated the causal relationsip to kava as „probable“. Escher et al. (2001) excluded an ethanol genesis in this case (14). The detection of caffeine is possibly related to the hospital breakfast and the detection of lidocaine (local anesthetic) and atracurium (muscle relaxant used for intubations) is likely a result of the co-medications related to the intubation procedure; presumably, this is also the case with metoclopramide, a motility-lowering drug. Administration of these preparations had not been documented by Escher et al.. The classification as „probable“ by the expert of the IKS is obviously based on erroneous information. He refers, in addition to the Stahl publication, to six kava side effect cases which were supposedly listed by the WHO. In reality, there were only three cases at the time of evaluation, but the searched keywords („hepatitis“, „cholestatic hepatitis“, „liver cell damage“ and „jaundice“) resulted in six hits from the database; the three relevant cases had overlapping symptom reports. The relevant WHO-cases correspond to the BfArM cases 93015209, 94006568 and 94901308. While for case 94006568 the causality to kava is very questionable, the other two cases indicate a causal relationship to co-medications (diazepam and terfenadine, respectively). For the support of causality based on previous cases, there is, at most, only one publication by Strahl et al. (1998) to consider. Therein, the causes are relatively well-clarified (see below) and should likely not represent a common mechanism. The causality to kava based on the previous incidences is possible, particularly because the usage clearly exceeded the recommended dosage. 8.3 Literature case: Kraft et al. (2001), Liver transplant The most recent case from the medical literature was reported by Kraft et al. (2001) (22). This case was classfied as drug abuse. Patient: female, 60 years Date of entry: September 7, 2001 Reported adverse effects: Fulminant liver failure with liver transplant Preparation: Antares (120 mg kavalactones, ethanol extract), 480-1200 mg kavalactones / day for over one year at a self-prescribed dosage increase. Co-medication: Etilefrine-HCl, occasionally for orthostatic dysregulation. No adverse effects listed. Diuretic: Piretanide for recidivating edematous tendencies based on a past ovariectomy. No label-stated side effects. The patient was hospitalized due to progradient exhaustion, weight loss and icterus with dark coloration of the urine and jaundice. At the time of hospital admission, the symptoms had been present for 14 days. The patient had suffered from pulmonary embolism 11 years ago, with cardiopulmonary reanimation, and 21 years ago, she had a ovariectomy and cholecystectomy. For 8 years, she suffered from increasing depression. Alcohol consumption was negative, according to the patient's statement. Transaminases and bilirubin were strongly elevated, and there were signs of beginning kidney failure. Assays for hepatitis A, B and C, HIV, CMV, EBV, HSV as well as for Varicella-Zoster-Virus were performed. The sonographic exam revealed nothing suspicious. There were no indications of an obstruction of the biliferous ducts. The histological exam revealed an extensive necrosis of the hepatic cells with intrahepatic cholestasis. Progressive encephalopathy and pulmonary failure requiring intubation, as well as rising bilirubin levels, made a liver transplant necessary. Kraft et al. (2001) (22) suspect a connection with an immunological event based on the cases reported by Strahl et al. (1998) (36) and Escher et al. (2001) (14). However, Escher et al. did not indicate a re-exposure, and the data from this case does not include sensitization as a contributing factor. Also, the lymphocyte transformation test is missing although Escher participated in the studies by Russmann et al. wherein, according to the Strahl case and the IKS case 2000-0014, a sensitization to kava could be detected (30). Finally, according to Kraft et al. (2001), a contribution by a co-medication (piretanide) cannot be excluded. It is apparent that kava was not used according to the label recommendation. The dosage prescribed by the physician exceeded the recommended daily dosage by a factor of 4, and the administration of kava was contraindicated for „depression“. Information from relatives revealed that the patient took extra doses ad libitum in addition to the already overdosed regimen. Some statements indicated the use of up to 10 tablets per day. In light of the abuse of the kava preparation and the co-medication which was not considered, a causal relationship to kava should be regarded as „possible“.

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