Case study reviewed: Humberston CL, Akhtar J, Krenzelok EP. Acute hepatitis induced by kava kava. J Toxicol Clin Toxicol 2003;41(2):109–13.
This article reports that a patient developed liver failure requiring a liver transplant following chronic ingestion of a kava-containing product, Tension Tamers® (Celestial Seasonings).
A 14-year-old female with no previous history of health problems was admitted to a hospital with hepatitis. Prior to admission, the patient had nausea and daily vomiting for 10 days. Two days prior to admission she developed jaundice and a laboratory work up revealed elevated bilirubin and liver enzymes. The patient had been taking 2 tablets daily of Tension Tamers® for anxiety for 4 months prior and denied taking acetaminophen, mushrooms or “other known hepatotoxins.” A comprehensive urine drug screen taken at the hospital was positive for ranitidine, ibuprofen, and caffeine. Her liver function continued to deteriorate post admission and a liver biopsy showed 70% hepatocellular necrosis. She was given supportive therapy consisting of daily plasmapheresis, lactulose, vitamin K and ranitidine. On day 8 of her admission, she had an orthotopic liver transplant. Seven months after the transplant, the patient was healthy and had normal results on her liver function tests. Her pathology report showed evidence of fulminant hepatitis with total hepatocyte necrosis.
Tension Tamers® is a combination formula containing kava (100 mg), chamomile (Matricaria chamomilla 100 mg), magnesium (25 mg), St. John’s wort (Hypericum perforatum 50 mg), vitamin B6 (3 mg), vitamin B12 (6 mcg) and vitamin C (150 mg). This case report sets out details of the historical uses of kava as well as a review of its constituents, legal status in Germany and Sweden, and theoretical mode of action as an anxiolytic. The case report details the hepatotoxic effects attributed to the use of germander (Teucrium chamaedrys) as a weight reduction aid and contains some discussion of the possible hepatotoxicity of chaparral (Larrea tridentata). The authors also review the uses of St. John’s wort and its action on the cytochrome P450 system and suggest the possibility that “the toxicity in our patient was potentiated by St. John’s wort because of its effect on the cytochrome P450 system.” The potential adverse effects of chamomile are also reviewed but the authors conclude that its compounds are not hepatotoxic. The case report concludes that the temporal connection between the ingestion of Tension Tamers® and “the failure to identify other causes of liver failure” suggests that kava caused the liver failure in this case. The authors close with a caution that there is an urgent need for legislation to control the quality of herbal preparations.
The case report does not discuss why ibuprofen or ranitidine were present in the patient’s urine and fails entirely to consider whether they may have caused or contributed to the patient’s liver failure. The corresponding author, in response to an inquiry regarding the patient’s use of these drugs responded: “She was healthy and the only medicine she took besides the kava kava was ibuprofen. This was infrequently used and was OTC. The history does not indicate when was the last use. The ranitidine was given in the hospital.”
Ibuprofen has caused liver failure at therapeutic doses.[1] Ranitidine can also cause liver failure in humans and rats.[2], [3] This case report has a major flaw due to its failure to even consider that ibuprofen may have caused the patient’s hepatitis. The report should also have analyzed the possibility that the ranitidine prescribed at the hospital may have precipitated or aggravated the liver failure that occurred 8 days after hospital admission. The conclusion that kava caused this case of liver failure is based on a erroneous determination that “a negative work-up for alternative causes of liver failure was negative.”
Even if this case were to represent a hepatotoxic reaction to kava, the evidence strongly suggests such reactions are idiosyncractic. If kava had an intrinsic hepatotoxic effect, the millions of daily kava users of kava daily would be developing liver ailments at much higher rates than those reported. Given the number of cases reported in Germany (removing duplicate reports) prior to the ban on kava there, the incidence of kava-related hepatotoxicity was 0.008 per one million users.[4] There are also documented cases of people taking far higher doses of kava without more than isolated elevated serum gamma-glutamyltransferase levels.[5] Finally, the patient’s supply of Tension Tamers® should have been analyzed to verify its contents and to determine whether it contained any adulterants or contaminants before the conclusion that kava caused this case of liver failure could be reached.
Eric Yarnell, ND, RH(AHG) and Kathy Abascal, BS, JD, AHG
This article reports that a patient developed liver failure requiring a liver transplant following chronic ingestion of a kava-containing product, Tension Tamers® (Celestial Seasonings).
A 14-year-old female with no previous history of health problems was admitted to a hospital with hepatitis. Prior to admission, the patient had nausea and daily vomiting for 10 days. Two days prior to admission she developed jaundice and a laboratory work up revealed elevated bilirubin and liver enzymes. The patient had been taking 2 tablets daily of Tension Tamers® for anxiety for 4 months prior and denied taking acetaminophen, mushrooms or “other known hepatotoxins.” A comprehensive urine drug screen taken at the hospital was positive for ranitidine, ibuprofen, and caffeine. Her liver function continued to deteriorate post admission and a liver biopsy showed 70% hepatocellular necrosis. She was given supportive therapy consisting of daily plasmapheresis, lactulose, vitamin K and ranitidine. On day 8 of her admission, she had an orthotopic liver transplant. Seven months after the transplant, the patient was healthy and had normal results on her liver function tests. Her pathology report showed evidence of fulminant hepatitis with total hepatocyte necrosis.
Tension Tamers® is a combination formula containing kava (100 mg), chamomile (Matricaria chamomilla 100 mg), magnesium (25 mg), St. John’s wort (Hypericum perforatum 50 mg), vitamin B6 (3 mg), vitamin B12 (6 mcg) and vitamin C (150 mg). This case report sets out details of the historical uses of kava as well as a review of its constituents, legal status in Germany and Sweden, and theoretical mode of action as an anxiolytic. The case report details the hepatotoxic effects attributed to the use of germander (Teucrium chamaedrys) as a weight reduction aid and contains some discussion of the possible hepatotoxicity of chaparral (Larrea tridentata). The authors also review the uses of St. John’s wort and its action on the cytochrome P450 system and suggest the possibility that “the toxicity in our patient was potentiated by St. John’s wort because of its effect on the cytochrome P450 system.” The potential adverse effects of chamomile are also reviewed but the authors conclude that its compounds are not hepatotoxic. The case report concludes that the temporal connection between the ingestion of Tension Tamers® and “the failure to identify other causes of liver failure” suggests that kava caused the liver failure in this case. The authors close with a caution that there is an urgent need for legislation to control the quality of herbal preparations.
The case report does not discuss why ibuprofen or ranitidine were present in the patient’s urine and fails entirely to consider whether they may have caused or contributed to the patient’s liver failure. The corresponding author, in response to an inquiry regarding the patient’s use of these drugs responded: “She was healthy and the only medicine she took besides the kava kava was ibuprofen. This was infrequently used and was OTC. The history does not indicate when was the last use. The ranitidine was given in the hospital.”
Ibuprofen has caused liver failure at therapeutic doses.[1] Ranitidine can also cause liver failure in humans and rats.[2], [3] This case report has a major flaw due to its failure to even consider that ibuprofen may have caused the patient’s hepatitis. The report should also have analyzed the possibility that the ranitidine prescribed at the hospital may have precipitated or aggravated the liver failure that occurred 8 days after hospital admission. The conclusion that kava caused this case of liver failure is based on a erroneous determination that “a negative work-up for alternative causes of liver failure was negative.”
Even if this case were to represent a hepatotoxic reaction to kava, the evidence strongly suggests such reactions are idiosyncractic. If kava had an intrinsic hepatotoxic effect, the millions of daily kava users of kava daily would be developing liver ailments at much higher rates than those reported. Given the number of cases reported in Germany (removing duplicate reports) prior to the ban on kava there, the incidence of kava-related hepatotoxicity was 0.008 per one million users.[4] There are also documented cases of people taking far higher doses of kava without more than isolated elevated serum gamma-glutamyltransferase levels.[5] Finally, the patient’s supply of Tension Tamers® should have been analyzed to verify its contents and to determine whether it contained any adulterants or contaminants before the conclusion that kava caused this case of liver failure could be reached.
Eric Yarnell, ND, RH(AHG) and Kathy Abascal, BS, JD, AHG
Citations
[1] Rodriguez-Gonzalez FJ, Montero JL, Puente J, et al. Orthotopic liver transplantation after subacute liver failure induced by therapeutic doses of ibuprofen. Am J Gastroenterol 2002;97(9):2476–7.
[2] Luparini RL, Rotundo A, Mattace R, Marigliano V. Possible ranitidine-associated autoimmune hepatitis. Annali Italiani di Medicina Interna 2000;15(3):214–7 [in Italian].
[3] Luyendyk JP, Maddox JF, Cosma GN, et al. Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats. J Pharmacol Exp Ther 2003;307(1):9–16.
[4] Schmidt M, Nahrstedt A. Ist Kava lebertoxisch? Eine Analyse der bekannten Daten zum Leberrisiko von Kava-Präparaten. Dtsch Apoth Ztg 2002;142(9):1006–11.
[5] Chanwai LG. Kava toxicity. Emerg Med 2000;12:142–5.
[2] Luparini RL, Rotundo A, Mattace R, Marigliano V. Possible ranitidine-associated autoimmune hepatitis. Annali Italiani di Medicina Interna 2000;15(3):214–7 [in Italian].
[3] Luyendyk JP, Maddox JF, Cosma GN, et al. Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats. J Pharmacol Exp Ther 2003;307(1):9–16.
[4] Schmidt M, Nahrstedt A. Ist Kava lebertoxisch? Eine Analyse der bekannten Daten zum Leberrisiko von Kava-Präparaten. Dtsch Apoth Ztg 2002;142(9):1006–11.
[5] Chanwai LG. Kava toxicity. Emerg Med 2000;12:142–5.