Sir,
We thank Dr. Stickel for his insightful comments on our recent letter (Aghdassi et al. 2015). He and Dr. Shouval had originally compiled detailed evidence that drug-induced liver injury associated with non-prescription herbal dietary supplements can, to a certain extent, be attributed to polymorphisms in the cytochrome P450 gene (Stickel and Shouval 2015). One of these agents is a pharmaceutical extract of the herbal antidepressant kava–kava, which was withdrawn from international markets by regulatory authorities because of a significant number of reported cases with severe kava-associated liver injury (Kraft et al. 2001; Stickel et al. 2003). We had collected four such cases and found that half of those requiring transplantation had a polymorphism in the uridine-diphosphate (UDP)-glucuronosyltransferase (UGT) gene that had previously been found to account for a reduced detoxification capacity (Vogel et al. 2001). We also found that none of the patients carried the poor metabolizer CYP2D6 genotype. Other UGT polymorphisms had already been found to be associated with an increased risk of gallstone formation (Buch et al. 2010) or pancreatic injury (Ockenga et al. 2003), but Dr. Stickel correctly points out that the initial association studies were fraught by a PCR amplification bias and subsequent reanalyses resulted in much less prominent associations.
For drug-induced pancreatic injury, very little is known about potential genetic associations (Grady et al. 1992; Keim et al. 2001). Even more regrettably, neither consented definitions nor drug injury consortia exist that would permit an analysis of underlying genetic and environmental factors, all of which are well-established features of liver injury networks (Navarro et al. 2014).
Dr. Stickel points out that our evidence for an association between drug-induced liver injury and UGT polymorphisms is weak at best, and we do agree with his assessment. After much confusion resulting from the PCR amplification bias that weakened initial studies (Vogel et al. 2001; Ockenga et al. 2003), more recent studies have improved in robustness, but investigations conducted by established liver injury networks are urgently needed before any definite conclusions about the role of UGT can be made. Our letter was meant to encourage such investigations and is clearly insufficient to establish a UGT gene association with kava-induced liver injury.
Dr. Stickel further points to a female predominance among patients with kava-related liver injury and suggests that consumer preference for mild herbal antidepressant may account for this skewed gender ratio. In this context, it is interesting that kava–kava originates from Polynesian islands where it is used in ceremonial (and sometimes recreational) drinking rituals, and its mild sedative, anaesthetic and anxiolytic properties are much appreciated. Unlike for pharmaceutical extracts, cases of liver injury have not been reported in connection with ceremonial use of fresh kava potions. One possible reason may be that women are traditionally excluded from kava-consuming rituals in the island societies of Vanuatu, Fiji and others, and sex-linked factor for liver injury may be a worthwhile target for further investigations. Dr. Stickel rightly indicates that kava extracts may no longer pose a medical problem because of its withdrawal from the markets. However, the liver toxicity of other herbal extracts like St. John’s Wort, Teucrium chamaedrys and certain types of green tea is still incompletely understood. We agree with Dr. Stickel that for these compounds drug-induced liver injury repositories and biobanks ought to play a much greater role in identifying the underlying mechanism of damage.
References
Aghdassi AA, Kraft M, Domschke W, Lerch MM, Weiss FU (2015) Genetic polymorphisms in the UDP-glucuronosyltransferase UGT1A7 gene in patients with acute liver failure after kava–kava consumption. Arch Toxicol. doi:10.1007/s00204-015-1578-6
Buch S, Schafmayer C, Völzke H et al (2010) Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition. Gastroenterology 139(6):1942–1951. doi:10.1053/j.gastro.2010.09.003
Grady T, Saluja AK, Steer ML et al (1992) In vivo and in vitro effects of the azidothymidine analog dideoxyinosine on the exocrine pancreas of the rat. J Pharmacol Exp Ther 262(1):445–449
Keim V, Bauer N, Teich N et al (2001) Clinical characterization of patients with hereditary pancreatitis and mutations in the cationic trypsinogen gene. Am J Med 111(8):622–626
Kraft M, Spahn TW, Menzel J, Senninger N, Dietl KH, Herbst H, Domschke W, Lerch MM (2001) Fulminant liver failure after administration of the herbal antidepressant kava–kava. Dtsch Med Wochenschr 126:970–972
Navarro VJ, Barnhart H, Bonkovsky HL et al (2014) Liver injury from herbals and dietary supplements in the US drug-induced liver injury network. Hepatology 60(4):1399–1408. doi:10.1002/hep.27317
Ockenga J, Vogel A, Teich N et al (2003) UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer. Gastroenterology 124(7):1802–1808 [Erratum in: Gastroenterology 140(5):1696]
Stickel F, Shouval D (2015) Hepatotoxicity of herbal and dietary supplements: an update. Arch Toxicol 89(6):851–865. doi:10.1007/s00204-015-1471-3
Stickel F, Baumüller HM, Seitz K, Vasilakis D, Seitz G, Seitz HK, Schuppan D (2003) Hepatitis induced by kava (Piper methysticum rhizoma). J Hepatol 39(1):62–67
Vogel A, Kneip S, Barut A et al (2001) Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGT1A7 gene. Gastroenterology 121(5):1136–1144
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Aghdassi, A.A., Weiss, F.U. & Lerch, M.M. Liver injury and genetic polymorphisms in the cytochrome P450 and UDP-glucuronosyltransferase genes. Arch Toxicol 90, 229–230 (2016). https://doi.org/10.1007/s00204-015-1649-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-015-1649-8