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HLA‐B*35:01 and Green Tea–Induced Liver Injury
Abstract
Background and Aims: Herbal supplements, and particularly multi‐ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea‐associated liver injury. Approach and Results: Among 1,414 patients enrolled in the U.S. Drug‐Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea–associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15‐448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re‐exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA‐B*35:01, found in 72% (95% confidence interval [CI], 58‐87) of green tea cases, but only 15% (95% CI, 10‐20) caused by other supplements and 12% (95% CI, 10‐14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5‐11.5). Conclusions: Green tea–related liver injury has distinctive clinical features and close association with HLA‐B*35:01, suggesting that it is idiosyncratic and immune mediated.
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“HLA polymorphisms shown to be significantly associated with multiple drugs include HLA-A*02:01 for AC and cefazolin DILI and HLA-B*35:01 for multiple HDS products, including green tea extract, turmeric, and Polygonum multiform.”
From The contemporary epidemiology, causes, and management of drug-induced liver injury (2026) · cites this paper as [32]
In the citing paper
“Interestingly, HLA-B*35:01 was associated with turmeric hepatotoxicity, as it had been previously associated with green tea extract hepatotoxicity. 32”
From The contemporary epidemiology, causes, and management of drug-induced liver injury (2026) · cites this paper as [32]
In the citing paper
“A focused analysis of GTE cases enrolled in the DILIN has led to recognition of the typical presentation of GTE as being hepatocellular and sometimes fatal, with a strong genetic association with HLA‐B*35:01.72”
From AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury (2023) · cites this paper as [72]
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Self-citationGreen Tea Consumption and Mortality Due to Cardiovascular Disease, Cancer, and All Causes in Japan
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Self-citationDrug-Induced Liver Injury Network (DILIN) Prospective Study: Rationale, Design and Conduct
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HIBAG—HLA genotype imputation with attribute bagging
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Cited by
ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury
Chalasani, N. P., Maddur, H., Russo, M. W., Wong, R. J., Reddy, K. R., & on behalf of the Practice Parameters Committee of the American College of Gastroenterology (2021) · American Journal of Gastroenterology · doi:10.14309/ajg.0000000000001259 · Cited by 430
AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury
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Halegoua-DeMarzio, D., Navarro, V., Ahmad, J., Avula, B., Barnhart, H., Barritt, A. S., Bonkovsky, H. L., Fontana, R. J., Ghabril, M. S., Hoofnagle, J. H., et al. (2023) · The American Journal of Medicine · doi:10.1016/j.amjmed.2022.09.026 · Cited by 119
Self-citationKesar, V., Channen, L., Masood, U., Grewal, P., Ahmad, J., Roth, N. C., & Odin, J. A. (2022) · Liver Transplantation · doi:10.1002/lt.26260 · Cited by 23
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Metadata
- Authors
- Hoofnagle, J. H., Bonkovsky, H. L., Phillips, E. J., Li, Y., Ahmad, J., Barnhart, H., Durazo, F., Fontana, R. J., Gu, J., Khan, I., Kleiner, D. E., Koh, C., Rockey, D. C., Seeff, L. B., Serrano, J., Stolz, A., Tillmann, H. L., Vuppalanchi, R., Navarro, V. J., & for the Drug‐Induced Liver Injury Network
- Affiliations
- Liver Disease Research Branch,Division of Digestive Diseases and Nutrition,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health (NIH),Bethesda,MD
- National Cancer Institute,National Institutes of Health (NIH),Bethesda,MD
- Department of Medicine,Vanderbilt University Medical Center,Nashville,TN
- Duke Clinical Research Institute,Duke University,Durham,NC
- Department of Medicine,Icahn School of Medicine at Mount Sinai,New York,NY
- University of California Los Angeles,David Geffen School of Medicine,Los Angeles,CA
- Department of Medicine,University of Michigan School of Medicine,Ann Arbor,MI
- National Center for Natural Products Research,University of Mississippi,University,MI
- The Laboratory of Pathology,National Cancer Institute, NIH,Bethesda,MD
- Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),Bethesda,MD
- Digestive Disease Research Center,Medical University of South Carolina,Charleston,SC
- Department of Medicine,Einstein Healthcare Network,Philadelphia,PA
- Department of Medicine,University of Southern California School of Medicine,Los Angeles,CA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine,East Carolina University,Greenville,NC
- Department of Medicine,Indiana University School of Medicine,Indianapolis,IN
- ORCID
- Vuppalanchi, Raj
- Venue
- Hepatology
- Published
- 2021-05-17
- Volume
- 73
- Issue
- 6
- Pages
- 2484-2493
- ISSN
- 0270-9139
- 1527-3350
- PMC
- PMC8052949
- Cited by
- 98
- References
- 36
- Language
- en
- Licence
- onlinelibrary.wiley.com/termsAndConditions#vor (vor)
- doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
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- Hoofnagle, J. H., Bonkovsky, H. L., Phillips, E. J., Li, Y., Ahmad, J., Barnhart, H., Durazo, F., Fontana, R. J., Gu, J., Khan, I., Kleiner, D. E., Koh, C., Rockey, D. C., Seeff, L. B., Serrano, J., Stolz, A., Tillmann, H. L., Vuppalanchi, R., Navarro, V. J., & for the Drug‐Induced Liver Injury Network. (2021). HLA‐B*35:01 and Green Tea–Induced Liver Injury. Hepatology. https://doi.org/10.1002/hep.31538
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