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DRUG RECORD

 

GREEN TEA

(CAMELLIA SINESIS)

OVERVIEW
Green Tea

 

Introduction

Green tea is a popular and commonly consumed drink and its extract is found in many herbal and dietary supplements (HDS).  Green tea extract and concentrated infusions of green tea have been implicated in many cases of clinically apparent acute liver injury, including instances of acute liver failure and death.

 

Background

Both green tea and black tea are produced from the leaves of the Chinese tea tree Camellia sinensis.  Green tea, unlike black tea, is unfermented, which helps to preserve its antioxidant polyphenolic catechols.  Green tea has long been believed to have health restoring properties and its ingredients to have antioxidant activity.  For this reason, extracts of green tea have been used as an herbal medication alone and in combination with other herbals and dietary supplements which are advertised to improve health, prevent cancer and heart disease, decrease serum lipid levels, promote weight loss, decrease periodontal disease and treat clostridial diarrhea.  Green tea extract is listed in more than 100 over-the-counter herbal preparations, but is not approved for any specific medical indication and is not strictly regulated by the FDA.  The multiple polyphenols in green tea are believed to be the active components responsible for its purported chemoprotective, antiproliferative and antioxidant properties.  The mechanism by which green tea may have such effects has not been elucidated.  Human clinical studies demonstrate that single doses of up to 1.6 grams of green tea extract are well tolerated.  The maximum tolerated dose in humans is reported to be 9.9 grams per day; a dose equivalent to 24 cups of green tea.  Side effects of high doses of green tea extract are usually mild and include headache, dizziness and nausea.  The safety and tolerability of long term use of green tea extracts has not been well defined.

 

Hepatotoxicity

Drinking green tea has not been associated with liver injury or serum aminotransferase elevations; indeed, cross sectional studies suggest that heavy use of green tea is associated with lower serum ALT and AST values.  Nevertheless, case series and a systematic review by the United States Pharmacopeia illustrate evidence for the potential for green tea extract to cause hepatotoxicity.  The prevalence of green tea extract induced liver injury is not known, but is probably low in comparison to the wide scale use of these products.  Liver injury typically arises within 3 months, with latency to onset of symptoms ranging from 10 days to 7 months.  The majority of cases present with an acute hepatitis-like syndrome and a markedly hepatocellular pattern of serum enzyme elevations.  Most patients recover rapidly upon stopping the extract or HDS, although fatal instances of acute liver failure have been described.  Biopsy findings show necrosis, inflammation, and eosinophils in a pattern resembling acute hepatitis.  Immunoallergic and autoimmune features are usually absent.  A small number of similar cases have also been described after drinking green tea “infusions” rather than taking oral preparations of extracts of green tea.

 

The most prominent regulatory action against green tea containing products concerned Exolise, a weight loss product which was withdrawn from Spain and France in 2003.  Also, green tea is an ingredient in other supplements including most over-the-counter weight loss agents, some of which have been implicated in causing rare instances of clinically apparent acute liver injury.

 

Mechanism of Injury

Preclinical and human data implicate the catechin component of green tea as the culprit of hepatotoxicity.  Approximately 10% of the green tea extract is composed of catechins; of these, epigallocatechin-3-gallate (EGCG) is present in highest concentration.  There is great variability in the concentration of green tea extract, EGCG and other components among marketed products, which may explain while some products have been implicated in hepatotoxicity.  Exposure of rat hepatocytes to EGCG has been shown to induce mitochondrial toxicity and generation of reactive oxygen species.  The association of liver injury with higher doses of green tea (as in extracts) suggests a component of direct hepatotoxicity, perhaps in the context of some degree of host susceptibility exacerbated by environmental features such as obesity, fasting or glutathionine depletion.

 

Outcome and Management

Given the wide spread consumption of green tea and its extract in various HDS, liver injury from green tea is rare.  Patients who present with acute liver injury particularly with a hepatocellular pattern without an obvious cause should be asked about the use of HDS and green tea extract, and should be advised to stop all herbal medications.  In typical cases, recovery is expected in one to two months.  As in any case of drug induced liver injury, the presentation with or development of abnormal liver function (abnormal mentation indicating encephalopathy), prolongation of the prothrombin time or elevation of the INR, and a depressed albumin, should prompt referral to be considered for liver transplantation.  Patients who developed acute liver injury attributable to green tea extract should be cautioned about reexposure and avoidance of HDS that might include green tea.

 

Drug Class:  Herbal and Dietary Supplements

 

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CASE REPORTS
Green Tea

 

Case 1.  37 year old woman with acute hepatitis after using weight loss supplement.
[Modified from:  Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 2006; 144: 68-71. PubMed Citation]

 

A 37 year old woman developed nausea, abdominal pain and jaundice 4 months after starting a weight loss supplement called The Right Approach Complex (Pharmanex, Provo, Utah), the major component of which was green tea extract.  She denied a history of liver disease, alcohol use, and risk factors for viral hepatitis.  On examination, she was jaundiced but had no fever or rash.  Laboratory tests showed serum bilirubin of 11.7 mg/dL and marked elevations in serum aminotransferase levels (~20 times ULN), with minimal increases in alkaline phosphatase (Table).  Tests for hepatitis A, B and C were negative as were autoantibodies, except for antinuclear antibody which was weakly positive (1:40, speckled pattern).  Liver biopsy revealed marked interface necrosis and inflammation and mild lobular inflammation.  Cholecystectomy and intraoperative cholangiography were performed.  The patient began to improve rapidly and was discharged after two weeks in the hospital.  One month later, liver tests had improved significantly.  One year later, she was again admitted with a one week history of abdominal pain and jaundice.  She admitted to resuming The Right Approach Complex one month earlier, but stopped taking it one week before presentation when she developed dysphagia.  On admission, she was jaundiced.  She again improved rapidly and six months later all liver tests were normal.

 

Key Points

Medication:The Right Choice (383.3 mg C. sinensis extract per 3 capsules)
Pattern: Hepatocellular
Severity:3+
Latency: 4 months initially, 1 month on reexposure
Recovery: 1 month
Other medications:None mentioned

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) AST (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
0 Started The Right Approach (~1 gram of green tea extract daily)
4 months 0 1788 1783 238 11.7 Liver biopsy
5 months ~1 month 92 79   1.9
Time After Restarting Time After Stopping Again Restarted The Right Approach 1 year later
4 weeks 0 1131 977 165 11.7 INR: 1.3
5 weeks 1 week 877 816 165 2.9
9 weeks 5 weeks 69 80
1.2
7 months 6 months 25 27 85 1.0
Normal Values <40 <40 <114 <1.2

Comment

This case demonstrates the typical acute viral hepatitis-like presentation of green tea hepatotoxicity with jaundice, accompanied by marked elevations in serum aminotransferase levels and minimal increases in alkaline phosphatase.  Recurrence with a similar pattern of liver injury upon reexposure to the same product provided strong evidence for a causal association.  Green tea extract was the major ingredient of the supplement and its other components have not been reported to cause liver injury (calcium, chromium, magnolia extract, epimedium extract, banaba leaf extract, β-sitosterol and vanadium).

 

Case 2.  27 year old man with hepatitis attributed to Hydroxycut.
[Modified from:  Stevens T, Qadri A, Zein NN. Two patients with acute liver injury associated with use of the herbal weight-loss supplement Hydroxycut. Ann Intern Med 2005; 142: 477-8. PubMed Citation]

 

A 27 year old man developed fatigue and jaundice 4 to 5 weeks after starting Hydroxycut (9 tablets per day) for weight loss.  He denied previous liver disease, alcohol abuse, recent travel or risk factors for viral hepatitis.  He denied taking any other medications or herbal preparations.  Laboratory tests showed serum biliubin of 7.8 mg/dL and marked elevations in serum aminotransferase levels (ALT 3131 U/L, AST 1808 U/L), with minimal increases in alkaline phosphatase (171 U/L) (Table).  Liver tests worsened for a day and then rapidly improved.

 

Key Points

Medication: Hydroxycut (1.8 grams C. sinensis extract per day)
Pattern: Hepatocellular (R=54)
Severity: 3+ (jaundice, hospitalization)
Latency: 4-5 weeks
Recovery: 1-2 months
Other medications: None

Laboratory Values

Time After Starting Time After Stopping ALT (U/L)

Alk P

(U/L)

Bilirubin (mg/dL) Other
Started Hydroxycut (1.86 g green tea extract daily)
5 weeks 0 3131 171 7.8 Admission
  2 days 3962
 
Peak values
9 weeks 4 weeks 304
 
1.3
Normal Values <40 <150 <1.2

Comment

Green tea hepatotoxicity typically presents with jaundice and an acute viral hepatitis-like syndrome, and a markedly hepatocellular pattern of serum enzyme elevations and rapid improvement upon stopping.  Hydroxycut contains high concentrations of green tea extract, although formulations frequently change.  Because Hydroxycut, like many dietary supplements, is a brand of many products with many ingredients, it is difficult to implicate a specific ingredient of the product as the cause for liver injury.  Other listed components of Hydroxycut included calcium, chromium, potassium Garcinia cambogia, Gymnema sylvestre leaf extract, glucomannan, alpha-lipoic acid, willow bark extract, L-carnitine, caffeine, guarana extract, gelatin, silica and cellulose.

 

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PRODUCT INFORMATION
Green Tea

 

REPRESENTATIVE TRADE NAMES
Green Tea – Generic

 

DRUG CLASS
Herbal and Dietary Supplements

 

SUMMARY INFORMATION

Fact Sheet at National Center for Complementary and Integrative Health, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Green Tea ID: CJ12600000 Herbal Mixture Not Applicable

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REFERENCES
Green Tea

 

References updated: 17 March 2014

  1. Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 731-4.  (Expert review of hepatotoxicity published in 1999; Chinese herbal medications are discussed, but not green tea extract specifically).

  2. Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbals and dietary supplements. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 631-58.  (Review of hepatotoxicity of herbal and dietary supplements [HDS] mentions that there have been at least 58 case reports of liver injury attributed to green tea extracts, powdered leaves or infusions including one fatal case).

  3. Green tea. In, PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Inc. 2007: pp. 414-22.  (Compilation of short monographs on herbal medications and dietary supplements).

  4. Imai K, Nakachi K. Cross-sectional study of effects of drinking green tea on cardiovascular and liver diseases. BMJ 1995; 310: 693-6. PubMed Citation  (In a population based survey of 1371 Japanese men, drinking >10 cups of green tea daily was associated with lower total cholesterol and triglycerides levels, increased HDL and lower ALT [19 vs 24 U/L] and AST [23 vs 25 U/L] values).

  5. Larrey D. Hepatotoxicity of herbal remedies. J Hepatol 1997; 52: 97-103. PubMed Citation  (Review of hepatotoxicity of herbals focusing upon pyrrolizidine alkaloids, germander and Chinese herbal medications, green tea was not mentioned).

  6. Gavilan JC, Bermudez FJ, Saigado F, Pena D. [Phytotherapy and hepatitis]. Rev Clin Exp 1999; 199: 693-4. Spanish. PubMed Citation  (19 year old woman developed jaundice 14 weeks after starting herbal tea and 8 weeks after starting capsules of green tea [bilirubin 11 mg/dL, ALT 1110 U/L], with severe recurrence 3 years later within 3-4 weeks of restarting the capsules).

  7. Stickel F, Egerer G, Seitz HK. Hepatotoxicity of botanicals. Public Health Nutr 2000; 3: 113-24. PubMed Citation  (Review of hepatotoxicity of herbals focusing upon Chinese herbals, germander, pyrrolizidine alkaloids, chaparral; no mention of green tea extracts).

  8. Seddick M, Lucidarme D, Creusy C, Filoche B. [Is Exolise hepatotoxic?] Gastroenterol Clin Biol 2001; 25: 834-835. French. PubMed Citation  (50 year old woman developed jaundice 2 months after starting "Exolise", a green tea extract containing commercial herbal product [bilirubin 7.5 mg/dL, ALT 40 times ULN, Alk P 1.5 times ULN], resolving within 2 months of stopping).

  9. Chantre P, Lairon D. Recent findings of green tea extract AR25(Exolise) and its activity for the treatment of obesity. Phytomedicine 2002; 9: 3-8. PubMed Citation  (Green tea extract AR25 [Exolise] is an 80% ethanol extract of green tea standardized to 25% catechins, primarily epigallocatechin gallate and caffeine, but also others; it inhibits gastric and pancreatic lipase in vitro and stimulates thermogenesis; in an open label study, 70 obese patients lost an average of 4.6% of body weight over a 6 month period; serum ALT elevations occurred in one patient, but no details given).

  10. Haller CA, Dyer JE, Ko R, Olson KR. Making a diagnosis of herbal-related toxic hepatitis. West J Med 2002; 176; 39-44. PubMed Citation  (Two cases demonstrating the difficulties of identifying the toxic component of herbals: 42 year old woman developed fatigue 10 weeks after starting 3 herbal medications [bilirubin 1.2 mg/dL, ALT 3386 U/L, Alk P 100 U/L], ultimately attributed to Jin Bu Huan; 39 year old woman developed acute liver failure after taking multiple herbals [bilirubin 42.7 mg/dL, ALT 349 U/L, INR 3.9] believed to be due to chaparral).

  11. Thiolet C, Mennecier D, Bredin C, Moulin O, Rimlinger H, Nizou C, Vergeau B, Farret O. [Acute cytolysis induced by Chinese tea]. Gastroenterol Clin Biol 2002; 26: 939-40. French. PubMed Citation  (39 year old woman developed fatigue 4 months after starting biweekly “infusions of Oolong tea fine tonic” [ALT peak 45 times and Alk P 3.5 times ULN, bilirubin not given], resolving within 8 weeks of stopping).

  12. Pedrós C, Cereza G, García N, Laporte JR. [Liver toxicity of Camellia sinensis dried ethanolic extract.] Med Clin(Barc). 2003; 121: 598-9. PubMed Citation  (4 reports of liver injury due to "Exolise" led to its withdrawal in Spain; women, ages 29 to 69 years, onset 15-45 days after starting herbal with hepatocellular injury [bilirubin 18-19 mg/L, ALT 4-40 times ULN, Alk P 1.5-2 times ULN], resolving in 3 subjects with follow up information).

  13. Vial T, Bernard G, Lewden B, Dumortier J, Descotes J. [Acute hepatitis due to Exolise, a Camellia sinensis-derived drug.] Gastroenterol Clin Biol. 2003; 27: 1166-7. PubMed Citation  (46 year old woman developed jaundice 12 weeks after starting "Exolise" [bilirubin 29.1 mg/dL, ALT 75 times and Alk P 2 times ULN], with rapid recovery and recurrence on reexposure).

  14. Pittler MH, Ernest E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther 2003; 18: 451-71. PubMed Citation  (Systematic review of published cases of hepatotoxicity due to herbal medications listing 52 case reports or case series, most common agents being greater celandine [3], chaparral [3], germander [8], Jin Bu Huan [3], kava [1], Ma Huang [3], pennyroyal [1], skullcap [2], Chinese herbs [9], valerian [1]; green tea not specifically listed or mentioned).

  15. Estes JD, Stolpman D, Olyaei A, Corless CL, Ham JM, Schwartz JM, Orloff SL. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003; 138: 852-8. PubMed Citation  (Among 20 patients undergoing liver transplantation for acute liver failure at two US transplant centers during 2001-2, 10 were attributed to herbals, but none to green tea extract).

  16. Lenz TL, Hamilton WR. Supplemental products used for weight loss. J Am Pharm Assoc 2004; 44: 59-67. PubMed Citation  (At least 50 herbal and dietary supplements have been promoted for weight loss, but none have strong clinical evidence of efficacy and several are toxic [ephedra and green tea]).

  17. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, 7 [5%] for herbal medications, including 1 attributed to kava and 1 to chaparral tea; green tea was not specifically mentioned).

  18. García-Morán S, Sáez-Royuela F, Gento E, López Morante A, Arias L. [Acute hepatitis associated with Camellia tea and Orthosiphon stamineus ingestion]. Gastroenterol Hepatol 2004; 27: 559-60. Spanish. PubMed Citation  (25 year old woman developed jaundice 2 months after starting green tea extract [bilirubin 19.9 mg/dL, ALT 2398 U/L, Alk P 164 U/L], resolving within 2 months of stopping).

  19. Duenas Sadornil C, Fabregas Puigtio S, Durandez R. [Hepatitis due to Camelia sinensis] Med Clin(Barc) 2004; 122: 677-8. PubMed Citation  (35 year old woman developed jaundice 5 weeks after starting "Exolise" [18.9 mg/dL, ALT 1558 U/L, Alk P 430 U/L], resolving within 2 months of stopping; same case as Pedros [2003]).

  20. Peyrin-Biroulet L, Petitpain N, Kalt P, Ancel D, Petit-Laurent F, Trechot P, Barraud H, Bronowicki JP. [Probable hepatoxicity from epigallocatecol gallate used for phytotherapy]. Gastroenterol Clin Biol 2004; 28: 404-6. French. PubMed Citation  (50 year old woman developed jaundice 15 days after starting Minifit [epigallocatechin gallate], with bilirubin 4.7 mg/dL, ALT 54 times ULN, resolving within 2 months of stopping, patient had a similar event a year earlier).

  21. Schmidt M, Schmitz HJ, Baumgart A, Guédon D, Netsch MI, Kreuter MH, Schmidlin CB, Schrenk D. Toxicity of green tea extracts and their constituents in rat hepatocytes in primary culture. Food Chem Toxicol 2005; 43: 307-14. PubMed Citation  (Green tea extracts were toxic to isolated rat hepatocytes in vitro, the active toxic component being epigallocatechin gallate, the major catechin in green tea).

  22. Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129: 512-21. PubMed Citation  (Reports of drug induced liver injury to a Spanish network found 570 cases, herbal medications accounted for 9 cases [~2%]).

  23. Gloro R, Hourmand-Ollivier I, Mosquet B, Mosquet L, Rousselot P, Salamé E, Piquet MA, Dao T. Fulminant hepatitis during self-medication with hydroalcoholic extract of green tea. Eur J Gastroenterol Hepatol 2005; 17: 1135-7. PubMed Citation  (48 year old woman developed jaundice 2 months after starting Exolise [bilirubin 26.3 mg/dL, ALT 102 times ULN, Alk P normal, prothrombin index 12%], with progressive liver failure requiring transplantation).

  24. Stevens T, Qadri A, Zein NN. Two patients with acute liver injury associated with use of the herbal weight-loss supplement Hydroxycut. Ann Intern Med 2005; 142: 477-8. PubMed Citation  (27 and 30 year old men developed jaundice 2 and 5 weeks after starting a Hydroxycut product [bilirubin 7.8 and 7.8 mg/dL, ALT 3131 and 45 U/L, Alk P 171 and 530 U/L], resolving within 1-2 months of stopping: Case 2).

  25. Porcel JM, Bielsa S, Madronero AB. Hepatotoxicity associated with green tea extracts. [Electronic letter]. Accessed by www.annals.org on June 3 2005.  (53 year old woman developed jaundice 2 weeks after stopping a 2 week course of a green tea extract [bilirubin 5.3 mg/dL, ALT 927 U/L, Alk P 187 U/L], resolving in 5 weeks).

  26. Abu el Wafa Y, Benavente Fernández A, Talavera Fabuel A, Pérez Ramos MA, Ramos-Clemente JI. [Acute hepatitis induced by Camellia sinensis (green tea)] Ann Med Intern 2005; 22: 298-9. Spanish. PubMed Citation  (35 year old woman developed jaundice 10 days after starting "Exolise" for obesity [bilirubin 19.5 mg/dL, ALT 2885, Alk P 182 U/L], resolving within 2 months).

  27. Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 2006; 144: 68-71. PubMed Citation  (37 year old woman developed jaundice 4 months after starting “The Right Approach Complex” [which contains green tea extract] for weight loss [bilirubin 11.7 mg/dL, ALT 1788 U/L, Alk P 238 U/L], with resolution in 1 month of stopping and recurrence within 1 month of restarting the product: Case 1).

  28. Martinez-Sierra C, Herrera PRULM. [Acute hepatitis after ingestion of green tea]. Med Clin(Barc) 2006; 27: 119. Spanish. PubMed Citation  (26 year old woman developed jaundice 4 months after starting weekly green tea “infusions” [bilirubin 6.5 mg/dL, ALT 3314, Alk P not mentioned], with recurrence within 2 weeks of restarting the drink [bilirubin 19 mg/dL, ALT 1750, Alk P 240] and resolving in 2 months after stopping).

  29. Galati G, Lin A, Sultan AM, O'Brien PJ. Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. Free Radic Biol Med 2006; 40: 570-80. PubMed Citation  (In vitro study of toxicity of green tea phenolic acids on rat hepatocytes, the most toxic component to mitochondrial membrane potential was epigallocatechin-3-gallate, which is the major component of green tea and is detoxified by glutathione).

  30. Javaid A, Bonkovsky HL. Hepatotoxicity due to extracts of Chinese green tea (Camellia sinensis): a growing concern. J Hepatol 2006; 45: 334-5. PubMed Citation  (Letter in response to editorial by Stickel [2005] describing a 46 year old woman who developed jaundice 7 months after starting green tea extracts [bilirubin 12.3 rising to 29.5 mg/dL, ALT 1100 U/L, Alk P 194 U/L]; scant information and no follow up provided).

  31. Jimenez-Saenz M, Martinez-Sanchez M del C. Acute hepatitis associated with the use of green tea infusions. J Hepatol 2006; 44: 616-7. PubMed Citation  (45 year old man drinking 6 cups of marketed green tea “infusions” daily for 4 months developed jaundice [bilirubin 7 mg/dL, ALT 1613 U/L, Alk P 310 U/L], resolving within 2 months of stopping and recurring within 1 month of restarting).

  32. Molinari M, Watt KD, Kruszyna T, Nelson R, Walsh M, Huang WY, Nashan B, Peltekian K. Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl 2006; 12: 1892-5. PubMed Citation  (44 year old woman developed jaundice 4 months after starting green tea extract [720 mg/day] for weight loss [bilirubin 13.1 rising to 43.2 mg/dL, ALT 3583 U/L, GGT 112 U/L], undergoing liver transplantation 17 days after admission; patient was also on progesterone injections for contraception).

  33. Jimenez-Saenz M, Martinez-Sanchez C. Green tea extracts and acute liver failure: the need for caution in their use and diagnostic assessment. Liver Transpl 2007; 13: 1067. PubMed Citation  (Letter in response to Molinari [2006] indicating that progesterone may have contributed to the injury and describing a 22 year old woman who developed jaundice 2 weeks after starting progesterone [bilirubin 13.5 mg/dL ALT 1584 U/L], with resolution on stopping).

  34. Federico A, Tiso A, Loguercio C. A case of hepatotoxicity caused by green tea. Free Radic Biol Med 2007; 43: 474. PubMed Citation  (51 year old woman was found to have abnormal liver enzymes during the 5 years that she drank green tea daily, which normalized when she stopped and became abnormal again when she restarted [ALT 4-5 times ULN, Alk P 1.5-2 times ULN]).

  35. Bjornsson E, Olsson R. Serious adverse liver reactions associated with herbal weight-loss supplements. J Hepatol 2007; 47: 295-7. PubMed Citation  (5 cases of liver injury from green tea containing herbal [Cuur] reported to Swedish Adverse Drug Reactions Advisory Committee over 2 years; 4 women and 1 man, ages 35 to 64 years, taking product for 5 to 20 weeks, 4 with jaundice [bilirubin 1-25 times ULN, ALT 25-95 times ULN, Alk P 1.4-8.3 times ULN], all resolved within 5-12 weeks of stopping, 4 received prednisone).

  36. Jones FJ, Andrews AH. Acute liver injury associated with the herbal supplement hydroxycut in a soldier deployed to Iraq. Am J Gastroenterol 2007; 102: 2357-8. PubMed Citation  (19 year old male US Army soldier in Iraq developed jaundice 4 months after starting a Hydroxycut weight loss product [bilirubin 11.7 mg/dL, ALT 1143 U/L, Alk P 153 U/L], resolving within 4 months of stopping).

  37. Elinav E, Pinsker G, Safadi R, Pappo O, Bromberg M, Anis E, Keinan-Boker L, et al. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity. J Hepatol 2007; 47: 514-20. PubMed Citation  (12 cases of hepatotoxicity attributed to Herbalife products in Israel, 11 women, 1 man, ages 32 to 78 years, onset after 2 to 35 months [mean peak bilirubin 9.1 mg/dL, ALT 1481 U/L, Alk P 282 U/L], 1 with ANA resolving on recovery; 11 patients recovered, one died of hepatitis B reactivation, 3 redeveloped liver injury upon reexposure).

  38. Schoepfer AM, Engel A, Fattinger K, Marbet UA, Criblez D, Reichen J, Zimmermann A, Oneta CM. Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products. J Hepatol 2007; 47: 521-6. PubMed Citation  (10 cases of hepatotoxicity due to Herbalife products in Switzerland; 3 men and 7  women, ages 30-69 years, with onset after 2 to 144 months, 9 with jaundice [bilirubin 0.4-28.2 mg/dL, ALT 4-50 times ULN, Alk P 1.1-6.5 times ULN], 2 with recurrence on rechallenge, 3 requiring liver transplant, 1 with sinusoidal obstruction syndrome, 1 with cirrhosis).

  39. Stickel F. Slimming at all costs: Herbalife-induced liver injury. J Hepatol 2007; 47: 444-6. PubMed Citation  (Editorial in reference to Schoepfer [2007] and Elinay [2007] discussing the difficulties in assigning causality and identifying the toxic component in herbal products, many patients take multiple products and each may include multiple components and possibly contain contaminants).

  40. Duque JM, Ferreiro J, Salgueiro E, Manso G. [Hepatotoxicity associated with the consumption of herbal slimming products]. Med Clin(Barc) 2007; 128: 238-9. Spanish. PubMed Citation  (3 cases of hepatotoxicity attributed to Herbalife products, women ages 49-54 years, with onset of liver injury after 1, 6 and 36 months [bilirubin 0.7, 0.8, and 26.6 mg/dL, ALT 138, 505 and 1890 U/L, Alk P 112, 166 and 425 U/L], resolving in all 3 upon stopping).

  41. Chao S, Anders M, Turbay M, Olaiz E, Mc Cormack L, Mastai R. [Toxic hepatitis by consumption Herbalife products a case report]. Acta Gastroenterol Latinoam 2008; 38: 274-7. Spanish. PubMed Citation  (63 year old woman developed jaundice and pruritus 2.5 months after starting Herbalife products [peak bilirubin 17.5 mg/dL, ALT 847 U/L, Alk P 3 times ULN], resolving within 5 months of stopping).

  42. Manso G, López-Rivas L, Duque JM, Salgueiro E. Spanish reports of hepatotoxicity associated with Herbalife products. J Hepatol 2008; 49: 289-90; author reply 290-1. PubMed Citation  (Discussion of 4 cases of Herbalife hepatotoxicity from Spain [3 reported by Duque 2007], 2 occurring in sisters, suggesting a genetic propensity and an idiosyncratic drug reaction).

  43. Ignarro L, Heber D, Henig YS, Bejar E. Herbalife nutritional products and liver injury revisited. J Hepatol 2008; 49: 291-3; author reply 293-4. PubMed Citation  (Comment on publications on Herbalife hepatotoxicity [Elinav and Schoepfer 2007] questioning whether their product was involved, as the product is used by millions).

  44. Vanstraelen S, Rahier J, Geubel AP. Jaundice as a misadventure of a green tea (camellia sinensis) lover: a case report. Acta Gastroenterol Belg 2008; 71: 409-12. PubMed Citation  (76 year old man who drank 6-7 “infusions” of green tea daily for years developed jaundice [bilirubin 16.7 mg/dL, ALT 646 U/L, Alk P 331 U/L], resolving within 10 weeks of stopping).

  45. García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. [Liver injury induced by "natural remedies": an analysis of cases submitted to the Spanish Liver Toxicity Registry]. Rev Esp Enferm Dig 2008; 100: 688-95. Spanish. PubMed Citation  (Among 521 cases of drug induced liver injury submitted to a Spanish registry, 13 [2%] were due to herbals, 3 due to green tea extracts; 23-27 year olds developed jaundice 5, 19 and 121 days after starting green tea [bilirubin 11.4-16.6 mg/dL, ALT 6-84 times ULN, Alk P 0.9-1.6 times ULN], resolving within 1.5-3 months of stopping).

  46. Sarma DN, Barrett ML, Chavez ML, Gardiner P, Ko R, Mahady GB, Marles RJ, et al. Safety of green tea extracts: a systematic review by the US Pharmacopeia. Drug Saf 2008; 31: 469-84. PubMed Citation  (US Pharmacopoeia review of green tea hepatotoxicity identified 216 adverse event reports, including 34 of liver injury [8 published, others from Spanish, French, US, UK, Canadian and Australian safety reports], which were scored as probable in 7 and possible in 27; in most cases, there were multiple agents involved; the committee recommending taking green tea with meals).

  47. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 9% of cases were attributed to herbal medications, green tea being prominently incriminated).

  48. Dara L, Hewett J, Lim JK. Hydroxycut hepatotoxicity: a case series and review of liver toxicity from herbal weight loss supplements. World J Gastroenterol 2008; 14: 6999-7004. PubMed Citation  (Two women ages 33 and 40 years with onset of symptoms 1 and 4 weeks after starting a Hydroxycut weight loss product [bilirubin 0.7 and 20.9 mg/dL, ALT 1150 and 934 U/L, Alk P 299 and 112 U/L], resolving rapidly upon stopping; ingredients included green tea extract but not ephedra).

  49. Lobb A. Hepatoxicity associated with weight-loss supplements: a case for better post-marketing surveillance. World J Gastroenterol 2009; 15: 1786-7. PubMed Citation  (Letter in response to Dara [2008] summarizing reports of liver injury attributed to Hydroxycut products and recommending more stringent regulations for HDS products in the United States).

  50. Verhelst X, Burvenich P, Van Sassenbroeck D, Gabriel C, Lootens M, Baert D. Acute hepatitis after treatment for hair loss with oral green tea extracts(Camellia Sinensis). Acta Gastro-Enterologica Belgica 2009; 72: 262-4. PubMed Citation  (41 year old woman developed jaundice 6 months after starting green tea containing herbal [bilirubin 13.6 mg/dL, ALT 2801 U/L, Alk P 251 U/L], with rapid resolution on stopping).

  51. Shim M, Saab S. Severe hepatotoxicity due to Hydroxycut: a case report. Dig Dis Sci 2009; 54: 406-8. PubMed Citation  (28 year old man developed jaundice 3 months after starting a Hydroxycut weight loss product containing green tea extract [bilirubin 18.1 mg/dL, ALT 2272 U/L, Alk P 152 U/L, ANA 1:40], with rapid improvement on stopping).

  52. Schneider C, Segre T. Green tea: potential health benefits. Am Fam Physician 2009; 79: 591-4. PubMed Citation  (Review of health benefits of green tea, the medical evidence for benefit being of limited quality and often inconsistent).

  53. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373-82. PubMed Citation  (Overview of the regulatory environment, clinical patterns, and future directions in research with HDS; specific discussion of green tea, Hydroxycut, Herbalife and traditional Chinese herbal medicines).

  54. Mazzanti G, Menniti-Ippolito F, Moro PA, Cassetti F, Raschetti R, Santuccio C, Mastrangelo S. Hepatotoxicity from green tea: a review of the literature and two published cases. Eur J Clin Pharmacol 2009; 65: 331-41. PubMed Citation  (Review of literature and addition of two cases from Italy; 81 year old woman developed jaundice 1 month after starting "Epinerve" which contained epigallocatechin gallate [bilirubin 21.8 mg/dL, ALT 2638 U/L], resolving within 3 months of stopping; and, 72 year old woman with jaundice 3 months after starting "Epinerve" [bilirubin 18 mg/dL; ALT >700 U/L], resolving rapidly on stopping).

  55. Amariles P, Angulo N, Agudelo-Agudelo J, Gaviria G. [Hepatitis associated with aqueous green tea infusions: a case study]. Farm Hosp 2009; 33: 289-91. Spanish. PubMed Citation  (43 year old woman taking green tea infusions for constipation for 8 months developed nausea [bilirubin 2.1 mg/dL, ALT 841 U/L, Alk P 100 U/L], with rapid recovery upon stopping).

  56. Bergmann J, Schjott J. Hepatitis caused by Lotus-f3? Basic Clin Pharmacol Toxicol 2009; 104: 414-6. PubMed Citation  (51 year old woman with psoriasis on etanercept developed jaundice 3 weeks after starting a green tea extract containing herbal [bilirubin 17.5 mg/dL, ALT 1871 U/L, Alk P 342 U/L], with resolution within 6 weeks of stopping herbal and etanercept, which was later reintroduced without recurrence).

  57. Lambert JD, Kennett MJ, Sang S, Reuhl KR, Ju J, Yang CS. Hepatotoxicity of high oral dose(-)-epigallocatechin-3-gallate in mice. Food Chem Toxicol 2010; 48: 409-16. PubMed Citation  (In mice, high oral doses of epigallocatechin gallate cause ALT elevations and acute hepatic necrosis within 24 to 48 hours).

  58. Sharma T, Wong L, Tsai N, Wong RD. Hydroxycut(®)(herbal weight loss supplement) induced hepatotoxicity: a case report and review of literature. Hawaii Med J 2010; 69: 188-90. PubMed Citation  (19 year old man developed fever, rash, fatigue and then jaundice 1 week after starting a Hydroxycut weight loss product [bilirubin 7.3 mg/dL, ALT 81 U/L, Alk P 298 U/L, protime 16.7 sec], biopsy showed scant necrosis, recovery within 14 weeks of stopping).

  59. Fong TL, Klontz KC, Canas-Coto A, Casper SJ, Durazo FA, Davern TJ 2nd, Hayashi P, et al. Hepatotoxicity due to hydroxycut: a case series. Am J Gastroenterol 2010; 105: 1561-6. PubMed Citation  (Details of 17 cases of hepatotoxicity due to Hydroxycut in the United States between 2002-9; latency to onset ranged from 2 to 12 weeks with two outliers at 1 and 2 years, typical pattern of injury was hepatocellular, often severe, 4 were fatal or led to liver transplantation).

  60. Rashid NN, Grant J. Hydroxycut hepatotoxicity. Med J Aust 2010; 192: 173-4. PubMed Citation  (23 year old woman developed jaundice approximately 8 weeks after starting Hydroxycut [bilirubin 6.6 mg/dL, ALT 2950 U/L, Alk P 121 U/L], resolving within 4 weeks of stopping).

  61. Stiefelhagen P. ["Doing something good" for the body? Definitely not! Liver damage caused by food supplements]. MMW Fortschr Med 2010; 152: 21. German. PubMed Citation  (News report on liver injury due to nutional supplements such as Herbalife products [at least 22 cases being reported between 1998 and 2004] and Hydoxycut products).

  62. Jóhannsson M, Ormarsdóttir S, Olafsson S. [Hepatotoxicity associated with the use of Herbalife]. Laeknabladid 2010; 96: 167-72. Icelandic. PubMed Citation  (5 cases of liver injury attributed to Herbalife products from Iceland; 4 women and 1 man, ages 29 to 78 years with onset after 1 to 7 months of use [bilirubin 1.3-15.6 mg/dL, ALT 456-2637 U/L, Alk P 149-712 U/L], all recovered upon stopping).

  63. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute
    liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010;
    52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury of which 12 [9%] were due to herbals, including several herbal mixtures, usnic acid, Ma Huang, black cohosh, and Hydroxycut).

  64. Harvey KJ. Hydroxycut hepatotoxicity. Med J Aust 2010; 192: 669-70. PubMed Citation  (Letter in response to Rashid [2010] stating that Hydroxycut preparations in Australia continue to have the same ingredients that led to its withdrawal in the US, including green tea extract).

  65. Chen GC, Ramanathan VS, Law D, Funchain P, Chen GC, French S, Shlopov B, et al. Acute liver injury induced by weight-loss herbal supplements. World J Hepatol 2010; 2: 410-5. PubMed Citation  (Three women, ages 31, 37 and 53 years, taking Hydroxycut or Herbalife products for weight loss developed jaundice 3, 4 and 12 months after starting [bilirubin 15.3, 29.9, and 18.2 mg/dL, ALT 1227, 2068 and 983 U/L, Alk P 268, 185 and 292 U/L], resolving within 2-3 months of stopping).

  66. Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of liver injury associated with dietary supplements. Liver Int 2011; 31: 595-605. PubMed Citation  (Review of current understanding of liver injury from herbals and dietary supplements focusing upon Herbalife and Hydroxycut products, green tea, usnic acid, noni juice, Chinese herbs, vitamin A and anabolic steroids).

  67. Radha Krishna Y, Mittal V, Grewal P, Fiel M, Schiano T. Acute liver failure caused by 'fat burners' and dietary supplements: a case report and literature review. Can J Gastroenterol 2011; 25: 157-60. PubMed Citation  (28 year old woman developed jaundice one month after starting two "fat burners" [Somalyz and Lipolyz] containing usnic acid and green tea as an aid to body building [bilirubin 4.8 mg/dL, ALT 1220 U/L, Alk P 111 U/L, INR 2.6], with rapid progression to acute liver failure requring liver transplantation; the explant showed massive necrosis).

  68. Thavanesan N. The putative effects of green tea on body fat: an evaluation of the evidence and a review of the potential mechanisms. Br J Nutr 2011; 106: 1297-309. PubMed Citation  (Review of mechanisms of action of green tea in weight loss suggesting that multiple mechanisms are involved).

  69. Appelhans K, Smith C, Bejar E, Henig YS. Revisiting acute liver injury associated with herbalife products. World J Hepatol 2011; 3: 275-7. PubMed Citation  (Letter in response to Chen [2010] arguing that the two cases attributed to Herbalife products were inadequately documented).

  70. Manso G, López-Rivas L, Salgueiro ME, Duque JM, Jimeno FJ, Andrade RJ, Lucena MI. Continuous reporting of new cases in Spain supports the relationship between Herbalife® products and liver injury. Pharmacoepidemiol Drug Saf 2011; 20: 1080-7. PubMed Citation  (Update on cases of liver injury reported to the Spanish Pharmacovigilance Database between 2003-2010 identified 20 cases of liver injury possibly due to Herbalife products; 16 in women, mean age 45 years, 12 hospitalized, [bilirubin 0.6 to 33.3 mg/dL, ALT 88 to 3269 U/L, Alk P 112 to 1034 U/L]; one patient developed cirrhosis, the others recovered; 1 to 9 different Herbalife products were implicated and no single ingredient appeared common to most cases).

  71. Appelhans K, Frankos V, Shao A. Misconceptions regarding the association between Herbalife products and liver-related case reports in Spain. Pharmacoepidemiol Drug Saf 2012; 21: 333-4; author reply 335. PubMed Citation  (Letter in response to Manso [2011] arguing that the causality process used was faulty and that application of WHO criteria would weaken the scoring of cases to conditional or only possibly related to the Herbalife products).

  72. Rohde J, Jacobsen C, Kromann-Andersen H. [Toxic hepatitis triggered by green tea]. Ugeskr Laeger 2011; 173: 205-6. Danish. PubMed Citation  (Abstract: Description of patient with liver injury arising 6 months after starting ingestion of 4-6 cups of green tea daily).

  73. Larrey D, Faure S. Herbal medicine hepatotoxicity: a new step with development
    of specific biomarkers. J Hepatol 2011; 54: 599-601. PubMed Citation  (Editorial on the problem of hepatotoxicity of herbal medications, the difficulties of causality assessment, the variability of the products, possibly of contamination, lack of rigorous regulations and need for biomarkers for hepatic injury).

  74. Appelhans K, Frankos V. Herbal medicine hepatotoxicity revisited. J Hepatol 2012; 56: 504-5. Reply by authors. PubMed PubMed Citation  (Letter in response to Larrey [2011] arguing that Herbalife products are carefully assessed for purity and and that the green tea extracts used have never been implicated in causing liver injury; authors reply that idiosyncratic liver injury occurs with many medications of proven purity).

  75. Weinstein DH, Twaddell WS, Raufman JP, Philosophe B, Mindikoglu AL. SlimQuick™ - associated hepatotoxicity in a woman with alpha-1 antitrypsin heterozygosity. World J Hepatol 2012; 4: 154-7. PubMed Citation  (24 year old woman developed jaundice 3 months after starting "SlimQuick", a weight loss agent with multiple herbal ingredients including green tea with 135 mg of EGCG, [bilirubin 4.0 mg/dL, ALT 2615 U/L, Alk P 200 U/L], with little improvement 30 days after stopping herbal, but prompt recovery with prednisone therapy and no relapse on subsequent withdrawal).

  76. Jiménez-Encarnación E, Ríos G, Muñoz-Mirabal A, Vilá LM. Euforia-induced acute
    hepatitis in a patient with scleroderma. BMJ Case Rep 2012; 2012. PubMed Citation  (45 year old woman with systemic sclerosis developed jaundice 1 month after starting "Euphoria", a combination herbal product whose ingredients included aloe vera, resveratrol, green tea, noni and several berries [bilirubin 17.7 mg/dL, ALT 837 U/L, Alk P 134 U/L], with slow recovery over the 18 months after stopping).

  77. Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a
    tabular compilation of reported cases. Liver Int 2012; 32: 1543-56. PubMed Citation  (A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs, herbal drugs and supplements including 19 publications on green tea, 13 on Herbalife and 6 on Hydroxycut products).

  78. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement
    hepatotoxicity. Aliment Pharmacol Ther 2013; 37: 3-17. PubMed Citation  (Systematic review of literature on HDS associated liver injury mentions that green tea has been associated with clinically apparent hepatotoxicity).

  79. Appelhans K, Najeeullah R, Frankos V. Letter: retrospective reviews of liver-related case reports allegedly associated with Herbalife present insufficient and inaccurate data. Aliment Pharmacol Ther 2013; 37: 753-4. PubMed Citation  (Letter in response to Bunchorntavakul [2013] arguing that the cases of liver injury attributed to Herbalife products in the review article were too poorly documented to assign causality).

  80. Patel SS, Beer S, Kearney DL, Phillips G, Carter BA. Green tea extract: a potential cause of acute liver failure. World J Gastroenterol 2013; 19: 5174-7. PubMed Citation  (16 year old boy developed jaundice 1-2 months after starting four HDS weight loss products including a green tea extract [bilirubin 14.8 mg/dL, ALT 2984 U/L, Alk P 186 U/L, INR 1.3], resolving within 3 months of stopping all four).

  81. Navarro VJ, Bonkovsky HL, Hwang SI, Vega M, Barnhart H, Serrano J. Catechins in dietary supplements and hepatotoxicity. Dig Dis Sc. 2013 Sep; 58(9): 2682-90. PubMed Citation  (Testing of 97 HDS products taken by 47 patients with suspected HDS related liver injury identified catechins in 50%, including 40% of those that were not labelled as containing catechins or green tea extracts; concentrations varied widely [1 mcg to 486 mg/g] and did not correlate with severity or type of injury).

  82. Teschke R, Schulze J, Schwarzenboeck A, Eickhoff A, Frenzel C. Herbal hepatotoxicity: suspected cases assessed for alternative causes. Eur J Gastroenterol Hepatol 2013; 25: 1093-8. PubMed Citation  (Review of the literature of case series of suspected HDS related liver injury found evidence of other explanations for the liver injury in 19 of 23 publications involving 278 of 573 patients [49%], including 9 of 34 cases [27%] attributed to green tea, and that these other diagnoses weakened the causality assessment in most instances).

  83. Licata A, Macaluso FS, Craxì A. Herbal hepatotoxicity: a hidden epidemic. Intern Emerg Med 2013; 8: 13-22. PubMed Citation  (Review and commentary on herbal hepatotoxicity discusses pyrrolizidine alkaloids, green tea, Echinacea, kava, usnic acid, ephedra and products made by Herbalife, Hydrocut and LipoKinetix).

  84. Appelhans K, Najeeullah R, Frankos V. Considerations regarding the alleged association between Herbalife products and cases of hepatotoxicity. Intern Emerg Med 2014 Jan 28. [Epub ahead of print] PubMed Citation  (Letter in response to Licata [2012] regarding the listing of Herbalife with other products implicated in causing liver injury, arguing that there are more than 100 Herbalife products which are mostly dietary supplements and foods, and no specific herbal has been identified in their products that might be a cause of liver injury).

  85. Rossi S, Navarro VJ. Herbs and Liver Injury: A Clinical Perspective. Clin Gastroenterol Hepatol. 2013 Aug 4. [Epub ahead of print] PubMed Citation  (Review of current status of liver injury due to HDS including discussion of challenges of establishing causality and difficulties in identifying the potentially hepatotoxic components).

  86. Teschke R, Frenzel C, Schulze J, Schwarzenboeck A, Eickhoff A. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests. World J Hepatol 2013; 5: 353-63. PubMed Citation  (Analysis of the published literature of outcome of rechallenge after suspected Herbalife hepatotoxicity identified 53 cases, 8 of which mentioned a positive rechallenge, however, documentation of the timing and results of rechallenge was frequently missing and only one case was suitably documented to judge the rechallenge using the RUCAM causality method).

  87. Teschke R, Genthner A, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: Analysis of cases with initially reported positive re-exposure tests. Dig Liver Dis 2014; 46: 264-9. PubMed Citation  (Reanalysis of 34 published cases of liver injury due to herbal medications in which there was a reported positive rechallenge, finding only 21 [62%] fulfilled the criteria of a positive rechallenge using RUCAM, the others having inconsistent [18%] or incomplete data [21%]; among 7 cases attributed to green tea, 3 rechallenges were considered uninterpretable).


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