Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


Hepatotoxicity due to herbal medications and dietary supplements

INTRODUCTION

Complementary and alternative medical (CAM) therapies are a diverse group of practices which includes the use of herbal and dietary supplements (HDS) (table 1) [1]. The use of CAM therapies in the United States increased dramatically since 1990. As many as 65 percent of the population reported the use of CAM therapies, depending upon how they were defined, with out-of-pocket costs in 2005 exceeding $27 billion [2-5]. The most commonly used CAM therapies are herbal and dietary supplements [1].

Between 1997 and 2002, overall CAM therapy use remained relatively stable [1]. By contrast, the use of HDS increased by 50 percent (from 23 million adult users to over 38 million) [1]. The estimated cost of HDS alone in 2008 was $4.8 billion [6]. In addition, about 95 percent of CAM users were self-medicating (compared to 85 percent in 1997) [1]. Women and non-Hispanic whites were more likely to use CAM therapies, with greater use in persons younger than 65 years of age and in those with a higher annual household income [1,2,7,8].

Use of herbal preparations can be traced back as far as ancient Egypt, China, India, and Sumeria, and formulations have been expanded upon over the centuries [9,10]. Many patients consider "natural" herbal remedies to be completely free of unwanted side effects [11-13]. This is concerning since many herbal products have biological activity that can lead to severe toxicity or that interact with each other or prescription medications. Fewer than 40 percent of patients disclose to their clinician that they are using these products [1,2,14].

DATABASE OF DRUGS, HERBS, AND SUPPLEMENTS ASSOCIATED WITH HEPATOTOXICITY

Over 1000 medications and herbal products have been implicated in the development of drug-induced liver injury, and the list continues to grow [15,16]. A searchable database of drugs, herbal medications, and dietary supplements associated with hepatotoxicity has been developed by the National Institutes of Health [17].

REGULATION

In 1962, the Kefauver-Harris Drug Amendment was introduced, which required that all over-the-counter and prescription products show proof of safety and efficacy [18]. CAMS were assigned to the food supplement category and had a lower threshold of required evidence for safety [18]. An attempt by the Food and Drug Administration (FDA) in the early 1990s to develop more strict regulations was met with significant opposition by supplement manufacturers, lobbyists, and consumers.

                       

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jun 2014. | This topic last updated: Oct 22, 2013.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Tindle HA, Davis RB, Phillips RS, Eisenberg DM. Trends in use of complementary and alternative medicine by US adults: 1997-2002. Altern Ther Health Med 2005; 11:42.
  2. Complementary and Alternative Medicine in the United States. Institute of Medicine Committee on the Use of Complementary and Alternative Medicine by the American Public; National Academies Press (US), Washington (DC), 2005.
  3. Saydah SH, Eberhardt MS. Use of complementary and alternative medicine among adults with chronic diseases: United States 2002. J Altern Complement Med 2006; 12:805.
  4. Strader DB, Bacon BR, Lindsay KL, et al. Use of complementary and alternative medicine in patients with liver disease. Am J Gastroenterol 2002; 97:2391.
  5. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data 2004; May 27;(343):1.
  6. American Botanical Council. Herbal Supplement Sales Experience Slight Increase in 2008. Herbal Gram 2009; 82:58.
  7. Ni H, Simile C, Hardy AM. Utilization of complementary and alternative medicine by United States adults: results from the 1999 national health interview survey. Med Care 2002; 40:353.
  8. Graham RE, Ahn AC, Davis RB, et al. Use of complementary and alternative medical therapies among racial and ethnic minority adults: results from the 2002 National Health Interview Survey. J Natl Med Assoc 2005; 97:535.
  9. Schuppan D, Jia JD, Brinkhaus B, Hahn EG. Herbal products for liver diseases: a therapeutic challenge for the new millennium. Hepatology 1999; 30:1099.
  10. Swerdlow J. Nature's medicine. Plants that heal. 2000 Nat'l Geographic Society.
  11. Larrey D, Pageaux GP. Hepatotoxicity of herbal remedies and mushrooms. Semin Liver Dis 1995; 15:183.
  12. Kaplowitz N. Hepatotoxicity of herbal remedies: insights into the intricacies of plant-animal warfare and cell death. Gastroenterology 1997; 113:1408.
  13. Larrey D. Hepatotoxicity of herbal remedies. J Hepatol 1997; 26 Suppl 1:47.
  14. Eisenberg DM, Kessler RC, Van Rompay MI, et al. Perceptions about complementary therapies relative to conventional therapies among adults who use both: results from a national survey. Ann Intern Med 2001; 135:344.
  15. Stirnimann G, Kessebohm K, Lauterburg B. Liver injury caused by drugs: an update. Swiss Med Wkly 2010; 140:w13080.
  16. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther 2013; 37:3.
  17. http://www.livertox.nih.gov/ (Accessed on October 15, 2012).
  18. Goldman P. Herbal medicines today and the roots of modern pharmacology. Ann Intern Med 2001; 135:594.
  19. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29:373.
  20. US Food and Drug Administration. Information for consumers: Dietary supplements. US Food and Drug Administration. http://www.fda.gov/Food/DietarySupplements/ConsumerInformation/default.htm (Accessed on July 10, 2012).
  21. Federal Food, Drug, and Cosmetic Act (FD&C) Act http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/default.htm (Accessed on July 10, 2012).
  22. United States Pharmacopeia (USP). About USP - an overview http://www.usp.org/aboutUSP (Accessed on July 10, 2012).
  23. US Food and Drug Administration. Center for Food Safety and Applied Nutrition. Dietary Supplements http://www.fda.gov/Food/DietarySupplements/default.htm (Accessed on July 10, 2012).
  24. US Food and Drug Administration. Claims that can be made for conventional foods and dietary supplements http://www.fda.gov/Food/LabelingNutrition/LabelClaims/ucm111447.htm (Accessed on July 10, 2012).
  25. US Food and Drug Administration. Guidance, Compliance & Regulatory Information http://www.fda.gov/food/DietarySupplements/GuidanceComplianceRegulatoryInformation (Accessed on July 10, 2012).
  26. Tomlinson B, Chan TY, Chan JC, et al. Toxicity of complementary therapies: an eastern perspective. J Clin Pharmacol 2000; 40:451.
  27. Cole MR, Fetrow CW. Adulteration of dietary supplements. Am J Health Syst Pharm 2003; 60:1576.
  28. Ernst E. Toxic heavy metals and undeclared drugs in Asian herbal medicines. Trends Pharmacol Sci 2002; 23:136.
  29. Chan TY, Chan JC, Tomlinson B, Critchley JA. Chinese herbal medicines revisited: a Hong Kong perspective. Lancet 1993; 342:1532.
  30. Ko RJ. Adulterants in Asian patent medicines. N Engl J Med 1998; 339:847.
  31. Chan TY, Critchley JA. Usage and adverse effects of Chinese herbal medicines. Hum Exp Toxicol 1996; 15:5.
  32. Huang WF, Wen KC, Hsiao ML. Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J Clin Pharmacol 1997; 37:344.
  33. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Intern Med 2002; 252:107.
  34. Espinoza EO, Mann MJ, Bleasdell B. Arsenic and mercury in traditional Chinese herbal balls. N Engl J Med 1995; 333:803.
  35. Gertner E, Marshall PS, Filandrinos D, et al. Complications resulting from the use of Chinese herbal medications containing undeclared prescription drugs. Arthritis Rheum 1995; 38:614.
  36. Kang-Yum E, Oransky SH. Chinese patent medicine as a potential source of mercury poisoning. Vet Hum Toxicol 1992; 34:235.
  37. Stickel F, Droz S, Patsenker E, et al. Severe hepatotoxicity following ingestion of Herbalife nutritional supplements contaminated with Bacillus subtilis. J Hepatol 2009; 50:111.
  38. Kennedy J. Herb and supplement use in the US adult population. Clin Ther 2005; 27:1847.
  39. Saper RB, Phillips RS, Sehgal A, et al. Lead, mercury, and arsenic in US- and Indian-manufactured Ayurvedic medicines sold via the Internet. JAMA 2008; 300:915.
  40. Kales SN, Christophi CA, Saper RB. Hematopoietic toxicity from lead-containing Ayurvedic medications. Med Sci Monit 2007; 13:CR295.
  41. Seeff LB, Lindsay KL, Bacon BR, et al. Complementary and alternative medicine in chronic liver disease. Hepatology 2001; 34:595.
  42. Koff RS. Herbal hepatotoxicity. Revisiting a dangerous alternative. JAMA 1995; 273:502.
  43. Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135:1924.
  44. Wai CT, Tan BH, Chan CL, et al. Drug-induced liver injury at an Asian center: a prospective study. Liver Int 2007; 27:465.
  45. Estes JD, Stolpman D, Olyaei A, et al. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003; 138:852.
  46. Zimmerman HJ, Ishak KG. General aspects of drug-induced liver disease. Gastroenterol Clin North Am 1995; 24:739.
  47. Larrey D, Vial T, Pauwels A, et al. Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity. Ann Intern Med 1992; 117:129.
  48. Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002; 22:145.
  49. Hayashi PH. Causality assessment in drug-induced liver injury. Semin Liver Dis 2009; 29:348.
  50. Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990; 11:272.
  51. USFDA Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf (Accessed on July 10, 2012).
  52. Navaro V. Hepatic adverse event nomenclature document http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/ucm080336.htm (Accessed on December 14, 2011).
  53. Kaplowitz N. Causality assessment versus guilt-by-association in drug hepatotoxicity. Hepatology 2001; 33:308.
  54. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 1993; 46:1331.
  55. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997; 26:664.
  56. Lucena MI, Camargo R, Andrade RJ, et al. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001; 33:123.
  57. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006; 354:731.
  58. O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439.
  59. Björnsson E. Drug-induced liver injury: Hy's rule revisited. Clin Pharmacol Ther 2006; 79:521.
  60. Reuben A. Hy's law. Hepatology 2004; 39:574.
  61. Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements. A 5-year toxicological study (1991-1995). Drug Saf 1997; 17:342.
  62. Pittler MH, Ernst E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther 2003; 18:451.
  63. Woolf GM, Petrovic LM, Rojter SE, et al. Acute hepatitis associated with the Chinese herbal product jin bu huan. Ann Intern Med 1994; 121:729.
  64. Picciotto A, Campo N, Brizzolara R, et al. Chronic hepatitis induced by Jin Bu Huan. J Hepatol 1998; 28:165.
  65. Neff GW, Reddy KR, Durazo FA, et al. Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid. J Hepatol 2004; 41:1062.
  66. Bajaj J, Knox JF, Komorowski R, Saeian K. The irony of herbal hepatitis: Ma-Huang-induced hepatotoxicity associated with compound heterozygosity for hereditary hemochromatosis. Dig Dis Sci 2003; 48:1925.
  67. Nadir A, Agrawal S, King PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol 1996; 91:1436.
  68. Lekehal M, Pessayre D, Lereau JM, et al. Hepatotoxicity of the herbal medicine germander: metabolic activation of its furano diterpenoids by cytochrome P450 3A Depletes cytoskeleton-associated protein thiols and forms plasma membrane blebs in rat hepatocytes. Hepatology 1996; 24:212.
  69. Laliberté L, Villeneuve JP. Hepatitis after the use of germander, a herbal remedy. CMAJ 1996; 154:1689.
  70. Mostefa-Kara N, Pauwels A, Pines E, et al. Fatal hepatitis after herbal tea. Lancet 1992; 340:674.
  71. Castot A, Larrey D. [Hepatitis observed during a treatment with a drug or tea containing Wild Germander. Evaluation of 26 cases reported to the Regional Centers of Pharmacovigilance]. Gastroenterol Clin Biol 1992; 16:916.
  72. Castot A, Djezzar S, Deleau N, et al. [Pharmacovigilance off the beaten track: herbal surveillance or pharmacovigilance of medicinal plants]. Therapie 1997; 52:97.
  73. Mimidis KP, Papadopoulos VP, Baltatzidis G, et al. Severe acute cholestasis caused by Teucrium polium. J Gastrointestin Liver Dis 2009; 18:387.
  74. MacGregor FB, Abernethy VE, Dahabra S, et al. Hepatotoxicity of herbal remedies. BMJ 1989; 299:1156.
  75. Harvey J, Colin-Jones DG. Mistletoe hepatitis. Br Med J (Clin Res Ed) 1981; 282:186.
  76. Hullar TE, Sapers BL, Ridker PM, et al. Herbal toxicity and fatal hepatic failure. Am J Med 1999; 106:267.
  77. Sheikh NM, Philen RM, Love LA. Chaparral-associated hepatotoxicity. Arch Intern Med 1997; 157:913.
  78. Katz M, Saibil F. Herbal hepatitis: subacute hepatic necrosis secondary to chaparral leaf. J Clin Gastroenterol 1990; 12:203.
  79. Gordon DW, Rosenthal G, Hart J, et al. Chaparral ingestion. The broadening spectrum of liver injury caused by herbal medications. JAMA 1995; 273:489.
  80. Smith BC, Desmond PV. Acute hepatitis induced by ingestion of the herbal medication chaparral. Aust N Z J Med 1993; 23:526.
  81. Batchelor WB, Heathcote J, Wanless IR. Chaparral-induced hepatic injury. Am J Gastroenterol 1995; 90:831.
  82. Bach N, Thung SN, Schaffner F. Comfrey herb tea-induced hepatic veno-occlusive disease. Am J Med 1989; 87:97.
  83. Ridker PM, McDermott WV. Comfrey herb tea and hepatic veno-occlusive disease. Lancet 1989; 1:657.
  84. Weston CF, Cooper BT, Davies JD, Levine DF. Veno-occlusive disease of the liver secondary to ingestion of comfrey. Br Med J (Clin Res Ed) 1987; 295:183.
  85. Yeong ML, Swinburn B, Kennedy M, Nicholson G. Hepatic veno-occlusive disease associated with comfrey ingestion. J Gastroenterol Hepatol 1990; 5:211.
  86. Stickel F, Seitz HK. The efficacy and safety of comfrey. Public Health Nutr 2000; 3:501.
  87. Kumana CR, Ng M, Lin HJ, et al. Herbal tea induced hepatic veno-occlusive disease: quantification of toxic alkaloid exposure in adults. Gut 1985; 26:101.
  88. Smith LW, Culvenor CC. Plant sources of hepatotoxic pyrrolizidine alkaloids. J Nat Prod 1981; 44:129.
  89. Mattocks AR. Toxicity of pyrrolizidine alkaloids. Nature 1968; 217:723.
  90. Gordon WP, Forte AJ, McMurtry RJ, et al. Hepatotoxicity and pulmonary toxicity of pennyroyal oil and its constituent terpenes in the mouse. Toxicol Appl Pharmacol 1982; 65:413.
  91. Centers for Disease Control and Prevention (CDC). Hepatic toxicity possibly associated with kava-containing products--United States, Germany, and Switzerland, 1999-2002. MMWR Morb Mortal Wkly Rep 2002; 51:1065.
  92. Ernst E. Safety concerns about kava. Lancet 2002; 359:1865.
  93. Wooltorton E. Herbal kava: reports of liver toxicity. CMAJ 2002; 166:777.
  94. Campo JV, McNabb J, Perel JM, et al. Kava-induced fulminant hepatic failure. J Am Acad Child Adolesc Psychiatry 2002; 41:631.
  95. Gow PJ, Connelly NJ, Hill RL, et al. Fatal fulminant hepatic failure induced by a natural therapy containing kava. Med J Aust 2003; 178:442.
  96. Yoshida EM, McLean CA, Cheng ES, et al. Chinese herbal medicine, fulminant hepatitis, and liver transplantation. Am J Gastroenterol 1996; 91:2647.
  97. Seeff LB. Herbal hepatotoxicity. Clin Liver Dis 2007; 11:577.
  98. Stegelmeier BL, Edgar JA, Colegate SM, et al. Pyrrolizidine alkaloid plants, metabolism and toxicity. J Nat Toxins 1999; 8:95.
  99. Pearson W. Pyrrolizidine alkaloids in higher plants: hepatic veno-occlusive disease associated with chronic consumption. J Neutraceuticals 2000; 3:87.
  100. Steenkamp V, Stewart MJ, Zuckerman M. Clinical and analytical aspects of pyrrolizidine poisoning caused by South African traditional medicines. Ther Drug Monit 2000; 22:302.
  101. Tandon HD, Tandon BN, Ramalingaswami V. Epidemic of toxic hepatitis in India of possible mycotoxic origin. Arch Pathol Lab Med 1978; 102:372.
  102. FDA advises dietary supplement manufacturers to remove comfrey products from the market http://www.fda.gov/Food/DietarySupplements/Alerts/ucm111219.htm (Accessed on December 14, 2011).
  103. Conradie J, Stewart MJ, Steenkamp V. GC/MS identification of toxic pyrrolizidine alkaloids in traditional remedies given to two sets of twins. Ann Clin Biochem 2005; 42:141.
  104. Gao H, Li N, Wang JY, et al. Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids. J Dig Dis 2012; 13:33.
  105. Neuman MG, Jia AY, Steenkamp V. Senecio latifolius induces in vitro hepatocytotoxicity in a human cell line. Can J Physiol Pharmacol 2007; 85:1063.
  106. Ji LL, Zhang M, Sheng YC, Wang ZT. Pyrrolizidine alkaloid clivorine induces apoptosis in human normal liver L-02 cells and reduces the expression of p53 protein. Toxicol In Vitro 2005; 19:41.
  107. Valla D, Benhamou JP. Drug-induced vascular and sinusoidal lesions of the liver. Baillieres Clin Gastroenterol 1988; 2:481.
  108. Schiano TD. Liver injury from herbs and other botanicals. Clin Liver Dis 1998; 2:607.
  109. Ridker PM, Ohkuma S, McDermott WV, et al. Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements. Gastroenterology 1985; 88:1050.
  110. Bateman J, Chapman RD, Simpson D. Possible toxicity of herbal remedies. Scott Med J 1998; 43:7.
  111. Farrell GC. Drug-induced hepatic injury. J Gastroenterol Hepatol 1997; 12:S242.
  112. Fau D, Lekehal M, Farrell G, et al. Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes. Gastroenterology 1997; 113:1334.
  113. Mattéi A, Rucay P, Samuel D, et al. Liver transplantation for severe acute liver failure after herbal medicine (Teucrium polium) administration. J Hepatol 1995; 22:597.
  114. Moro PA, Cassetti F, Giugliano G, et al. Hepatitis from Greater celandine (Chelidonium majus L.): review of literature and report of a new case. J Ethnopharmacol 2009; 124:328.
  115. Stickel F, Pöschl G, Seitz HK, et al. Acute hepatitis induced by Greater Celandine (Chelidonium majus). Scand J Gastroenterol 2003; 38:565.
  116. Benninger J, Schneider HT, Schuppan D, et al. Acute hepatitis induced by greater celandine (Chelidonium majus). Gastroenterology 1999; 117:1234.
  117. Crijns AP, de Smet PA, van den Heuvel M, et al. [Acute hepatitis after use of a herbal preparation with greater celandine (Chelidonium majus)]. Ned Tijdschr Geneeskd 2002; 146:124.
  118. De Smet PA. Safety concerns about kava not unique. Lancet 2002; 360:1336.
  119. Greving I, Meister V, Monnerjahn C, et al. Chelidonium majus: a rare reason for severe hepatotoxic reaction. Pharmacoepidemiol Drug Saf 1998; 7 Suppl 1:S66.
  120. Rifai K, Flemming P, Manns MP, et al. Severe drug hepatitis caused by Chelidonium. 2006; Internist 47:749.
  121. Teschke R, Glass X, Schulze J, Eickhoff A. Suspected Greater Celandine hepatotoxicity: liver-specific causality evaluation of published case reports from Europe. Eur J Gastroenterol Hepatol 2012; 24:270.
  122. Teschke R, Glass X, Schulze J. Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports. Regul Toxicol Pharmacol 2011; 61:282.
  123. Kassler WJ, Blanc P, Greenblatt R. The use of medicinal herbs by human immunodeficiency virus-infected patients. Arch Intern Med 1991; 151:2281.
  124. Zaim N, Guemouri L, Lamnaouer D, Benjouad A. [Study of four cases of poisoning by Atractylis gummifera L. in Morocco]. Therapie 2008; 63:49.
  125. Skalli S, Alaoui I, Pineau A, et al. [Atractylis gummifera L. poisoning: a case report]. Bull Soc Pathol Exot 2002; 95:284.
  126. Obatomi DK, Brant S, Anthonypillai V, Bach PH. Toxicity of atractyloside in precision-cut rat and porcine renal and hepatic tissue slices. Toxicol Appl Pharmacol 1998; 148:35.
  127. Gruenwald J, Brendler T, Jaenicke C. Pennyroyal. In: PDR for Herbal Medicines, second edition, Medical Economics Company, New Jersey 2000. p.579.
  128. Anderson IB, Mullen WH, Meeker JE, et al. Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature. Ann Intern Med 1996; 124:726.
  129. Bakerink JA, Gospe SM Jr, Dimand RJ, Eldridge MW. Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants. Pediatrics 1996; 98:944.
  130. Thomassen D, Slattery JT, Nelson SD. Menthofuran-dependent and independent aspects of pulegone hepatotoxicity: roles of glutathione. J Pharmacol Exp Ther 1990; 253:567.
  131. Stickel F, Baumüller HM, Seitz K, et al. Hepatitis induced by Kava (Piper methysticum rhizoma). J Hepatol 2003; 39:62.
  132. Teschke R. Kava hepatotoxicity: pathogenetic aspects and prospective considerations. Liver Int 2010; 30:1270.
  133. Sarris J, Kavanagh DJ, Byrne G, et al. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology (Berl) 2009; 205:399.
  134. Teschke R, Genthner A, Wolff A. Kava hepatotoxicity: comparison of aqueous, ethanolic, acetonic kava extracts and kava-herbs mixtures. J Ethnopharmacol 2009; 123:378.
  135. Javaid A, Bonkovsky HL. Hepatotoxicity due to extracts of Chinese green tea (Camellia sinensis): a growing concern. J Hepatol 2006; 45:334.
  136. Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 2006; 144:68.
  137. Molinari M, Watt KD, Kruszyna T, et al. Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl 2006; 12:1892.
  138. Weinstein DH, Twaddell WS, Raufman JP, et al. SlimQuick™ - associated hepatotoxicity in a woman with alpha-1 antitrypsin heterozygosity. World J Hepatol 2012; 4:154.
  139. Ishak KG. Hepatic lesions caused by anabolic and contraceptive steroids. Semin Liver Dis 1981; 1:116.
  140. Hepatic effects of 17 alpha-alkylated anaboli-androgenic steroids. HIV Hotline 1998; 8:2.
  141. Kafrouni MI, Anders RA, Verma S. Hepatotoxicity associated with dietary supplements containing anabolic steroids. Clin Gastroenterol Hepatol 2007; 5:809.
  142. Food and Drug Administration. Body Building Products Marketed as Containing Steroids or Steroid-Like Substances http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm173965.htm (Accessed on July 10, 2012).
  143. Chalasani N, Vuppalanchi R, Navarro V, et al. Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis: a case series. Ann Intern Med 2012; 156:857.
  144. 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.
  145. 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.
  146. 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.
  147. Shim M, Saab S. Severe hepatotoxicity due to Hydroxycut: a case report. Dig Dis Sci 2009; 54:406.
  148. Fong TL, Klontz KC, Canas-Coto A, et al. Hepatotoxicity due to hydroxycut: a case series. Am J Gastroenterol 2010; 105:1561.
  149. US Food and Drug Administration. Warning on Hydroxycut products http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm152152.htm (Accessed on July 10, 2012).
  150. US Food and Drug Administration. FDA Warns Consumers to Stop Using Hydroxycut Products http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149575.htm (Accessed on July 10, 2012).
  151. Schoepfer AM, Engel A, Fattinger K, et al. Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products. J Hepatol 2007; 47:521.
  152. Elinav E, Pinsker G, Safadi R, et al. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity. J Hepatol 2007; 47:514.
  153. Duque JM, Ferreiro J, Salgueiro E, Manso G. [Hepatotoxicity associated with the consumption of herbal slimming products]. Med Clin (Barc) 2007; 128:238.
  154. Chao S, Anders M, Turbay M, et al. [Toxic hepatitis by consumption Herbalife products a case report]. Acta Gastroenterol Latinoam 2008; 38:274.
  155. Manso G, López-Rivas L, Duque JM, Salgueiro E. Spanish reports of hepatotoxicity associated with Herbalife products. J Hepatol 2008; 49:289.
  156. Ramanathan VS, Mitropoulos E, Shlopov B, et al. An Enzyte'ing' case of acute hepatitis. J Clin Gastroenterol 2011; 45:834.
  157. Martin DJ, Partridge BJ, Shields W. Hepatotoxicity associated with the dietary supplement N.O.-XPLODE. Ann Intern Med 2013; 159:503.
  158. Centers for Disease Control and Prevention (CDC). Notes from the field: acute hepatitis and liver failure following the use of a dietary supplement intended for weight loss or muscle building--May-October 2013. MMWR Morb Mortal Wkly Rep 2013; 62:817.
  159. Wang ZG, Ren J. Current status and future direction of Chinese herbal medicine. Trends Pharmacol Sci 2002; 23:347.
  160. Perharic-Walton L, Murray V. Toxicity of Chinese herbal remedies. Lancet 1992; 340:674.
  161. Graham-Brown R. Toxicity of Chinese herbal remedies. Lancet 1992; 340:673.
  162. Jung KA, Min HJ, Yoo SS, et al. Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum multiflorum Thunb. Gut Liver 2011; 5:493.
  163. Horowitz RS, Feldhaus K, Dart RC, et al. The clinical spectrum of Jin Bu Huan toxicity. Arch Intern Med 1996; 156:899.
  164. Borum ML. Fulminant exacerbation of autoimmune hepatitis after the use of ma huang. Am J Gastroenterol 2001; 96:1654.
  165. Itoh S, Marutani K, Nishijima T, et al. Liver injuries induced by herbal medicine, syo-saiko-to (xiao-chai-hu-tang). Dig Dis Sci 1995; 40:1845.
  166. Kamiyama T, Nouchi T, Kojima S, et al. Autoimmune hepatitis triggered by administration of an herbal medicine. Am J Gastroenterol 1997; 92:703.
  167. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998; 158:2200.
  168. Perron AD, Patterson JA, Yanofsky NN. Kombucha "mushroom" hepatotoxicity. Ann Emerg Med 1995; 26:660.
  169. Favreau JT, Ryu ML, Braunstein G, et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002; 136:590.
  170. Nadir A, Reddy D, Van Thiel DH. Cascara sagrada-induced intrahepatic cholestasis causing portal hypertension: case report and review of herbal hepatotoxicity. Am J Gastroenterol 2000; 95:3634.
  171. Adachi M, Saito H, Kobayashi H, et al. Hepatic injury in 12 patients taking the herbal weight loss AIDS Chaso or Onshido. Ann Intern Med 2003; 139:488.
  172. Kao WF, Hung DZ, Tsai WJ, et al. Podophyllotoxin intoxication: toxic effect of Bajiaolian in herbal therapeutics. Hum Exp Toxicol 1992; 11:480.
  173. Uc A, Bishop WP, Sanders KD. Camphor hepatotoxicity. South Med J 2000; 93:596.
  174. Mallat A, Dhumeaux D. Cocaine and the liver. J Hepatol 1991; 12:275.
  175. Wurtz AS, Vial T, Isoard B, Saillard E. Possible hepatotoxicity from Copaltra, an herbal medicine. Ann Pharmacother 2002; 36:941.
  176. Millonig G, Stadlmann S, Vogel W. Herbal hepatotoxicity: acute hepatitis caused by a Noni preparation (Morinda citrifolia). Eur J Gastroenterol Hepatol 2005; 17:445.
  177. Jorge OA, Jorge AD. Hepatotoxicity associated with the ingestion of Centella asiatica. Rev Esp Enferm Dig 2005; 97:115.
  178. Beuers U, Spengler U, Pape GR. Hepatitis after chronic abuse of senna. Lancet 1991; 337:372.
  179. Mazzanti G, Menniti-Ippolito F, Moro PA, et al. Hepatotoxicity from green tea: a review of the literature and two unpublished cases. Eur J Clin Pharmacol 2009; 65:331.