Herbal-induced Hepatotoxicity: Increasing our Index of Suspicion

It is estimated that 57.6 million Americans (approximately 18% of the US population) have utilized herbal and dietary supplements, which include a wide range of products such as multivitamins, minerals, amino acids, and herbs, present in a range of products from energy drinks to oral supplements.¹ Some are derived from natural sources (eg, plants), but many others are man-made. Ingestible forms are capsules, pills, gel tablets, and liquids; other forms are tinctures, extracts, and powders. Though identifiable in more than 5000 different products available in the United States, herbals do not undergo rigorous clinical testing and are not regulated by the FDA like prescribed or chemically defined medications.^2,3 This means that they do not have to meet the same standards as drugs and over-the-counter (OTC) medications for proof of safety, effectiveness, and what the FDA calls Good Manufacturing Practices.⁴

Studies have shown that the general population perceives herbal products as safe and not a topic that requires a conversation with their primary care givers or other healthcare professionals^5-7—underreporting that can have harmful repercussions. Because of the potential for negative interactions with prescription and OTC drugs, and impact on elective surgery (eg, changes in heart rate, blood pressure, and increased bleeding), patients should be encouraged to talk openly about their use of herbal supplements. Moreover, while many herbal products have no, or minimal, adverse effects, others have been reported to potentially induce hepatotoxicity.⁸

There are at least 1000 medications and herbal products that have been implicated in the development of drug-induced liver injury; however, the discussion of drug interactions and additional adverse effects is beyond the scope of this summary.⁹ The purpose of this review is to increase awareness of selected common herbal products with reports of hepatotoxicity in order to increase vigilance in documenting complete medication histories that may include herbal products.

Data collected by the Drug-Induced Liver Injury Network between 2004 and 2013 found that approximately 15% of enrolled patients experienced liver injury due to herbal or dietary supplements. A clear and steady increasing trend of herbal and dietary supplement-induced liver injury was also reported. Identifying a specific herb, or group of herbs, that caused the liver injury, however, is not always possible, due to the likelihood of multiple herbal products being combined in one product. Inconsistencies of reporting can also be attributed to variations in doses of herbal compounds in each product. 

According to reports, herbal-induced hepatotoxicity can be observed from 1 week to several months after initiation of the herbal product.^10,11 In general, there are not specific risk factors associated with herbal-induced hepatotoxicity; however, it has been reported that women over the age of 40 with high levels of education more commonly use supplements.^12-15 General symptoms may include jaundice, pruritus, anorexia, abdominal pain, nausea, and malaise.¹⁶ Elevations in serum liver function tests, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin may also be detected. High mean AST and ALT values were detected for liver injury patients in a previous trial.¹⁷ When herbal-induced hepatotoxicity is suspected, the management first involves discontinuing the offending agent(s) and monitoring the resolution of symptoms.^18,19 In addition, it is necessary to investigate the inclusion of hepatotoxic agents, such as herbal products (Table), on the medication profile by requesting the original package of the herbal product and reviewing the ingredients.¹⁹

Reports have shown that herbal-induced hepatotoxicity may lead to death or liver transplantation. In fact, Navarro et al¹⁷ showed that herbal and dietary supplements utilization more frequently led to death or liver transplantation when compared to patients developing liver injury on conventional medications. Considering the previously stated results, it is important to be mindful of selected herbal products associated with hepatotoxicity (Table) and keep a high index of suspicion for herbal products when providing care to patients experiencing symptoms of liver disease. This also includes specifically asking patients about herbals/supplements when doing medication histories.

Benjamin T. Duhart, Jr.,MS, PharmD.is associate professor of clinical pharmacy at the University of Tennessee Health Science Center.

Timothy Self, PharmD, is professor of clinical pharmacy at the University of Tennessee Health Science Center and Program Director, PGY2 Internal Medicine Pharmacy Residency, Methodist University Hospital in Memphis.

References:

1. Clarke TC, Black LI, Stussman BJ, et al. Trends in the use of complementary health approaches among adults: United States, 2002-2012. Hyattsville, MD: National Center for Health Statistics; 2015.

2.  De Smet PA. Herbal remedies. N Engl J Med. 2002;347(25):2046-2056.

3. Cohen PA. Hazards of hindsight—monitoring the safety of nutritional supplements. N Engl J Med. 2014;370(14):1277-1280.

4. Dietary supplements. FDA Web site. www.fda.gov/Food/DietarySupplements/default.htm. Accessed February 15, 2015. 

5. Klepser TB, Doucette WR, Horton MR, et al. Assessment of patients’ perceptions and beliefs regarding herbal therapies. Pharmacotherapy. 2000;20(1):83-87.

6.  Hensrud DD, Engle DD, Scheitel SM. Underreporting the use of dietary supplements and nonprescription medications among patients undergoing a periodic health examination. Mayo Clin Procc. 1999;74(5):443-447.

7. Kennedy J, Wang CC, Wu CH. Patient disclosure about herb and supplement use among adults in the US. Evid Based Complement and Alternat Med. 2008;5(4):451-456.

8. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther. 2013;37(1):3-17.

9.  Stirnimann G, Kessebohm K, Lauterburg B. Liver injury caused by drugs: an update. Swiss Med Wkly. 2010;140:w13080.

10. Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of liver injury associated with dietary supplements. Liver Int. 2011;31(5)595-605.

11. Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatology. 2005;43(5):901-910.

12. Radimer K, Bindewald B, Hughes J, et al. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol. 2004;160(4):339-349.

13. Bailey RL, Gahche JJ, Miller PE, et al. Why US adults use dietary supplements. JAMA Intern Med. 2013;173(5):355-361.

14. Foote JA, Murphy SP, Wilkens LR, et al. Factors associated with dietary supplement use among healthy adults of five ethnicities: the Multiethnic Cohort Study. Am J Epidemiol. 2003;157(10):888-897.

15. Block G, Jensen CD, Norkus EP, et al. Usage patterns, health, and nutritional status of long-term multiple dietary supplement users: a cross-sectional study. Nutr J. 2007;6:30.

16. Furbee RB, Barlotta KS, Allen MK, Holstege CP. Hepatotoxicity associated with herbal products. Clin Lab Med. 2006;26(1):227-241.

17. Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the U.S. drug-induced liver injury network. Hepatology. 2014;60(4):1399-1408.

18. Maddrey WC. Drug-induced hepatotoxicity:2005. J Clin Gastroenterol. 2005;39(4 suppl 2):S83-S89.

19. Haller CA, Dyer JE, Ko R, Olson KR. Making a diagnosis of herbal-related toxic hepatitis. West J Med. 2002;176(1):39-44. polarisations: CAMIAT. Lancet. 1997;349:675-682.

20. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust. 2002;177(8):440-443. 

21. Nisbet BC, O’Connor RE. Black cohosh-induced hepatitis. Del Med J. 2007;79(11):441-444.

22. Gloro R, Hourmand-Ollivier I, Mosquet B, et. al. Fulminant hepatitis during self-medication with hydroalcoholic extract of green tea.  Eur J Gastroenterol Hepatol. 2005;17(10):1135-1137.

23. Jimenz-Saenz M, Martinez-Sanchez M del C. Acute hepatitis associated with the use of green tea infusions. J Hepatol. 2006; 44(3):616-617.

24. Sarma DN, Barrett ML, Chavez ML, et al. Safety of green tea extracts: a systematic review by the US Pharmacopeia. Drug Saf. 2008;31(6):469-484.
25. Chojkier M. Hepatic sinusoidal-obstruction syndrome: toxicity of pyrrolizidine alkaloids.  J Hepatol. 2003;39(3):437-446.

26. 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(2):129-132.

27. Mostefa-Kara N, Pauwels A, Pines E, et al. Fatal hepatitis after herbal tea. Lancet. 1992;340(8820):674.

28. Benninger J, Schneider HT, Schuppan D, et al. Acute hepatitis induced by greater celandine (Chelidonium majus). Gastroenterology. 1999;117(5):1234-1237.

29.  Benninger J, Schneider HT, Schuppan D, et al. Acute hepatitis induced by greater celandine (Chelidonium majus). Gastroenterology. 1999;117(5):1234-1237.

30.  Stickel F, Seitz HK, Hahn EG, et al. Acute hepatitis induced by Greater Celandine. Scand J Gastroenterol. 2003;38(5):565-568.

31.  Stickel F, Baumuller HM, Seitz KH, Vasilakis D, et al. Hepatitis induced by Kava (Piper methysticum rhizoma). J Hepatol. 2003;39(1):62-67.

32.  Escher M, Desmeules J, Giostra E, Mentha G. Hepatitis associated with kava, a herbal remedy for anxiety. BMJ.2001;322(7279):139.

33. Russman S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med. 2001;135(1):68-69.

34.  Sheikh NM, Philen RM, Love LA. Chaparral-associated hepatotoxicity. Arch Intern Med. 1997; 157(8):913-919.

35.  Gordon DW, Rosenthal G, Hart J, et. al. Chaparral ingestion. The broadening spectrum of liver injury caused by herbal medications. JAMA. 1995;273(6):489-490.

36.  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;124:726-734.

37.  Sullivan JB Jr, Rumack BH, Thomas H Jr, et al. Pennyroyal oil poisoning and hepatotoxicity. JAMA. 1979;242(26):2873-2874.

38.  Beuers U, Spengler U, Pape G. Hepatitis after chronic abuse of senna. Lancet. 1991;337(8737):372-373.

39.  Seybold U, Landauer N, Hillebrand S, Goebel FK. Senna-induced hepatitis in a poor metabolizer. Ann Intern Med. 2004;141(8):650-651.

40.  Vanderperren B, Rizzo M, Angenot L, et al. Acute liver failure with renal impairment related to the abuse of senna anthraquinone glycosides. Ann Pharmacother. 2005;39(7-8):1353-1357.

41.  Soyuncu S, Cete Y, Nokay AE. Portal vein thrombosis related to Cassia angustifolia. Clin Toxicol (Phila). 2008;46(8):774-777.

42.  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(7):1436-1438.

43.  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(6):1062-1064.

44.  Millonig G, Stadelmann S, Vogel W. Herbal hepatotoxicity: acute hepatitis caused by a Noni preparation (Morinda citrifolia). Eur J Gastroenterol Hepatol. 2005;17(4):445-447.

45.  Stadbauer V, Weiss S, Payer F, Stauber RE. Herbal does not at all mean innocuous: the sixth case of hepatotoxicity associated with morinda citrifolia (noni). Am J Gastroenterol. 2008;103(9):2406-2407.

46.  Durazo FA, Lassman C, Han SB, et al. Fulminant liver failure due to usnic acid for weight loss.  Am J Gastroenterol. 2004;99(5):950-952.

47.  Favreau JT, Ryu ML, Braunstein G, et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med. 2002;136(8):590-595.

48.  Sanchez W, Maple JT, Burgart LJ, Kamath PS. Severe hepatotoxicity associated with use of a dietary supplement containing usnic acid. Mayo Clin Proc. 2006;81(4):541-544.