Ashwagandha (Withania somnifera), often called Indian ginseng, is widely used in Ayurvedic medicine and has gained popularity in the West. Though typically well-tolerated, there have been reports of severe liver injury associated with its use, including cases of cholestatic hepatitis and elevated liver enzymes.

28.10.2024

Herb-induced liver injury (HILI) caused by herbal preparations and dietary supplements is a significant cause of acute liver dysfunction and failure (1-4). Herbal products and supplements account for approximately 16-20% of all drug-induced liver injury (DILI) cases (3,4). These liver injuries are typically caused by combination products, making it difficult to identify the specific ingredient responsible for the damage (4,5). In recent years, evidence of liver damage associated with ashwagandha and turmeric/curcumin has increased (5,6).

Ashwagandha

Ashwagandha (Withania somnifera) is a medicinal herb also known as Indian ginseng. Ashwagandha-based herbal products have been widely used in Ayurvedic medicine for the treatment of various conditions and have gained popularity in Western countries (5). Clinical studies evaluating ashwagandha have rarely reported significant adverse effects (7,8,9). However, twenty-two cases of severe liver injury linked to ashwagandha use have been reported, with causality described as definite or probable (5,6, 23,24,25). These liver injuries were typically cholestatic or mixed in nature, characterized by significant hyperbilirubinemia, severe jaundice, and itching (5,24,25). Some patients also experienced significantly elevated liver transaminase levels (5,24,25). Liver biopsies revealed mild to moderate inflammatory cholestatic hepatitis and bile duct obstruction (5). In several cases, necrosis of liver tissue associated with cholestatic hepatitis were described (6,24). Bilirubin and transaminase levels typically returned to normal within 1-9 months after discontinuation of the herbal product (5,6,24). However, one case-report described ashwagandha-associated acute liver failure requiring liver transplantation (23).

Although ashwagandha is widely used in Ayurvedic medicine and generally considered safe, twenty-two cases of severe liver injury have been reported. These injuries were typically cholestatic or mixed, with symptoms including severe jaundice, elevated liver enzymes, and, in one case, acute liver failure requiring a transplant.

Turmeric

Turmeric (Curcuma longa) is a widely used spice, and its medicinal use has increased in Western countries. Turmeric contains curcuminoids, the most significant of which is curcumin (0.6-5% dry weight; 77% of curcuminoids) (10). The European Food Safety Authority (EFSA) has set the acceptable daily intake (ADI) of curcumin at 3 mg/kg/day, which equates to approximately 210 mg per day for a 70 kg adult (11). Curcumin has low systemic absorption, and its bioavailability is limited when taken orally (12,13). Various methods have been explored to improve curcumin’s bioavailability, the most common of which is the addition of piperine (an alkaloid extracted from black pepper) to curcumin supplements (14,15). This may increase curcumin bioavailability by up to 20 times (14,15). The mechanism by which piperine enhances curcumin exposure is not fully estabished, but it may involve the inhibition of UDP-glucuronosyltransferases (UGTs) or sulfotransferases (SULTs), and potentially the inhibition of CYP enzymes at higher doses (16,17,18).

Turmeric and curcumin supplements are generally well tolerated, with significant side effects being rare, apart from mild gastrointestinal symptoms (14,19). However, liver injuries related to turmeric supplements are becoming a growing concern (19,20). At least 48 cases of liver injury, typically acute non-infectious hepatitis or mixed cholestatic hepatitis, some of which were severe, have been linked to turmeric and curcumin use (14,19,20,21). Symptoms of hepatotoxicity appeared 2 weeks to 10 months after starting the supplements, and patients showed markedly elevated transaminase and total bilirubin levels (14,19,20). Patients experienced nausea, epigastric pain, jaundice, and itching (14,19,20). In one patient, a liver biopsy revealed significant accumulation of curcuminoids in the sample (19). In most hepatotoxicity cases, the suspected turmeric/curcumin product also contained piperine (14,19). In approximately 67% of hepatotoxicity cases, the daily dose of curcumin was 1.6 to 7 times higher than EFSA’s recommended daily intake (11,14,19). It is possible that concurrent exposure to piperine further increased systemic exposure to curcumin and its metabolites (14,15,19). Additionally, high doses of piperine may themselves be hepatotoxic (14,19). The presence of the HLA-B*35:01 allele may also be a risk factor for curcumin-induced liver injury (20,21).

In most cases, liver function tests returned to normal after discontinuation of the turmeric/curcumin supplement (positive dechallenge), but three patients died (14,19,20).

Awareness of liver damage caused by dietary supplements and herbal products has increased (1,2,3,5,19,20,21,24,25). The Working Group of Heads of European Food Safety Authorities has published a list of 13 substances that it seeks to ban or restrict in dietary supplements due to potential health risks (22). Ashwagandha, curcumin (in turmeric products), and piperine are among these substances (22). It is essential for healthcare professionals to consider the hepatotoxic potential of herbal products in differential diagnoses and actively inquire about patients’ use of dietary supplements and herbal products during medical history-taking.

Learn more about ashwagandha and curcumin in the Herbalbase

News produced by Medbase Medical Team

References

1. Hillman L, Gottfried M, Whitsett M, Rakela J, Schilsky M, Lee WM, Ganger D. Corrigendum: Clinical Features and Outcomes of Complementary and Alternative Medicine Induced Acute Liver Failure and Injury. Am J Gastroenterol. 2016 Oct;111(10):1504.
2. Navarro VJ, Khan I, Björnsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology. 2017 Jan;65(1):363-373.
3. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013 Jun;144(7):1419-25, 1425.e1-3; quiz e19-20.
4. Navarro VJ, Barnhart H, Bonkovsky HL, Davern T, Fontana RJ, Grant L, Reddy KR, Seeff LB, Serrano J, Sherker AH, Stolz A, Talwalkar J, Vega M, Vuppalanchi R. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014 Oct;60(4):1399-408.
5. Björnsson HK, Björnsson ES, Avula B, Khan IA, Jonasson JG, Ghabril M, Hayashi PH, Navarro V. Ashwagandha-induced liver injury: A case series from Iceland and the US Drug-Induced Liver Injury Network. Liver Int. 2020 Apr;40(4):825-829.
6. Ireland PJ, Hardy T, Burt AD, Donnelly MC. Drug-induced hepatocellular injury due to herbal supplement ashwagandha. J R Coll Physicians Edinb. 2021 Dec;51(4):363-365.
7. Andrade C, Aswath A, Chaturvedi SK, Srinivasa M, Raguram R. A double-blind, placebo-controlled evaluation of the anxiolytic efficacy of an ethanolic extract of withania somnifera. Indian J Psychiatry 2000 Jul;42(3):295-301.
8. Cooley K, Szczurko O, Perri D, Mills EJ, Bernhardt B, Zhou Q, Seely D. Naturopathic care for anxiety: a randomized controlled trial ISRCTN78958974. PLoS One 2009 Aug 31;4(8):e6628.
9. Chandrasekhar K, Kapoor J, Anishetty S. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med 2012 Jul;34(3):255-62.
10. Final assessment report on Curcuma longa L., rhizoma – Revision 1. EMA Committee on Herbal Medicinal Products. Published 24/01/2019.
11. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) Scientific Opinion on the re‐evaluation of curcumin (E 100) as a food additive. EFSA Journal. 2010;8(9):1679. Available from: www.efsa.europa.eu/en/efsajournal/pub/1679.
12. Liu W, Zhai Y, Heng X, Che FY, Chen W, Sun D, Zhai G. Oral bioavailability of curcumin: problems and advancements. J Drug Target 2016 Sep;24(8):694-702.
13. Shen L, Liu CC, An CY, Ji HF. How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies. Sci Rep 2016 Feb 18;6:20872.
14. Menniti-Ippolito F, Ippoliti I, Pastorelli AA, Altieri I, Scalise F, De Santis B, Debegnach F, Brera C, Pacifici R, Pichini S, Pellegrini M, Rotolo MC, Graziano S, Palazzino G, Multari G, Gallo FR, Neri B, Giannetti L, Russo K, Fedrizzi G, Bonan S, Mazzanti G, Moro PA, Salvi E, Firenzuoli F, Valeri A, Moretti U, Traversa G, Silano M, Stacchini P, Boniglia C. Turmeric (Curcuma longa L.) food supplements and hepatotoxicity: an integrated evaluation approach. Ann Ist Super Sanita. 2020 Oct-Dec;56(4):462-469.
15. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998 May;64(4):353-6.
16. Zeng X, Cai D, Zeng Q, Chen Z, Zhong G, Zhuo J, Gan H, Huang X, Zhao Z, Yao N, Huang D, Zhang C, Sun D, Chen Y. Selective reduction in the expression of UGTs and SULTs, a novel mechanism by which piperine enhances the bioavailability of curcumin in rat. Biopharm Drug Dispos. 2017 Jan;38(1):3-19.
17. Volak LP, Ghirmai S, Cashman JR, Court MH. Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos. 2008 Aug;36(8):1594-605.
18. Volak LP, Hanley MJ, Masse G, Hazarika S, Harmatz JS, Badmaev V, Majeed M, Greenblatt DJ, Court MH. Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2013 Feb;75(2):450-62.
19. Lombardi N, Crescioli G, Maggini V, Ippoliti I, Menniti-Ippolito F, Gallo E, Brilli V, Lanzi C, Mannaioni G, Firenzuoli F, Vannacci A. Acute liver injury following turmeric use in Tuscany: An analysis of the Italian Phytovigilance database and systematic review of case reports. Br J Clin Pharmacol. 2021 Mar;87(3):741-753.
20. Halegoua-DeMarzio D, Navarro V, Ahmad J, Avula B, Barnhart H, Barritt AS, Bonkovsky HL, Fontana RJ, Ghabril MS, Hoofnagle JH, Khan IA, Kleiner DE, Phillips E, Stolz A, Vuppalanchi R. Liver Injury Associated with Turmeric-A Growing Problem: Ten Cases from the Drug-Induced Liver Injury Network [DILIN]. Am J Med. 2023 Feb;136(2):200-206.
21. Garaizabal Azkue ÍJ, Castiella A, Aburruza Ucar L, Torrente Iranzo S, Zapata Morcillo E. Turmeric associated liver injury (DILI) with susceptible HLA. Rev Esp Enferm Dig. 2024 Sep 19;
22. Working Group Food Supplements of Heads of Food Safety Agencies: First report of the HoA Working Group “Food Supplements” (2024).
23. Suryawanshi G, Abdallah M, Thomson M, Desai N, Chauhan A, Lim N. Ashwagandha-Associated Acute Liver Failure Requiring Liver Transplantation. Am J Ther. 2023 Jan-Feb 01;30(1):e80-e83.
24. Philips CA, Valsan A, Theruvath AH, Ravindran R, Oommen TT, Rajesh S, Bishnu S, Augustine P. Ashwagandha-induced liver injury-A case series from India and literature review. Hepatol Commun. 2023 Oct 1;7(10).
25. Koturbash I, Yeager RP, Mitchell CA, Ferguson S, Navarro VJ, Paine MF, Roe AL. Botanical-induced toxicity: Liver injury and botanical-drug interactions. A report on a society of Toxicology Annual Meeting symposium. Regul Toxicol Pharmacol. 2024 Sep 19;153:105708.