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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].
Show detailsOVERVIEW
Introduction
Gymnema sylvestre is perennial tree-climbing vine with small yellow flowers, the leaves of which have been used extensively in traditional medicine for many conditions including diabetes, hyperlipidemia, obesity, arthritis, liver diseases, malaria, dysentery, and general wellbeing. Gymnema has recently become a popular in the United States, as extracts of its leaves have been promoted for blood glucose control and weight loss. There have been isolated rare reports of liver injury from herbal products containing Gymnema sylvestre, but attribution to the herb was usually weak.
Background
Gymnema sylvestre is a flowering, perennial, tree-climbing vine native to Asia, Africa and Australia, the leaves, fruits, and seeds of which have been used extensively in traditional medicine for many conditions including diabetes, dyslipidemia, obesity, arthritis, liver diseases, malaria, dysentery, and general wellbeing. In vitro and in vivo analysis of Gymnema sylvestre leaf extracts have shown hypoglycemic effects which have led to its use in diabetes and in weight loss control. Chemical analyses have demonstrated more than 50 components, the most distinctive being multiple gymnemic acids that are triterpene saponins. Other components include flavones, anthraquinones, alkaloids, phytin, resins, and tannins. In vitro, gymnemic acids have been shown to bind to and inhibit human, sweet taste receptors, and both animal and human studies indicate the ingredients can suppress taste response to sweet substances. Gymnema extracts may have other antidiabetic actions, such as enhanced insulin secretion and inhibition of glucose absorption as well as cholesterol-lowering, antioxidant, antiinflammatory, antibacterial, and antineoplastic activities. Several trials of Gymnema extracts in humans have shown mild decreases in fasting plasma glucose levels accompanied by increases in hemoglobin A1c levels, but the overall effectiveness in the treatment of diabetes has not been shown, and Gymnema has not been approved as therapy of any medical condition in the United States. Extracts of Gymnema sylvestre are available over-the-counter in various forms and concentrations including raw powders or capsules alone or in combination with other herbal products or dietary supplements. The typical recommended dose is 400 mg three times daily, but some commercial products recommend as much as several grams daily. At present there is little standardization of purity and concentration of extracts in Gymnema products. Side effects of conventional doses are uncommon but may include nausea, abdominal discomfort, diarrhea, headaches, and rash. Its long term safety has not been well documented in humans.
Hepatotoxicity
In small rather short term clinical studies of different preparations and concentrations of Gymnema sylvestre, adverse side effects were usually described as uncommon, unrelated to therapy, and minimal with no changes in serum ALT, AST, GGT or bilirubin levels. The effects of long term use and of higher doses, however, have not been assessed in humans. Over the last 25 years, there have been rare, isolated reports of clinically apparent liver injury in patients taking Gymnema sylvestre (Case 1). On the other hand, large case series and literature searches do not mention it as a potential cause of herb induced liver injury.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
Gymnema sylvestre has multiple constituents and the chemical compounds that are possibly responsible for liver injury are not known. The clinical features of the described cases of Gymnema sylvestre liver injury suggest that it is immunologically mediated. Cases may be more frequent and more severe in patients receiving higher doses or with preexisting liver disease.
Outcome and Management
Liver injury reported from Gymnema sylvestre has been self-limited in course and chronic injury has not been clearly described. At issue with most cases has been the possible role of contaminants, other acute causes (other drugs being taken, gallstones), or worsening preexisting liver disease.
Drug Class: Herbal and Dietary Supplements
Other names: Gymnema, Australian Cow Plant, Periploca, Miracle Plant, Gumar (Hindi for “sugar destroyer”).
CASE REPORT
Case 1. Acute liver injury with jaundice attributed to herbal tea containing Gymnema sylvestre.(1)
A 60 year old woman developed weakness, fatigue, loss of appetite, weight loss and jaundice 7 days after starting an Gymnema sylvestre in the form of an herbal tea, taken 3 days daily for type 2 diabetes. After 3 days of symptoms, she stopped the herbal tea and a week later of worsening symptoms sought medical care. She had no history of liver disease, alcohol abuse, risk factors for viral hepatitis, or drug allergies. Her only other medication was acetazolamide for glaucoma that she had taken for two years. Physical examination revealed obesity (BMI 33 kg/m2) and jaundice. Laboratory tests revealed a bilirubin of 15.6 (direct 9.0) mg/dL, ALT 760 U/L, AST 657 U/L, alkaline phosphatase 160 U/L, and GGT 273 U/L (R=16). Tests for acute hepatitis A, B, C and E were negative as were antibodies to Epstein Barr virus and cytomegalovirus. Autoantibodies including ANA, SMA and ANA were also negative. Abdominal ultrasound showed mild hepatomegaly and steatosis, but no evidence of biliary dilatation or gallstones. Prednisone was started in a dose of 60 mg daily. A liver biopsy, however, showed an acute hepatitis with ductular reaction on top of macro- and micro-vesicular steatosis with changes interpreted as due to drug induced liver injury. She was discharged on tapering doses of prednisone. In follow up, corticosteroids were discontinued, and liver tests fell and remained in the normal range.
Key Points
| Medication: | Gymnema sylvestre in herbal tea (unknown dose) for 10 days |
|---|---|
| Pattern: | Hepatocellular (R=16.0) |
| Severity: | Moderate—hospitalized (3+) |
| Latency: | 7 days to symptoms, 17 to medical presentation |
| Recovery: | Within 6 months |
| Other medications: | Acetazolamide |
Laboratory Values
| Time After Starting | Time After Stopping | ALT (U/L) | Alk P (U/L) | Bilirubin (mg/dL) | Comments |
|---|---|---|---|---|---|
| 0 | Pre | Started herbal tea of G. sylvestre [3 times daily] | |||
| 7 days | Pre | Symptoms of fatigue and poor appetite | |||
| 10 days | 0 | Jaundice, stopped herbal tea | |||
| 17 days | 7 | 760 | 160 | 15.6 | Hospital admission |
| 8-14 days | Ultrasound, CT, Liver biopsy | ||||
| Prednisone, gradual tapered | |||||
| 6 months | 25 | 36 | 0.5 | ||
| Upper Limit of Normal | 31 | 104 | 1.2 | ||
* Standard values
Comment
A 60 year old woman with type 2 diabetes developed a moderately severe acute hepatocellular injury within 1 to 2 weeks of starting an herbal tea containing Gymnema sylvestre extract. She was treated with prednisone initially, but it was withdrawn after liver biopsy findings suggested drug induced liver injury rather than autoimmune hepatitis. Other causes of acute hepatitis were adequately excluded. However, liver injury from herbal tea is exceedingly rare and no similar cases attributable to Gymnema have been reported. The short latency to onset and severity were also unexpected from herbal tea induced liver injury. Acetazolamide can cause acute liver injury, but usually within a few weeks of starting and frequently accompanied Stevens Johnson syndrome and prominence of immunoallergic symptoms. Gall bladder disease can also present as an acute hepatitis initially, but imaging demonstrated no evidence of gall stones or biliary obstruction. Finally, the possibility of a spontaneous onset of autoimmune hepatitis must be considered, which was indeed the initial diagnosis before a liver biopsy suggested otherwise. Because she received prednisone and had a clinical response, the diagnosis of spontaneous autoimmune hepatitis cannot be completely discounted without long term follow up. In this case, all liver tests were normal 6 months later when she was no longer taking prednisone. Thus, this report is reasonably convincing of liver injury due to Gymnema sylvestre and indicates that taking a history of exposure to herbal teas should be a part of the differential diagnosis of new onset acute liver injury of unclear cause.
PRODUCT INFORMATION
REPRESENTATIVE TRADE NAMES
Gymnema sylvestre – Generic
DRUG CLASS
Herbal and Dietary Supplements
CHEMICAL FORMULA AND STRUCTURE
| DRUG | CAS REGISTRY NUMBER | MOLECULAR FORMULA | STRUCTURE |
|---|---|---|---|
| Gymnemic Acid I | 122168-40-5 | C43-H66-O14 |
|
CITED REFERENCE
- 1.
- Shiyovich A, Sztarkier I, Nesher L. Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus. Am J Med Sci. 2010;340:514-7. [PubMed: 20856101]
ANNOTATED BIBLIOGRAPHY
References updated: 28 October 2024
Abbreviations: HDS, herbal and dietary supplements.
- 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 book on hepatotoxicity published in 1999; several herbal medications are discussed, but not Gymnema sylvestre).
- Liu LU, Schiano TD. Hepatotoxicity of herbal medicines, vitamins and natural hepatotoxins. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, pp. 733-54.(Book on hepatotoxicity published in 2007 in which herbal and dietary supplements are discussed, but with no mention of Gymnema sylvestre).
- Shanmugasundaram ER, Rajeswari G, Baskaran K, Rajesh Kumar BR, Radha Shanmugasundaram K, Kizar Ahmath B. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J Ethnopharmacol. 1990;30:281-94. [PubMed: 2259216](Among 27 patients with insulin-dependent diabetes on insulin who were treated with Gymnema sylvestre for 6-8 months, fasting blood sugars were reduced [232 to 177 mg/dL] while not decreasing in an untreated group on insulin, and with this a decrease in insulin doses and HgbA1c [12.8 to 9.5%], and there were no “undesirable” side effects).
- Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K, Shanmugasundaram ER. Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients. J Ethnopharmacol. 1990;30:295-300. [PubMed: 2259217](Among 22 patients with type 2 diabetes on conventional oral drugs who were treated with addition of Gymnema sylvestre [400 mg daily] for 18-20 months, fasting blood glucose and HbA1c levels decreased in all patients and serum lipids improved; no mention of adverse events but most patients also felt better, and 5 were able to stop their conventional antidiabetic medications).
- Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care. 2003;26:1277-94. [PubMed: 12663610](Literature review of herbal therapies for glucose control in diabetes, identified 108 trials of 36 herbs and 9 vitamins or minerals, one herbal being Gymnema sylvestre which had been studied in 2 trials, both of which were positive but the evidence was “suggestive but inconclusive”; no mention of adverse events).
- Al-Romaiyan A, Liu B, Asare-Anane H, Maity CR, Chatterjee SK, Koley N, Biswas T, et al. A novel Gymnema sylvestre extract stimulates insulin secretion from human islets in vivo and in vitro. Phytother Res. 2010;24:1370-6. [PubMed: 20812281](Among 11 adults with type 2 diabetes treated with a high molecular weight extract of G. sylvestre [500 mg] twice daily before meals for 60 days, fasting blood glucose levels improved in 10 [mean levels falling from 162 to 119 mg/dL] with no change in body weight, and accompanied by increases in mean serum insulin [24 to 32 μM/mL] and C-peptide [298 to 447 pmol/L] suggesting herb induced increases in insulin secretion; no mention of adverse events or serum ALT or AST levels).
- Kumar SN, Mani UV, Mani I. An open label study on the supplementation of Gymnema sylvestre in type 2 diabetics. J Diet Suppl. 2010;7:273-82. [PubMed: 22432517](Among 58 “free-living” adults with type 2 diabetes self-assigned to receive Gymnema silvestre or no therapy for 3 months, treated patients reported improvements in fatigue, polyuria, and hunger and had mild weight loss and improvements in fasting blood glucose [189 to 163 mg/dL] and HbA1c [9.6 to 8.6] levels, while values worsened in the control group; serum ALT and AST levels were normal in both groups and did not change).
- Al-Romaiyan A, King AJ, Persaud SJ, Jones PM. A novel extract of Gymnema sylvestre improves glucose tolerance in vivo and stimulates insulin secretion and synthesis in vitro. Phytother Res. 2013;27:1006-11. [PubMed: 22911568](Studies of ob/ob mice with insulin resistance found that injections of Gymnema sylvestre high molecular weight extracts resulted in improved glucose tolerance tests and administration to isolated mouse islet cells resulted in increased insulin secretion).
- Li Y, Zheng M, Zhai X, Huang Y, Khalid A, Malik A, Shah P, et al. Effect of Gymnema sylvestre, Citrullus colocynthis, and artemisia absinthium on blood glucose and lipid profile in diabetic human. Acta Pol Pharm. 2015;72:981-5. [PubMed: 26665406](Among 32 patients with type 2 diabetes, treated in 4 groups [n=8] with 3 different herbs [one being G. sylvestre] or placebo in doses of 500 mg twice daily, those on Gymnema had decreases in fasting glucose levels averaging 37% [from 219 to 138 mg/dL]; no mention of results in the placebo group or of adverse events).
- Zuñiga LY, González-Ortiz M, Martínez-Abundis E. Effect of Gymnema sylvestre administration on metabolic syndrome, insulin sensitivity, and insulin secretion. J Med Food. 2017;20:750-754. [PubMed: 28459647](Among 24 adults with obesity and the metabolic syndrome who were treated with G. sylvestre [300 mg] vs placebo twice daily for 12 weeks, body weight deceased slightly [-3.4 kg vs +1.5 kg], but there were minimal changes in fasting blood glucose [-7.2 vs 0 mg/dL] and serum lipids and no change insulin secretion or sensitivity, while adverse events included diarrhea, fever, polydipsia, and abdominal distension but all were transient not requiring dose adjustment or discontinuation and similar in frequency to those receiving placebo).
- Jacobsson I, Jönsson AK, Gerdén B, Hägg S. Spontaneously reported adverse reactions in association with complementary and alternative medicine substances in Sweden. Pharmacoepidemiol Drug Saf 2009; 18: 1039-47. [PubMed: 19650152](Review of 778 spontaneous reports of adverse reactions to herbals in a Swedish Registry does not list Gymnema sylvestre among products associated with 5 or more reports).
- Shiyovich A, Sztarkier I, Nesher L. Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus. Am J Med Sci. 2010;340:514-7. [PubMed: 20856101](60 year old woman developed fatigue, anorexia, weight loss, and jaundice 17 days after starting an over-the-counter herbal tea that contained Gymnema three times daily [bilirubin 15.9 mg/dL, ALT 760 U/L, Alk P 160 U/L, GGT 273 U/L], biopsy suggesting drug induced injury and ultimate resolution after stopping [Case 1]).
- 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: 22928722](A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs and herbal supplements but does not list Gymnema sylvestre as a single implicated agent).
- Pothuraju R, Sharma RK, Chagalamarri J, Jangra S, Kumar Kavadi P. A systematic review of Gymnema sylvestre in obesity and diabetes management. J Sci Food Agric. 2014;94:834-40. [PubMed: 24166097](Review of the effects of gymnemic acids on regulation of carbohydrate and lipid metabolism in animals and humans; no discussion of adverse events, ALT levels, or hepatotoxicity).
- Sanematsu K, Kusakabe Y, Shigemura N, Hirokawa T, Nakamura S, Imoto T, Ninomiya Y. Molecular mechanisms for sweet-suppressing effect of gymnemic acids. J Biol Chem. 2014;289:25711-20. [PMC free article: PMC4162174] [PubMed: 25056955](Using an in vitro transfected cell assay, gymnemic acids were found to bind to human sweet taste receptors and inhibit their activation).
- Brown AC. Liver toxicity related to herbs and dietary supplements: online table of case reports. Part 2 of 5 series. Food Chem Toxicol 2017; 107: 472-501. [PubMed: 27402097](Description of an online compendium of cases of liver toxicity attributed to HDS products does not list or discuss Gymnema sylvestre).
- Medina-Caliz I, Garcia-Cortes M, Gonzalez-Jimenez A, Cabello MR, Robles-Diaz M, Sanabria-Cabrera J, Sanjuan-Jimenez R, et al.; Spanish DILI Registry. Herbal and dietary supplement-induced liver injuries in the Spanish DILI Registry. Clin Gastroenterol Hepatol. 2018;16:1495-1502. [PubMed: 29307848](Among 856 cases of hepatotoxicity enrolled in the Spanish DILI Registry between 1994 and 2016, 32 were attributed to herbal products, the most frequent cause being green tea [n=8] and Herbalife products [n=6]; no mention of Gymnema sylvestre).
- Ballotin VR, Bigarella LG, Brandão ABM, Balbinot RA, Balbinot SS, Soldera J. Herb-induced liver injury: Systematic review and meta-analysis. World J Clin Cases. 2021;9:5490-5513. [PMC free article: PMC8281430] [PubMed: 34307603](Systematic review of the literature on herb induced liver injury identified 446 references describing 936 cases due to 79 different herbal products, the most common being He Shou Wu [91], green tea [90] Herbalife products [64], kava kava [62], and greater celandine [48]; does not mention Gymnema sylvestre).
- Majeed M, Majeed A, Nagabhusahnam K, Mundkur L, Paulose S. A randomized, double-blind clinical trial of a herbal formulation (GlycaCare-II) for the management of type 2 diabetes in comparison with metformin. Diabetol Metab Syndr. 2021;13:132. [PMC free article: PMC8596953] [PubMed: 34789340](Among 69 adults with pre-diabetes or newly diagnosed diabetes treated with a combination product containing 7 herbs including Eurycoma longifolia vs metformin twice daily for 120 days, fasting blood glucose and HbA1c levels improved in both groups to a similar extent and there were “no adverse events reported”, evidently including no change in ALT or AST levels).
- Philips CA, Theruvath AH, Ravindran R. Toxic hepatitis-associated aplastic anaemia after dual homeopathic remedies and Gymnema sylvestre use. BMJ Case Rep. 2022;15:e247867. [PMC free article: PMC8943757] [PubMed: 35318201](50 year old man with diabetes started Gymnema [4 gm daily] and developed itching and jaundice 1 month later [bilirubin 15.6 mg/dL, ALT 79 U/L, Alk P 244 U/L] and while the product was stopped, he developed progressive and fatal aplastic anemia 4 months later; chemical analysis of the herbal product revealed industrial solvents and heavy metals [arsenic and mercury]).
- Bessone F, García-Cortés M, Medina-Caliz I, Hernandez N, Parana R, Mendizabal M, Schinoni MI, et al. Herbal and dietary supplements-induced liver injury in Latin America: experience from the LATINDILI Network. Clin Gastroenterol Hepatol. 2022;20:e548-e563. [PubMed: 33434654](Among 367 cases of hepatotoxicity enrolled in the Latin American DILI Network between 2011 and 2019, 29 [8%] were attributed to herbal products, the most frequent being green tea [n=7], Herbalife products [n=5], and garcinia [n=3], while Gymnema sylvestre was not mentioned).
- Kahksha, Alam O, Naaz S, Sharma V, Manaithiya A, Khan J, Alam A. Recent developments made in the assessment of the antidiabetic potential of gymnema species - From 2016 to 2020. J Ethnopharmacol. 2022;286:114908. [PubMed: 34906636](Review of recent studies on the mechanism of action and biologically activities of Gymnema sylvestre concludes that the antidiabetic effects of Gymnema are the result of synergistic actions of several components on multiple targets involved in glucose metabolism; no discussion of adverse events).
- PMCPubMed Central citations
- PubChem SubstanceRelated PubChem Substances
- PubMedLinks to PubMed
- Ultrasound-assisted extraction of gymnemic acids from Gymnema sylvestre leaves and its effect on insulin-producing RINm-5 F β cell lines.[Phytochem Anal. 2015]Ultrasound-assisted extraction of gymnemic acids from Gymnema sylvestre leaves and its effect on insulin-producing RINm-5 F β cell lines.Sheoran S, Panda BP, Admane PS, Panda AK, Wajid S. Phytochem Anal. 2015 Mar-Apr; 26(2):97-104. Epub 2014 Dec 3.
- Production of Gymnemic Acid from Cell Suspension Cultures of Gymnema sylvestre.[Methods Mol Biol. 2016]Production of Gymnemic Acid from Cell Suspension Cultures of Gymnema sylvestre.Nagella P, Dandin VS, Murthy HN. Methods Mol Biol. 2016; 1391:229-39.
- Review Gymnema sylvestre for Diabetes: From Traditional Herb to Future's Therapeutic.[Curr Pharm Des. 2017]Review Gymnema sylvestre for Diabetes: From Traditional Herb to Future's Therapeutic.Tiwari P, Ahmad K, Baig MH. Curr Pharm Des. 2017; 23(11):1667-1676.
- Gymnema Sylvestre Supplementation Restores Normoglycemia, Corrects Dyslipidemia, and Transcriptionally Modulates Pancreatic and Hepatic Gene Expression in Alloxan-Induced Hyperglycemic Rats.[Metabolites. 2023]Gymnema Sylvestre Supplementation Restores Normoglycemia, Corrects Dyslipidemia, and Transcriptionally Modulates Pancreatic and Hepatic Gene Expression in Alloxan-Induced Hyperglycemic Rats.Muzaffar H, Qamar I, Bashir M, Jabeen F, Irfan S, Anwar H. Metabolites. 2023 Apr 4; 13(4). Epub 2023 Apr 4.
- Review Comprehensive Review on Phytochemicals, Pharmacological and Clinical Potentials of Gymnema sylvestre.[Front Pharmacol. 2019]Review Comprehensive Review on Phytochemicals, Pharmacological and Clinical Potentials of Gymnema sylvestre.Khan F, Sarker MMR, Ming LC, Mohamed IN, Zhao C, Sheikh BY, Tsong HF, Rashid MA. Front Pharmacol. 2019; 10:1223. Epub 2019 Oct 29.
- Gymnema - LiverToxGymnema - LiverTox
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