Glucosamine and Chondroitin
Glucosamine is a popular nutritional supplement and natural component of cartilage that is frequently combined with chondroitin sulfate and used for osteoarthritis and nonspecific joint pain. Glucosamine has been implicated in isolated case reports in causing clinically apparent liver injury, but the role of glucosamine as opposed to other herbal components or contaminants has not been shown and liver injury due to glucosamine or chondroitin must be very rare if it occurs at all.
Glucosamine (gloo kose' a meen) is a natural component of cartilage that is a widely used as an over-the-counter nutritional supplement purported to decrease the pain and cartilage loss of osteoarthritis. Glucosamine is commonly taken in combination with chondroitin (kon droe' i tin) which is a glycosaminoglycan that is also present in cartilage. Glucosamine is an amino sugar and a prominent molecule in the biochemical pathways of synthesis of glycosylated proteins and lipids. It is also a major component of keratin sulfate and hyaluronic acid which are present in articular cartilage and synovial fluid. Both glucosamine and chondroitin are reduced in osteoarthritis. Glucosamine is commercially available alone and in combination with chondroitin and widely used for osteoarthritis and arthritic pain. Controlled trials of glucosamine with and without chondroitin have yielded conflicting results. In the largest U.S. study of glucosamine for early osteoarthritis, glucosamine alone and the combination of glucosamine and chondroitin were no more beneficial than placebo in alleviating joint pain or preventing progression of cartilage damage. Glucosamine is typically taken in doses of 500 mg three times daily and chondroitin sulfate in doses of 200 to 400 mg three times daily. Side effects are uncommon and mild and may include abdominal discomfort, nausea, fatigue and headache; but in placebo controlled trials, side effects during glucosamine therapy were no more frequent than with receipt of placebo.
In controlled trials, glucosamine and its combination with chondroitin have not been linked to serum enzyme elevations or to instances of clinically apparent liver injury. In addition, cases of clinically apparent liver injury have not been reported from prospective trials. Recently, several cases reports and small series of clinically apprent liver injury attributed to glucosamine (with or without chondroitin) have been published, but the relationship of glucosamine itself as opposed to other herbals in the implicated products or to potential contaminants, remains unclear and several cases were considered only "possibly" related to glucosamine. The time to onset is usually 1-4 weeks after starting the preparation and the pattern of injury is typically hepatocellular or mixed. At least one instance of acute liver failure has been reported. Immunoallergic features (rash, fever, eosinophilia) can occur but are usually not prominent. Most patients were reported to recover within 4 to 8 weeks of stopping. There have not been instances of rechallenge with glucosamine, and the purity and concentration of glucosamine in the products used have not been reported.
Mechanism of Injury
The mechanism by which glucosamine or chondroitin might cause liver injury is unclear. Glucosamine is a simple amino sugar and chondroitin a glycosaminoglycan. Both are natural products found in cartillage in humans and mammals. The glucosamine in commercially available dietary supplements is usually prepared from the exoskeletons of shellfish or from fermentation of grain. The concentration, purity and freedom from contaminants in commercially available preparations of glucosamine and chondroitin is not always clear.
Outcome and Management
The severity of the liver injury in reports of glucosamine hepatotoxicity has varied from mild, asymptomatic elevations in serum enzymes to clinically apparent hepatitis that can be severe and even fatal. There is no information on management or the role for corticosteroids or other interventions except for prompt discontinuation of the suspected agent.
Case 1. Acute liver injury attributed to a glucosamine containing dietary and herbal supplement.
[Modified from: Ossendza RA, Grandval P, Chinoune F, Rocher F, Chapel F, Bernardini D. [Acute
cholestatic hepatitis due to glucosamine forte]. Gastroenterol Clin Biol 2007; 31: 449-50. French. PubMed Citation].
A 52 year old man developed weakness followed by jaundice and generalized itching arising 3 weeks after starting capsules of Glucosamine forte. He had no previous history of liver disease or drug allergies and died alcohol abuse and risk factors for viral hepatitis. He had no other major medical illnesses and was taking glucosamine for low back pain. On presentation, physical examination revealed jaundice but no fever or rash. Laboratory testing showed a total bilirubin of 10.9 mg/dL, ALT 263 U/L, AST 63 U/L, GGT 240 U/L and alkaline phosphatase 714 U/L (Table). He tested negative for markers of hepatitis A, B, C and E as well as EBV, cytomegalovirus and herpes simplex. These for autoantibodies were negative. Abdominal ultrasound and CT scans were normal with no evidence of biliary obstruction. A liver biopsy showed canalicular cholestasis, hepatocellular necrosis and lobular inlmmation with one microgranuloma, which was considered compatible with drug-induced liver injury. Glucosamine had been stopped a week before clinical presentation and he improved rapidly. Serum bilirubin rose to 13.9 and then gradually began to improve. Liver tests fell into the near normal range within 8 weeks of stopping the supplement and were completely normal when he was seen 4 months later.
||Mixed (R = 2.5)
||3+ (Jaundice and hospitalized)
||3 weeks to symptoms, 4 weeks to jaundice
|Time After Starting
||Time After Stopping
||Alk P* (U/L)
| 6 weeks
| 7 weeks
* Some values estimated from Figure 1.
This was a typical case of cholestatic-mixed hepatitis due to a medication but in this instance the only drug being taken was a commercial preparation of glucosamine. Typical of cholestatic hepatitis was the presentation with pruritus and the somewhat delayed recovery. While the dietary supplement appears to be fairly convincingly implicated as the cause of the liver injury, what is uncertain is whether glucosamine per se versus a possible contaminant was responsible. Glucosamine is a simple amino sugar and is used by millions of people. Reports of hepatic injury from glucosamine are few (less than a dozen in the published literature) and always limited by the lack of proof of purity of the dietary supplement used.
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Glucosamine and Chondroitin
REPRESENTATIVE TRADE NAMES
Glucosamine – Generic
Chondroitin sulfate – Generic
Herbals and Dietary Supplements
||CAS REGISTRY NUMBER
Glucosamine and Chondroitin
References Last Updated: 30 October 2013
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; glucosamine and chondroitin are not discussed).
Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbs 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]; glucosamine and chondroitin are not discussed).
Glucosamine. In, PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Inc. 2007: pp. 967-71. (Compilation of short monographs on herbal medications and dietary supplements).
Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001; 357: 251-6. PubMed Citation (Controlled trial from Belgium of 3 years of glucosamine sulphate vs placebo in 212 patients with osteoarthritis of the knees; found no differences in side effects and no serious adverse events attributable to glucosamine; no mention of hepatotoxicity or results of liver tests).
Pavelká K, Gatterová J, Olejarová M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002; 162: 2113-23. PubMed Citation (Controlled trial of from Italy of glucosamine sulphate vs placebo in 202 patients with knee osteoarthritis; there were no significant differences in frequency of adverse events between the two groups or in safety laboratory results; hepatotoxicity and ALT levels were not mentioned).
De Smet PAGM. Herbal remedies. N Engl J Med 2002; 347: 2046-56. PubMed Citation (Review of status and difficulties of herbal medications including lack of standardization, federal regulation, contamination, safety, hepatotoxicity and drug-herb interactions; specific discussion of 4 herbs with therapeutic promise: ginkgo, hawthorn, saw palmetto and St. John’s wort).
Schiano TD. Hepatotoxicity and complementary and alternative medicines. Clin Liver Dis 2003; 7: 453-73. PubMed Citation (Comprehensive review of herbal associated hepatotoxicity; glucosamine is not listed as causing hepatotoxicity).
Ossendza RA, Grandval P, Chinoune F, Rocher F, Chapel F, Bernardini D. [Acute
cholestatic hepatitis due to glucosamine forte]. Gastroenterol Clin Biol 2007; 31: 449-50. French. PubMed Citation. (52 year old man developed jaundice and pruritus 1 week after stopping 3 week course of glucosamine for low back pain [bilirubin 10.9 mg/dL, ALT 263 U/L, Alk P 714 U/L, eosinophils 1140/uL] with biopsy showing cholestatic hepatitis and a granuloma; episode resolving within 2 months of stopping).
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, including 7 [5%] for herbal medications, none were attributed to glucosamine or chondroitin).
Rozendaal RM, Koes BW, van Osch GJ, Uitterlinden EJ, Garling EH, Willemsen SP, Ginai AZ, et al. Effect of glucosamine sulfate on hip osteoarthritis: a randomized trial. Ann Intern Med 2008; 148: 268-77. PubMed Citation (Controlled trial from the Netherlands of 2 years of glucosamine sulfate vs placebo in 222 patients with hip osteoarthritis; there was no significant differences in adverse events between the two groups and no serious adverse events related to the liver).
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 Spanish registry, 13 [2%] were due to herbals but none were attributed to glucosamine or chondroitin).
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 or dietary supplements, but none of the cases were linked to glucosamine or chondroitin).
Smith A, Dillon J. Acute liver injury associated with the use of herbal
preparations containing glucosamine: three case studies. BMJ Case Rep 2009 ;2009.
PubMed Citation. (Three patients developed liver injury after taking glucosamine: 2 women and 1 man, ages 55-64 years, developed liver injury 5 days, 4 weeks and 6 months after starting the product [bilirubin 24.5, 11.6 mg/dL and normal; ALT 1461, 1130 and 175 U/L, Alk P 141, 198 and 187 U/L], one patient died of acute liver failure, a second developed cirrhosis and a third resolved without symptoms or jaundice; details of products not provided but some included other potentially hepatotoxic herbals).
Wilkens P, Scheel IB, Grundnes O, Hellum C, Storheim K. Effect of glucosamine on pain-related disability in patients with chronic low back pain and degenerative lumbar osteoarthritis: a randomized controlled trial. JAMA 2010; 304: 45-52. PubMed Citation (Controlled trial from Norway of 6 months of glucosamine vs placebo in 250 patients with back pain and degenerative osteoarthritis; rates of adverse events were similar in the two groups: hepatotoxicity and ALT elevations were not mentioned).
Sawitzke AD, Shi H, Finco MF, Dunlop DD, Harris CL, Singer NG, Bradley JD, et al. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann Rheum Dis 2010; 69: 1459-64. PubMed Citation (Controlled trial from US of 24 months of glucosamine, chondroitin, their combination, or celecoxib vs placebo in 662 patients with knee osteoarthritis; rates of adverse events were similar across treatment groups and no liver related serious adverse event occurred).
Miller KL, Clegg DO. Glucosamine and chondroitin sulfate. Rheum Dis Clin North
Am 2011; 37: 103-18. PubMed Citation (Review of the structure, pharmacokinetics, possible mechanisms of action, clinical efficacy and safety of glucosamine and chondroitin as therapy for osteoarthritis; other than a possible interaction with warfarin, no serious adverse events have been linked to long term use of glucosamine and chondroitin).
Linnebur SA, Rapacchietta OC, Vejar M. Hepatotoxicity associated with chinese
skullcap contained in Move Free Advanced dietary supplement: two case reports and
review of the literature. Pharmacotherapy 2010; 30: 750, 258e-262e. PubMed Citation. (Abstract only: 2 patients developed liver injury after taking "Move Free Advanced", a dietary supplement which contains glucosamine, chondroitin but also extracts of several herbs including Chinese skullcap which the authors suggested was the responsible agent).
Ebrahim V, Albeldawi M, Chiang DJ. Acute liver injury associated with
glucosamine dietary supplement. BMJ Case Rep 2012; 2012. PubMed Citation. (55 year old woman developed jaundice 2 weeks after starting glucosamine [bilirubin 9.1 mg/dL, ALT 1553 U/L, Alk P 303 U/L], resolving within 4 weeks of stopping).
Cerda C, Bruguera M, Parés A. Hepatotoxicity associated with glucosamine and
chondroitin sulfate in patients with chronic liver disease. World J
Gastroenterol 2013; 19): 5381-4. PubMed Citation. (Transient elevations in serum ALT levels [from 33 and 53 to 282 and 162 U/L] were found in 2 patients with chronic hepatitis C taking glucosamine which improved upon stopping [falling to 85 and 37 U/L]).
von Felden J, Montani M, Kessebohm K, Stickel F. Drug-induced acute liver
injury mimicking autoimmune hepatitis after intake of dietary supplements
containing glucosamine and chondroitin sulfate. Int J Clin Pharmacol Ther 2013; 51; 219-23. PubMed Citation (65 year old man developed severe autoimmune hepatitis while taking glucosamine and chondroitin sulfate [bilirubin 7.7 mg/dL, ALT 2744 U/L, Alk P 199 U/L, ANA negative, IgG 1820 mg/dL], which responded to corticosteroid therapy and was judged as "possibly" due to the supplement).
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Glucosamine and Chondroitin
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