Glatiramer Acetate

Publication Details



Glatiramer acetate is a mixture of synthetic polypeptides that has unique antiinflammatory and immunomodulatory activities and that is used to treat relapsing-remitting multiple sclerosis. Glatiramer therapy is associated with a low rate of transient serum enzyme elevations during therapy and has been linked to rare instances of clinically apparent liver injury with jaundice.


Glatiramer (gla tir' a mer) acetate is a mixture of synthetic polypeptides containing 4 amino acids: glutamic acid, alanine, tyrosine and lysine. The amino acid polymers have distinctive immunomodulatory activities in multiple sclerosis which are believed to be due to inhibition of binding of myelin proteins to major histocompatibility complex (MHC) molecules, which interrupts T cell activation directed at basic myelin. In several large, randomized controlled trials, glatiramer was shown to reduce relapse rates and improve neuroradiologic outcomes in adult patients with relapsing-remitting multiple sclerosis. Glatiramer was approved for use for multiple sclerosis in the United States in 1996 and is available in prefilled syringes of 20 mg and 40 mg generically and under the brand names Copaxone and Glatopa. The recommended dose is 20 mg subcutaneously once daily or 40 mg three times weekly. Common side effects are injection site reactions (pain, erythema, pruritus, induration), as well as mild and transient hypersensitivity reactions of flushing, chest tightness, dyspnea and anxiety occurring within minutes of the injection in about 10% of patients.


In large randomized controlled trials of glatiramer acetate in patients with multiple sclerosis, serum ALT elevations above 3 times ULN were reported in 7% of glatiramer compared to 3% of placebo recipients. The enzyme elevations were usually transient and not associated with symptoms or jaundice, requiring drug discontinuation in less than 1% of patients. No cases of acute hepatitis or clinically apparent liver injury were reported in the preregistration trials of glatiramer. Subsequent to the approval and more wide spread use of glatiramer, however, more than a dozen instances of clinically apparent liver injury with jaundice have been reported. The onset has been within 1 to 3 months of starting therapy, and the typical presentation has been with a hepatocellular pattern of serum enzyme elevations sometimes with autoantibodies (ANA, SMA), but without hyperglobulinemia or histologic features of autoimmune hepatitis. Reported cases have been self-limited with recovery within 1 to 3 months of stopping treatment. Autoantibodies also resolve with resolution of the liver injury. Some patients have later presented with spontaneous autoimmune hepatitis, which has been described in patients with multiple sclerosis not on disease modifying agents.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which glatiramer might cause liver injury is not known, but is likely due to a triggering of an underlying predisposition to autoimmune hepatitis. The synthetic polypeptides are metabolized in multiple cells and the amino acids are probably reused in protein synthesis. Thus, the polypeptides are more likely to trigger an autoimmune reaction rather than cause direct hepatic injury or provide an immunogenic metabolic break-down product.

Outcome and Management

While chronic therapy with glatiramer acetate can be associated with mild-to-moderate serum aminotransferase elevations, these elevations are usually transient and asymptomatic and rarely require dose interruption. Rare instances of acute liver injury with jaundice have resolved with discontinuation. Corticosteroid therapy should be considered in instances with severe or persistent liver injury, but the dose and duration of therapy should be kept to a minimum. There is little evidence for cross sensitivity to liver injury among the various disease modifying drugs for multiple sclerosis such as methyl fumarate, fingolimod, teriflunomide and interferon beta. However, in several instances, the pattern of injury is similar and autoimmunity a likely mechanism.

Drug Class: Multiple Sclerosis Agents


Case 1. Acute self-limited hepatitis attributed to glatiramer acetate therapy.

[Modified from: Subramaniam K, Pavli P, Llewellyn H, Chitturi S. Glatiramer acetate induced hepatotoxicity. Curr Drug Saf 2012; 7: 186-8. PubMed Citation].

A 31 year old woman with relapsing multiple sclerosis developed fatigue, anorexia and jaundice five weeks after starting glatiramer acetate (20 mg subcutaneously once daily). Her multiple sclerosis had been recently diagnosed and she had not received previous disease modifying therapy. She had no history of liver disease, drank alcohol sparingly and denied having risk factors for viral hepatitis. She had a melanoma removed surgically 5 years previously, but did not receive systemic chemotherapy and had no evidence of recurrence. Her only other medication was thyroxine for hypothyroidism. She had a history of depression, but was not receiving antidepressants. She had no history of drug allergies and was not taking over-the-counter or herbal medications. Examination revealed jaundice, but no other evidence for acute or chronic liver disease. Laboratory testing showed a serum bilirubin of 6.4 mg/dL, ALT 1056 U/L, AST 276 U/L, alkaline phosphatase 143 U/L and GGT 341 U/L. Values had been normal when tested before glatiramer therapy (Table). Serum albumin was 3.7 g/dL, globulins 2.9 g/dL and prothrombin time 21 seconds. Tests for hepatitis A, B and C and for EBV and CMV infections were negative. While antinuclear and liver-kidney membrane antibodies were negative, smooth muscle antibodies (SMA) were present (1:320). Ultrasonography showed increased echogenicity of the liver without evidence of biliary obstruction or masses. A liver biopsy showed acute hepatitis with bridging hepatic necrosis, which was considered more likely due to a toxic than autoimmune process. Glatiramer was stopped, and she began to improve rapidly. Two months and eight months later her symptoms had resolved, SMA was no longer positive and all liver tests were normal.

Key Points

Laboratory Values


A young woman with new onset multiple sclerosis developed jaundice within 5 weeks of starting subcutaneous injections of glatiramer acetate. She had no other risk factors for liver disease and laboratory testing and hepatic imaging excluded other common causes of jaundice. The disease resolved rapidly once glatiramer was stopped. This case is fairly typical of the clinically apparent acute liver injury reported with glatiramer, with onset between 1 and 3 months of starting, a hepatocellular pattern of liver injury, occasional autoantibody formation (which can also accompany multiple sclerosis), and rapid improvement upon stopping. The cause of the injury is unclear as it is unlikely that small polypeptides could be hepatotoxic. Thus, a more likely possibility is that the liver injury is due to autoimmune response induced by the therapy, perhaps as a part of the autoimmune predisposition that accompanies multiple sclerosis. The liver injury typically resolves even without immunosuppressive therapy. Glatiramer acetate therapy has been associated with activation of other autoimmune conditions during treatment including myasthenia gravis and autoimmune thyroiditis.



Glatiramer Acetate – Generic, Copaxone®, Glatopa®


Multiple Sclerosis Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 14 March 2018

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    (Two women with relapsing multiple sclerosis, ages 29 and 41 years, developed jaundice one month after starting glatiramer, having had serum enzyme elevations without jaundice on interferon beta [bilirubin 4 and 5 mg/dL, ALT 1260 and 4410 U/L, Alk P 342 and 383 U/L, ANA 1:160 and 1:320], resolving with stopping in one patient, but requiring long term corticosteroid therapy in the second).
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    (42 year old woman with multiple sclerosis on glatiramer for 6 months was found to have ALT elevations [bilirubin 2.2 mg/dL, ALT 602 U/L, Alk P normal] which fell into the near normal range within one month of stopping, although ANA became positive [1:640]).
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    (65 year old woman with multiple sclerosis developed abnormal liver tests one week after starting glatiramer acetate [bilirubin normal, ALT 481 rising to 667 U/L, Alk P normal], resolving 5 months after stopping).