Acta Neurol Belg DOI 10.1007/s13760-015-0506-0
LETTER TO THE EDITOR
Glatiramer acetate-induced hepatitis in a patient with multiple sclerosis A. Flaire1 • Clarisse Carra-Dalliere1 • X. Ayrignac1 • P. Blanc2 • P. Labauge1
Received: 29 May 2015 / Accepted: 24 June 2015 Ó Belgian Neurological Society 2015
Dear sir, Glatiramer acetate (GA) is an immunomodulator widely used for several years in the treatment of relapsing-remitting multiple sclerosis (MS) and usually considered as safe. We report a case of cytolytic hepatitis related to recent prescription of GA in a patient without any previous hepatotoxic treatment and sign of hepatic autoimmunity. A 56-year-old woman, without medical history, presented a first relapse in December 2013. Spinal cord MRI showed C2–C3 myelitis; occurrence of typical white matter hyperintensities on cerebral MRI led to diagnosis of MS. There was no personal or family history of liver disease, no alcohol consumption, and no previous or concomitant hepatotoxic treatment. GA was started on October 31st 2014, as biological parameters including liver function were normal. A few days later, the patient suffered from left inflammatory optic neuropathy treated with high dose methylprednisolone pulses for 3 days, with excellent recovery. On January 6th 2015, routine blood tests showed hepatic cytolysis (aspartate-aminotransferase (ASAT): 330 UI/L, alanine-aminotransferase (ALAT): 150 UI/L). Prothrombin time, serum albumin, and bilirubin levels were normal. There was no sign of liver failure. GA was immediately stopped. Ultrasonography showed a normal liver echogenicity, without ascites, sus-hepatic veins thrombosis, portal & Clarisse Carra-Dalliere [email protected] 1
Department of Neurology, CHU Montpellier, 80, Avenue Augustin Fliche, 34295 Montpellier, France
2
Department of Hepatogastroenterology, CHU Montpellier, Montpellier, France
hypertension, or lithiasis. Hepatitis A, B, C, E and HSV serologies were negative. EBV and CMV serologies showed past infection. Exhaustive autoimmune screening was negative, especially for antinuclear, anti-smooth muscle, anti-liver kidney microsomal 1, anti-mitochondrial, and anti-soluble liver antigen antibodies. One month after GA withdrawal, ALAT levels were still 10 times higher than normal (Fig. 1). A liver biopsy was performed and showed predominant centro-lobular hepatocyte necrosis with inflammatory infiltrates compound of lymphocytes and eosinophils. There were very few plasmocytes and no granulomas. Histopathology was consistent with drug-induced toxic hepatitis. Liver tests improved 6 weeks after withdrawal of GA and were normalized 4 months later. In our patient, the imputability of GA is supported by several elements. First, the strict negativity of autoimmune screening and the absence of portal and periportal lesions on the liver biopsy make the diagnosis of auto-immune hepatitis very unlikely. Second, GA was the only medication taken by the patient and liver tests improved after GA withdrawal. The link between GA and acute hepatitis may be classified as probable according to Naranjo adverse drug reaction probability scale [1] (with 7 points on a scale ranging from -3 to 13). GA is usually considered as a safe treatment. Nevertheless, some cases have already been published in which various autoimmune diseases were revealed by GA intake [2, 3]. Anti-liver antibodies have been temporarily found without evidence of autoimmune hepatitis [4]. Some authors assume that GA induce T-helper type 2 cells releasing cytokines like IL-4, IL-6 and IL-10, which may increase the production of auto-antibodies leading to the induction of the autoimmune process [5]. However, in our case, we could not confirm the exact nature of the
123
Acta Neurol Belg Fig. 1 Monitoring of liver enzyms revealed cytolytic hepatitis, 10 weeks after GA initiation and normalization of the tests 4 months after its withdrawal (ASAT aspartateaminotransferase, ALAT alanine-aminotransferase)
hepatotoxic injury, in the absence of autoantibodies directed against the liver. GA-hepatotoxicity has already been reported in few cases [4], but its mechanism is unclear since GA is not metabolized by the liver. Interestingly, in our case, systematic biological monitoring led to recognition of the asymptomatic hepatitis. In other reports, diagnosis was made once clinical symptoms had occured [4]. Currently, routine biological monitoring under GA is not recommended by guidelines. Despite the rare occurence of GA-induced hepatitis, we strongly suggest to monitor routine laboratory tests, including liver enzymes, during the first semester of GA treatment to detect hepatitis. Indeed, in most reported cases, GA-induced hepatitis occurred within the first 6 months of the treatment. Conflict of interest A. Flaire: no conflict of interest. C. CarraDalliere: received travel grants from Novartis, Merck-Serono and TEVA. X. Ayrignac: has participated in scientific congresses and received honoraria for attending conferences and has serving as a
123
consultant (in alphabetical order): Bayer Schering, Genzyme, MerckSerono, Novartis, Sanofi. P. Blanc: no conflict of interest. P. Labauge: received travel grants from Genzyme, Merck-Serono and TEVA.
References 1. Naranjo CA, Busto U, Sellers EM et al (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30(2):239–245 2. Heesen C, Gbadamosi J, Schoser BG, Po¨hlau D (2001) Autoimmune hyperthyroidism in multiple sclerosis under treatment with glatiramer acetate––a case report. Eur J Neurol 8(2):199 3. Neumann H, Csepregi A, Sailer M, Malfertheiner P (2007) Glatiramer acetate induced acute exacerbation of autoimmune hepatitis in a patient with multiple sclerosis. J Neurol 254(6):816–817 4. Antezana A, Herbert J, Park J, Kister I (2014) Glatiramer acetateinduced acute hepatotoxicity in an adolescent with MS. Neurology 82(20):1846–1847 5. Miller A, Shapiro S, Gershtein R et al (1998) Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation. J Neuroimmunol 92(1–2):113–121
LETTER TO THE EDITOR
Glatiramer acetate-induced hepatitis in a patient with multiple sclerosis A. Flaire1 • Clarisse Carra-Dalliere1 • X. Ayrignac1 • P. Blanc2 • P. Labauge1
Received: 29 May 2015 / Accepted: 24 June 2015 Ó Belgian Neurological Society 2015
Dear sir, Glatiramer acetate (GA) is an immunomodulator widely used for several years in the treatment of relapsing-remitting multiple sclerosis (MS) and usually considered as safe. We report a case of cytolytic hepatitis related to recent prescription of GA in a patient without any previous hepatotoxic treatment and sign of hepatic autoimmunity. A 56-year-old woman, without medical history, presented a first relapse in December 2013. Spinal cord MRI showed C2–C3 myelitis; occurrence of typical white matter hyperintensities on cerebral MRI led to diagnosis of MS. There was no personal or family history of liver disease, no alcohol consumption, and no previous or concomitant hepatotoxic treatment. GA was started on October 31st 2014, as biological parameters including liver function were normal. A few days later, the patient suffered from left inflammatory optic neuropathy treated with high dose methylprednisolone pulses for 3 days, with excellent recovery. On January 6th 2015, routine blood tests showed hepatic cytolysis (aspartate-aminotransferase (ASAT): 330 UI/L, alanine-aminotransferase (ALAT): 150 UI/L). Prothrombin time, serum albumin, and bilirubin levels were normal. There was no sign of liver failure. GA was immediately stopped. Ultrasonography showed a normal liver echogenicity, without ascites, sus-hepatic veins thrombosis, portal & Clarisse Carra-Dalliere [email protected] 1
Department of Neurology, CHU Montpellier, 80, Avenue Augustin Fliche, 34295 Montpellier, France
2
Department of Hepatogastroenterology, CHU Montpellier, Montpellier, France
hypertension, or lithiasis. Hepatitis A, B, C, E and HSV serologies were negative. EBV and CMV serologies showed past infection. Exhaustive autoimmune screening was negative, especially for antinuclear, anti-smooth muscle, anti-liver kidney microsomal 1, anti-mitochondrial, and anti-soluble liver antigen antibodies. One month after GA withdrawal, ALAT levels were still 10 times higher than normal (Fig. 1). A liver biopsy was performed and showed predominant centro-lobular hepatocyte necrosis with inflammatory infiltrates compound of lymphocytes and eosinophils. There were very few plasmocytes and no granulomas. Histopathology was consistent with drug-induced toxic hepatitis. Liver tests improved 6 weeks after withdrawal of GA and were normalized 4 months later. In our patient, the imputability of GA is supported by several elements. First, the strict negativity of autoimmune screening and the absence of portal and periportal lesions on the liver biopsy make the diagnosis of auto-immune hepatitis very unlikely. Second, GA was the only medication taken by the patient and liver tests improved after GA withdrawal. The link between GA and acute hepatitis may be classified as probable according to Naranjo adverse drug reaction probability scale [1] (with 7 points on a scale ranging from -3 to 13). GA is usually considered as a safe treatment. Nevertheless, some cases have already been published in which various autoimmune diseases were revealed by GA intake [2, 3]. Anti-liver antibodies have been temporarily found without evidence of autoimmune hepatitis [4]. Some authors assume that GA induce T-helper type 2 cells releasing cytokines like IL-4, IL-6 and IL-10, which may increase the production of auto-antibodies leading to the induction of the autoimmune process [5]. However, in our case, we could not confirm the exact nature of the
123
Acta Neurol Belg Fig. 1 Monitoring of liver enzyms revealed cytolytic hepatitis, 10 weeks after GA initiation and normalization of the tests 4 months after its withdrawal (ASAT aspartateaminotransferase, ALAT alanine-aminotransferase)
hepatotoxic injury, in the absence of autoantibodies directed against the liver. GA-hepatotoxicity has already been reported in few cases [4], but its mechanism is unclear since GA is not metabolized by the liver. Interestingly, in our case, systematic biological monitoring led to recognition of the asymptomatic hepatitis. In other reports, diagnosis was made once clinical symptoms had occured [4]. Currently, routine biological monitoring under GA is not recommended by guidelines. Despite the rare occurence of GA-induced hepatitis, we strongly suggest to monitor routine laboratory tests, including liver enzymes, during the first semester of GA treatment to detect hepatitis. Indeed, in most reported cases, GA-induced hepatitis occurred within the first 6 months of the treatment. Conflict of interest A. Flaire: no conflict of interest. C. CarraDalliere: received travel grants from Novartis, Merck-Serono and TEVA. X. Ayrignac: has participated in scientific congresses and received honoraria for attending conferences and has serving as a
123
consultant (in alphabetical order): Bayer Schering, Genzyme, MerckSerono, Novartis, Sanofi. P. Blanc: no conflict of interest. P. Labauge: received travel grants from Genzyme, Merck-Serono and TEVA.
References 1. Naranjo CA, Busto U, Sellers EM et al (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30(2):239–245 2. Heesen C, Gbadamosi J, Schoser BG, Po¨hlau D (2001) Autoimmune hyperthyroidism in multiple sclerosis under treatment with glatiramer acetate––a case report. Eur J Neurol 8(2):199 3. Neumann H, Csepregi A, Sailer M, Malfertheiner P (2007) Glatiramer acetate induced acute exacerbation of autoimmune hepatitis in a patient with multiple sclerosis. J Neurol 254(6):816–817 4. Antezana A, Herbert J, Park J, Kister I (2014) Glatiramer acetateinduced acute hepatotoxicity in an adolescent with MS. Neurology 82(20):1846–1847 5. Miller A, Shapiro S, Gershtein R et al (1998) Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation. J Neuroimmunol 92(1–2):113–121
