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Case Report/Case Series |

Liraglutide-Induced Autoimmune Hepatitis

Emily Kern, MD1; Lisa B. VanWagner, MD, MS2; Guang-Yu Yang, MD, PhD3; Mary E. Rinella, MD2
[+] Author Affiliations
1Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
2Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
JAMA Intern Med. 2014;174(6):984-987. doi:10.1001/jamainternmed.2014.674.
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Importance  Use of incretin-based hypoglycemic agents is increasing, but safety data remain limited. We treated a woman with marker-negative autoimmune hepatitis associated with the glucagon-like peptide 1 agonist liraglutide.

Observations  A young woman with type 2 diabetes mellitus and vitiligo presented with a 10-day history of acute hepatitis. Other than starting liraglutide therapy 4 months prior, she reported no changes in medication therapy and no use of supplements. At admission, aspartate aminotransferase level was 991 U/L; alanine aminotransferase level, 1123 U/L; total bilirubin level, 9.5 mg/dL; and international normalized ratio, 1.3. Results of a liver biopsy demonstrated interface hepatitis with prominent eosinophils and rare plasma cells. The patient’s liraglutide therapy was withheld at discharge but her symptoms worsened. A second biopsy specimen revealed massive hepatic necrosis. She started oral prednisone therapy for presumed liraglutide-induced marker-negative autoimmune hepatitis.

Conclusions and Relevance  This case represents, to our knowledge, the first report of liraglutide-induced autoimmune hepatitis. Hepatotoxicity may be an incretin analogue class effect with a long latency period. This case raises prescriber awareness about the potential adverse effects of glucagon-like peptide 1 agonists. Postmarketing studies are needed to define the hepatotoxic potential of these agents.

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Figure 1.
Results of the First Liver Biopsy

Portal and interface inflammation with a mixed inflammatory infiltrate consisting of lymphocytes, occasional plasma cells (black arrowheads), and prominent eosinophils (yellow arrowheads) are seen (hematoxylin-eosin, original magnification ×40). Inset is of the boxed area in the larger slide (original magnification ×200).

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Figure 2.
Results of the Second Liver Biopsy

Lobular necrosis and portal and interface inflammation with predominant lymphocytes and scattered eosinophils (yellow arrowheads) are seen (hematoxylin-eosin, original magnification ×200). Inset is taken from a portion of the biopsy not captured on the larger slide (original magnification ×400).

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Figure 3.
Trend in Liver Function Test Results During the Course of the Patient’s Disease

Results over time for the patient’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (A) and the bilirubin level (B). The upper limit of the reference range for the ALT level is 52 U/L; for AST, 39 U/L. To convert AST and ALT to microkatals per liter, multiply by 0.0167; bilirubin to micromoles per liter, multiply by 17.104.

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Did Liraglutide induce Autoimmune Hepatitis?
Posted on September 2, 2014
Franco Folli, Sylka Rodovalho, Carmine Cardillo
Department of Medicine, University of Texas Health Science Center at San Antonio, Texas, USA; Division of Endocrinology, Pontificia Universidade de Campinas, Campinas, S.P., Brazil; Department of Inte
Conflict of Interest: None Declared
To the Editor: We have read with interest the case report by Dr. Kern and collaborators, entitled “Liraglutide-Induced Autoimmune Hepatitis”. A young woman affected by type 2 diabetes mellitus and vitiligo, presented with acute hepatitis since 10 days. The patients had been treated with liraglutide, 1.2 mg/day, for 4 months before presentation. Prior to liraglutide, she had been treated with exenatide, 10 μg twice daily. Autoantibodies were absent and viral markers were negative. AST, ALT and bilirubin were elevated and 2 liver biopsies demonstrated the presence of portal and interface inflammation (lymphocytes, plasma cells and eosinophils), and subsequently lobular necrosis. The Authors suggested that autoimmune hepatitis (AIH) secondary to antibodies toliraglutidewas the probable diagnosis (1).We believe that there might be an alternative explanation to the acute hepatitis in this patient. The occurrence of acute hepatitis in a young patient affected by diabetes and vitiligo, which is associated with AIH in approximately 2% of the cases, could also suggest autoantibody negative AIH (2). The time course of ALT and AST levels, depicted in Figure 3, had a biphasic behavior, with a drop of around 50% almost 2-3 weeks after cessation of liraglutide and a new elevation later on. At that point, prednisone was started leading to a dramatic reduction of liver enzymes. The second peak of enzyme elevation, occurring 28 to 30 days after the drug withdrawal, argues against liraglutide as the cause of this hepatitis (1, 3). Also, utilization of the RUCAM scale, a method for causality assessment of adverse reactions to drugs, suggests that the hepatitis in this case is unlikely related to liraglutide, given the final score of +1 (1, 3).Around 8% of patients treated with liraglutide will form anti-liraglutide antibodies, but the presence of those autoantibodies has not been demonstrated in this patient (1, 4). Therefore the mechanism hypothesized by the Authors, i.e. formation of a ternary complex between GLP-1, anti-liraglutide antibodies and GLP-1 receptor on the hepatocyte membrane, is lacking the supposed “primum movens”, i.e. anti-liraglutide antibodies. By contrast, the revised original diagnostic scoring system of the International Autoimmune Hepatitis Group suggests that autoantibody negative AIH is the most likely diagnosis in this patient, since her score is 14 or 15 (5).Recognizing the critical importance of continue pharmacovigilance , we suggest that scoring systems like the RUCAM and the IAIHG are employed to objectively evaluate suspected drug-induced liver injuries vs. autoimmune hepatitis (3,5).Sincerely.Franco FolliSylka RodovalhoCarmine CardilloReferences:1) Kern E, VanWagner LB, Yang GY, Rinella ME. Liraglutide-induced autoimmune hepatitis. JAMA Intern Med. 2014 Jun 1;174 (6):984-72) Teufel A, Weinmann A, Kahaly GJ et al. Concurrent autoimmune diseases in patients with autoimmune hepatitis. J Clin Gastroenterol. 2010 Mar;44(3):208-133) Danan G, Benichou C . Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993 Nov;46 (11):1323-30.4) Buse JB, Garber A, Rosenstock J et al.Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials. J ClinEndocrinolMetab. 2011 Jun;96(6):1695-702.5) Czaja AJ. Autoantibody-negative autoimmune hepatitis. Dig Dis Sci. 2012 Mar;57(3):610-24.
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