A Case of Methimazole-Induced Acute Pancreatitis With an HLA Allele Causing Antithyroid Drug-Induced Agranulocytosis

Abstract

Among the side effects of methimazole (MMI) for the treatment of Graves' disease, MMI-induced acute pancreatitis (MIP) is a rare adverse reaction, with only 7 cases being reported to date. However, 2 large-scale population-based studies recently revealed that the risk of MIP was significantly higher, ranging from 0.02% to 0.56%. Although MIP is common in middle-aged and elderly Asian women, its pathogenesis remains largely unknown. We herein present a case of a 72-year-old Japanese woman with Graves' disease who developed MIP 12 days after the initiation of MMI. The MMI was discontinued, the patient was switched to propylthiouracil (PTU) therapy, and pancreatitis gradually resolved. Serological human leukocyte antigen (HLA) typing identified HLA-DRB1*08:03:02. This HLA allele was previously detected in a patient with MIP and is one of the major risk factors for agranulocytosis induced by antithyroid drugs, including PTU as well as MMI. In cases of MIP, PTU is being considered as an alternative to MMI; however, its safety needs further investigation and patients require close monitoring after the switch to PTU. Further studies are warranted, particularly on the relationship between MIP and the presence of HLA alleles causing antithyroid drug-induced agranulocytosis.

Keywords: Graves’ disease; acute pancreatitis; human leukocyte antigen; methimazole.

Figure 1.

Color Doppler ultrasound findings of the patient on admission. A thyroid examination with color Doppler ultrasonography revealed a diffusely increased blood flow, which is typical of untreated Graves’ disease. Abbreviations: IJV, internal jugular vein; CCA, common carotid artery; T, thyroid gland.

Figure 2.

Clinical course during hospitalization. Abbreviations: Amy, amylase; CMZ, cefmetazole; CRP, C-reactive protein; FT3, free triiodothyronine; FT4, free thyroxine; IPM/CS, imipenem/cilastatin sodium; IVD, intravenous drip; KI, potassium iodide; MMI, methimazole; PO, per os; PTU, propylthiouracil.

Figure 3.

The geographic distribution of the frequency of HLA-DRB1*08:03. The map chart shows the geographic distribution of the frequency of HLA-DRB1*08:03 by country. In “HLA > Allele Frequency Search > Classical” of the Allele Frequency Net Database (http://www.allelefrequencies.net/) [22]), we searched the frequency of HLA-DRB1*08:03 in the following settings: Locus: DRB1, Starting Allele: DRB1*08:03, Ending Allele: DRB1*08:03, Population: All populations, Country: All countries, Source of dataset: Literature, Region: All regions, Type of Study: All Studies, Sort by: Allele, Highest to Lowest Frequency, Population standard: Gold only, Show frequencies. We then compiled allele frequency data by country and drew the map chart. We excluded data from Australia because only Aboriginal people were examined, which did not represent the overall population of the country. Abbreviation: HLA, human leukocyte antigen.

Figure 4.

A schematic diagram of current insights and future perspectives on MIP. Abbreviations: AP, acute pancreatitis; CBC, complete blood count; CQ, clinical question; CRP, C-reactive protein; CT, computed tomography; GD, Graves’ disease; HLA, human leukocyte antigen; MIP, methimazole-induced acute pancreatitis; MMI, methimazole; MRI, magnetic resonance imaging; PTU, propylthiouracil.