Hypoglycemia is associated with various clinical conditions, and some are critical and associated with poor prognosis, such as sepsis.¹⁾ Insulin autoimmune syndrome (IAS) or Hirata disease is a rare condition characterized by hyperinsulinemic hypoglycemia associated with a high titer of antibodies against endogenous insulin in the absence of pathological abnormalities in the pancreatic islets and exposure to exogenous insulin.²⁾ Most IAS cases have been reported in Japan.²⁾ A history of other autoimmune disorders, particularly Graves’ disease, and treatment with sulfhydryl medications, particularly methimazole, have been reported in IAS. In this paper, we report a case of methimazole-induced IAS successfully treated with propylthiouracil (PTU) without other immunotherapies such as steroids and studied related literature review in Korean cases.

A 48-year-old woman visited the emergency department with a hypoglycemic mental alteration. After infusion of a 50% dextrose solution, the patient awakened with elevated blood sugar. Her height, weight, and body mass index were 155 cm, 47 kg, and 19 kg/m², respectively. She had been taking medications for Graves’ disease for the past six months at another hospital, including methimazole and propranolol.

Laboratory tests revealed a low serum glucose level of 42 mg/dL, a high insulin level of 300 μU/mL (normal range, up to 30 μU/mL), and a C-peptide level of 4.7 ng/dL (normal range, 0.5-3.5 ng/mL). During hypoglycemia, her cortisol level was 10.8 μg/dL, growth hormone level was 3.1 ng/mL (normal range, up to 8 ng/mL), and serum ketone was negative. Thyroid function test was abnormal: free T4 2.27 ng/dL (normal range, 0.77-1.94 ng/dL), T3 2.26 ng/dL (normal range, 0.75-1.9 ng/dL), thyroid-stimulating hormone 0.01 μIU/mL (normal range, 0.3-4 μIU/mL), anti-microsomal antibody 285.9 IU/mL (normal value, <60 IU/mL), thyroid-stimulating antibody 11.28 IU/L (normal value, <1.5 IU/L).

The hemoglobin A1c level was 5.4%, and an anti-insulin antibody titer of 96.7 U/mL (normal value, <7 U/mL) was detected. Other laboratory findings included normal complete blood count (white blood cells 5600/uL, hemoglobin 13.6 g/dL, platelet count 180,000), normal clotting factors (prothrombin time 0.92 [international normalized ratio 0.85-1.15], activated partial prothromboplastin time 32.7 s), elevated aspartate aminotransferase 62 U/L (normal range, 7-38 U/L), alanine aminotransferase 86 U/L (normal range, 4-43 U/L), alkaline phosphatase 339 IU/L (normal range, 104-338 IU/L), and normal total bilirubin 0.5 mg/dL (normal range, 0.3-1.2 mg/dL).

Her serum laboratory examinations revealed results as follows: hepatitis viral marker (-), antinuclear antibody (-), anti-mitochondrial antibody (-), anti-smooth muscle antibody (-), anti-liver kidney 1 antibody (-), immunoglobulin G (IgG) 1436 mg/dL (normal range, 700-1600 mg/dL), and anti-dsDNA antibody IgG (-). Abdominal computed tomography was negative for pancreatic tumors.

The patient was diagnosed with methimazole-induced IAS based on hypoglycemia episodes accompanied by markedly high insulin and C-peptide levels and the presence of anti-insulin antibodies to endogenous insulin. After methimazole discontinuation and dietary treatment, such as eating six small meals per day and a low-carbohydrate diet, her hypoglycemia symptoms improved. She rejected other treatments, such as radioactive iodine or surgery, for her Graves’ disease. Therefore, she was treated with PTU, which has no sulfhydryl group, to treat Graves’ disease. After one year of treatment, her insulin antibody level decreased to 45 U/mL; two years later, this level dropped to 20 U/mL.

Previously, six cases of methimazole-induced IAS were reported in Korea (Table 1).^3-6) In most cases, Graves’ disease treatment was changed to radioactive iodine after the event. Our case was the first to perform well with medical therapy (PTU) without other hypoglycemia treatments, such as steroids.

Hirata first described the IAS in 1970.⁷⁾ It is characterized by episodes of hyperinsulinemic hypoglycemia and the presence of insulin autoantibodies in individuals who have not previously received insulin injections. The mechanism of spontaneous hypoglycemia in IAS is due to excess free insulin released by insulin-autoantibody complexes several hours after glucose loading. In a retrospective survey of endogenous hyperinsulinemic hypoglycemia cases observed at a tertiary hospital in Korea, the prevalence of IAS was 6%, markedly higher than that in the West.⁸⁾

Most patients with IAS have comorbidities and take various medications. This syndrome is often associated with rheumatological diseases, such as systemic lupus erythematosus or rheumatoid arthritis, and hematological diseases, such as benign monoclonal gammopathy and multiple myeloma.⁹⁾ Occasionally, IAS is triggered by exposure to various medications. A clear association between drugs containing a sulfhydryl group and IAS occurrence has been found in Japanese cases.¹⁰⁾ Over 50% of patients with IAS have previously received drugs containing a sulfhydryl group, which is associated with the production of insulin autoantibodies through chemical and immunological reactions with insulin molecules.

The prevalence of methimazole-induced IAS is high in East Asia, particularly in Japan. There have been 64 reported cases of methimazole-induced IAS in Japan, 16 cases in East Asians (excluding Japanese), and two cases in Caucasians. Only five of these cases were reported in Korea.^3-6) IAS exhibits a strong genetic predisposition. In particular, IAS has been documented to be strongly associated with HLA-DRB1*0406, DQB1*0302, and DQA1*0301.¹¹⁾ Patients with Graves’ disease who have DRB1*0406 develop IAS after methimazole treatment.¹²⁾ The DRB1*0406 genotype is relatively common in East Asians, which explains why IAS is common in East Asians.¹³⁾ However, we were unable to confirm the presence of this genetic factor in our case.

Approximately 80% of patients with IAS experience spontaneous remission of hypoglycemia in less than three months without special treatment other than avoiding the offending drug, although persistent hypoglycemia has also been observed in a few patients.⁷⁾ Discontinuation of the offending drug, eating six or more small meals per day, and a low-carbohydrate diet are currently the recommended treatments for methimazole-induced hypoglycemia.¹⁴⁾

In hypoglycemia, α-glucosidase inhibitors can be helpful by reducing intestinal glucose uptake and preventing hypersecretion of insulin by the β-cells. If hypoglycemia persists, immunosuppressive therapy with prednisolone or plasmapheresis should be considered.¹⁵⁾ Furthermore, antiCD20 monoclonal antibodies such as rituximab are remarkably effective in blocking de novo antibody responses and are known to suppress insulin autoantibodies.¹⁶⁾ Thus, this approach may help reduce insulin autoantibodies during persistent hypoglycemia in methimazole-induced IAS.

In Case 3 (Table 1), steroid therapy was administered to improve hypoglycemia and immunomodulation. Since PTU can induce hepatotoxicity in Graves’ disease, the patient continued to take methimazole. She received oral hydrocortisone (50 mg/m²), which was slowly tapered over two months. The patient responded well to the treatment, and hypoglycemia resolved after six days of steroid therapy. Insulin autoantibody titers decreased one month after hydrocortisone discontinuation. In our case, the hypoglycemic episodes resolved within one week after methimazole discontinuation. Serum total insulin, C-peptide, and insulin autoantibody titers gradually normalized within one year. After the methimazole-induced autoimmune hypoglycemic event, most treatments for Graves’ disease were changed from medical therapy to radioactive iodine. Our case is the first in which medical therapy (PTU, not methimazole) responded well without other hypoglycemic treatments, such as steroids.

In conclusion, the mechanism underlying methimazole-induced IAS may be related to the sulfhydryl group. Therefore, PTU, which does not contain a sulfhydryl group, can be an option for treating Graves’ disease and methimazole-induced IAS.

No potential conflict of interest relevant to this article was reported.