Hirata – Is Not a Peaceful Rice Paddy

Background:
Insulin autoantibodies are an uncommon cause of non-diabetic hypoglycaemia in people who have never been exposed to insulin before. This condition is called Insulin Autoimmune Syndrome (IAS), or Hirata's Disease. Because of increased clinical awareness, instances are increasingly being found in various populations, although being more frequently reported in East Asian nations.
Case Presentation:
We describe two cases of middle-aged women, a 45-year-old homemaker and a 38-year-old nurse, who had low random blood glucose levels (35–59 mg/dL), giddiness, sweating, weariness, and tremors as symptoms of recurrent postprandial hypoglycaemia. Both received baseline blood tests and systemic checks that were normal. The results of the investigations showed significantly higher levels of C-peptide (1772 and 9782 pmol/L), insulin autoantibody titers (>100 and >200), and serum insulin (>1000 µU/mL). Both patients had a history of taking multivitamins that contained the known trigger alpha-lipoic acid. Hypoglycaemic episodes continued even after dietary changes and steroid treatment, although rituximab treatment produced long-lasting clinical improvement.
Discussion:
IAS is a rare but crucial differential diagnosis for hypoglycaemia that is not diabetic, particularly in individuals who are not receiving insulin therapy. It has been determined that alpha-lipoic acid frequently acts as a precipitating agent. Similar to findings in steroid-refractory cases reported by Batra et al., our patients showed conventional biochemical characteristics of IAS and reacted positively to rituximab, in accordance with earlier investigations. Prolonged morbidity and needless investigations can be avoided with early detection and awareness of IAS.
Conclusion:
Patients with increased insulin levels and spontaneous hypoglycaemia should be evaluated for IAS, especially if exogenous insulin is not being used. Effective care requires a high index of suspicion, triggering agent identification, and customized treatment, including immunosuppressive medication like rituximab.

Hirata, Insulin autoantibodies , IAS

1. Hirata Y. Insulin autoimmunity in a case of spontaneous hypoglycemia. J. Jpn. Diabet. Soc.. 1970;13:312-9. [Google Scholar] [Crossref]

2. Censi S, Mian C, Betterle C. Insulin autoimmune syndrome: from diagnosis to clinical management. Annals of Translational Medicine. 2018 Sep;6(17):335. [Google Scholar] [Crossref]

3. Cappellani D, Macchia E, Falorni A, Marchetti P. Insulin autoimmune syndrome (Hirata disease): a comprehensive review fifty years after its first description. Diabetes, Metabolic Syndrome and Obesity. 2020 Apr 1:963-78. [Google Scholar] [Crossref]

4. Ito Y, Nieda M, Uchigata Y, Nishimura M, Tokunaga K, Kuwata S, Obata F, Tadokoro K, Hirata Y, Omori Y. Recognition of human insulin in the context of HLA-DRB1* 0406 products by T cells of insulin autoimmune syndrome patients and healthy donors. Journal of immunology (Baltimore, Md.: 1950). 1993 Nov 15;151(10):5770-6. [Google Scholar] [Crossref]

5. Boro H, Gupta U, Singh C, Malhotra R, Khadgawat R. Insulin autoimmune syndrome–A case series. European endocrinology. 2020 Oct 6;16(2):168. [Google Scholar] [Crossref]

6. Wong SL, Priestman A, Holmes DT. Recurrent hypoglycemia from insulin autoimmune syndrome. Journal of general internal medicine. 2014 Jan;29(1):250-4. [Google Scholar] [Crossref]

7. Ishida Y, Ohara T, Okuno Y, Ito T, Hirota Y, Furukawa K, Sakaguchi K, Ogawa W, Kasuga M. α-Lipoic acid and insulin autoimmune syndrome. Diabetes Care. 2007 Sep 1;30(9):2240-1. [Google Scholar] [Crossref]

8. Gopal K, Priya G, Gupta N, Praveen EP, Khadgawat R. A case of autoimmune hypoglycemia outside Japan: Rare, but in the era of expanding drug-list, important to suspect. Indian journal of endocrinology and metabolism. 2013 Nov 1;17(6):1117-9. [Google Scholar] [Crossref]

9. Batra CM, Kumar K, Goyal Sr M, BATRA CM, Pasam KK, GOYAL Sr MO. Steroid-refractory insulin autoimmune syndrome treated with rituximab and continuous glucose monitoring. Cureus. 2021 Jul 20;13(7). [Google Scholar] [Crossref]

10. Van Vollenhoven RF, Emery P, Bingham III CO, Keystone EC, Fleischmann RM, Furst DE, Tyson N, Collinson N, Lehane PB. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Annals of the rheumatic diseases. 2013 Sep 1;72(9):1496-502. [Google Scholar] [Crossref]