Refractory Hypoglycaemia Due to Insulin Autoimmune Syndrome: A Review of Published Cases

Abstract

Background: Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare cause of spontaneous, often postprandial,
hyperinsulinaemic hypoglycaemia driven by high-titre autoantibodies against endogenous insulin, arising without prior
exogenous insulin exposure. Objective: To review published cases and epidemiological/mechanistic literature on IAS, focusing on drug-induced and idiopathic presentations and management of refractory disease. Methods: Narrative review of individually verified case reports, case series, systematic reviews and diagnostic/management literature. Findings: IAS is disproportionately reported in Japan and linked to HLA-DRB1*0406, but is increasingly recognised worldwide following sulfhydryl-group drugs (methimazole, alpha-lipoic acid) and clopidogrel. Diagnosis rests on markedly elevated total insulin with disproportionate C-peptide, insulin autoantibody positivity, and PEG precipitation to distinguish IAS from insulinoma or factitious hypoglycaemia. Most cases remit after dietary modification and trigger withdrawal within months; refractory disease has responded to corticosteroids, rituximab and immunoadsorption. Conclusions: IAS should be considered early in unexplained hyperinsulinaemic hypoglycaemia to avoid unnecessary insulinoma work-up, reserving immunosuppression for genuinely refractory disease.