“The Unusual Suspect” - Insulin Autoimmune Syndrome, an Extremely Rare Cause of Hypoglycemia

Background: Insulin autoimmune syndrome (IAS), also called Hirata syndrome, is a rare diagnosis which is characterized by hypoglycemia, normal or elevated fasting insulin level, and elevated anti-insulin antibody titers. Clinical Case: 45-year-old nondiabetic Caucasian female presented to the emergency department (ED) with chief complaint of near-syncope. She reported difficulty concentrating and feeling faint roughly 1 hour after consuming breakfast. Upon ED arrival, fingerstick glucose (FSG) was 47 mg/dL. Her symptoms resolved with ingestion of orange juice and repeat blood glucose (BG) 15 minutes later was 120 mg/dL. She reported similar symptoms in the last 5 years happening “every few months” without a predictable pattern; twice with witnessed loss of consciousness. Workup for syncope in the past included normal neurologic, cardiac, and tilt-table testing. She had no prior low FSG/BG recorded, no personal history of bariatric surgery or family history of diabetes mellitus and no access to antihyperglycemic medications. Past medical history included ulcerative colitis and medications included sulfasalazine and multivitamins. Pertinent review of systems was negative for weight loss, nausea, and diarrhea. Vital signs were within normal limits. Physical exam was unremarkable. Height was 165 cm, weight 67.8 kg and body mass index 24.9 kg/m(2). Blood draw after overnight fast revealed BG of 78 mg/dL, C-peptide 0.7 ng/mL (ref range 0.8–3.5), insulin 10 µIU/mL (3–19), proinsulin <1.6 pmol/L (<8.0), insulin-like growth factor-2 (IGF-2) 339 ng/mL (180–580) and insulin antibody level 10.0 U/mL (0.0–0.4). She was managed conservatively with frequent small meals and patient has continued to do well without recurrence of symptoms. Conclusion: IAS is an exceedingly rare disease entity with about 460 cases described in literature, mostly in patients of Asian descent. Workup for hypoglycemia in non-diabetic patients should include insulin antibody titers to rule out IAS. There appears to be a genetic predisposition to developing IAS in patients with major histocompatibility complex (MHC) genes HLA-DQA1, HLA-DQB1 and HLA-DRB1. It is now being more frequently described in patients of non-Asian descent, particularly those with other autoimmune or plasma cell dyscrasias. It is also associated with drugs containing sulfhydryl groups and viral infections. Treatment should be tailored to severity of disease. Most drug induced IAS resolves after cessation of culprit drug. Conservative management is usually the first step with frequent, low carbohydrate meals with diazoxide or octreotide as adjunctive options. Immunosuppression (high-dose prednisolone or rituximab) and plasma exchanged are reserved severe or refractory cases.