Hypoglycemia due to insulin autoimmune syndrome (Hirata’s disease): a rare cause of hypoglycaemia

Although the most common cause of recurrent hypoglycaemia is diabetes mellitus as patient is on antidiabetic medications which can be prevented by modification of antidiabetic doses, nutrition therapy and lifestyle modifications. Some endogenous hyperinsulinemic conditions like insulinoma, functional beta cell disorders and insulin autoimmune syndromes, hormonal deficiencies can cause serious and sometimes life threatening hypoglycaemia. So further laboratory evaluation like plasma/serum glucose levels, c-peptide levels, insulin levels, insulin antibodies and imaging studies are needed to evaluate unexplained hypoglycaemia. Here we report a case of insulin autoimmune syndrome in a 67 year old Indian male who had presented to us with multiple episodes of spontaneous hypoglycaemia. On further workup, the patient was found to have endogenous hyperinsulinemic hypoglycemia. As the patient’s abdominal imaging revealed no apparent cause of EHH, on further evaluation he came positive for insulin antibodies. Patient was diagnosed as IAS and he was given frequent small meals and complex carbohydrate diet and he had improved symptomatically. The incidence of IAS is most common in Japan and very few cases have been reported from India, so it should be kept in differential diagnosis of recurrent hypoglycaemia.

A novel approach to a rare case of non-islet cell hypoglycaemia

Summary Insulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab. Learning points Insulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded. Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia. Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS). Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.

A Curious Case of Hypoglycemia: A Rare Occurrence of Insulin Autoimmune Syndrome

Background: Hypoglycemia can be challenging, requiring close monitoring and evaluation. Although treating diabetes can cause hypoglycemia, the coexistence of autoimmune syndromes contributes to rare etiologies. They are characterized by elevated insulin levels with either insulin autoantibodies (IAA) or insulin receptor antibodies (IRA). It has been observed commonly in Japan but is scarce among non-Asian groups. We present a unique case of insulin autoimmune syndrome (IAS) that posed a diagnostic challenge in an African American male. Case: A 73-year-old African American male was admitted with altered mental status. Medical history included type 2 diabetes, hypertension, and hyperlipidemia. Home medications were carvedilol and simvastatin. On arrival, vital signs were normal. A fingerstick glucose was 52 mg/dL with a serum level of 68 mg/dL (70–110). Other labs were normal. Given symptomatic hypoglycemia, an IV dextrose infusion was initiated. Once his mentation improved, a diet was started. Despite this, he had recurrent hypoglycemia with glucose levels as low as 22 mg/dL, predominantly in fasting state with sporadic hyperglycemia. On rare occasions, he received correctional insulin for the same. An HbA1c was <4% (4–6). Thyroid function test and AM cortisol were normal. A cosyntropin stimulation test was negative for adrenal insufficiency. A hypoglycemia panel showed inappropriately high levels of insulin, highest at 77.4 μIU/mL(<=29.1), proinsulin of 19.7 pmol/L (<=8), and C-peptide of 5.6 (0.8–3.69 ng/mL) when serum glucose was 25 mg/dL. An MRI abdomen was normal. Octreotide study was negative for insulinoma. He had a normal response to IM glucagon, inferring normal glycogen stores. He was started on Diazoxide 160 mg thrice a day for recurrent hypoglycemia. An endoscopic ultrasound and DOTATATE scan were negative. He had no hypoglycemia for a few days, attributable to lingering effects of diazoxide. Eventually, his serum glucose was 52 mg/dL. Labs prior to glucose correction included an insulin level elevated at 1,000 (normal <3 mcIU/mL), c-peptide at 0.90 ng/mL, and proinsulin of 5.6 pmol/L. Given exceedingly high insulin levels, we measured an IAA level. This was >50 u/mL (normal <0.4 u/mL). With negative imaging and high IAAs, a diagnosis of IAS was made. Discussion: IAS or Hirata disease is a rare condition with hyperinsulinemic hypoglycemia and high titers of antibodies to endogenous insulin. The binding kinetics of endogenous insulin to these antibodies causes physiologically inappropriate levels of bioavailable insulin, causing either hyper- or hypoglycemia. IAA should be measured in patients with high insulin levels that are inconsistent with C peptide levels. We believe this to be the first African American patient to have been diagnosed with Hirata disease. Making a correct diagnosis may spare a hypoglycemic patient from unnecessary pancreatic surgical intervention.