Insulin autoimmune syndrome: a rare cause of spontaneous hypoglycaemia in non-diabetic individuals

Abstract

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycaemia, characterised by recurrent hypoglycaemic episodes secondary to insulin autoantibodies in individuals who are not exposed to exogenous insulin. We are reporting a case of IAS in a 64-year-old gentleman, who presented with predominant postprandial hypoglycaemic episodes. On biochemical evaluation, he was found to have hyperinsulinemic hypoglycaemia. Localisation studies with MRI abdomen and endoscopic ultrasound (EUS) were negative for pancreatic tumour. Tests sent for insulin antibody levels were elevated. The patient was treated with frequent meals, acarbose and glucocorticoids. Patient condition improved and did not experience hypoglycaemia on follow-up.

Background

Insulin autoimmune syndrome (IAS) was first described by Hirata et al.¹ IAS is a rare cause of endogenous hyperinsulinemic hypoglycaemia. It can be triggered by viral infections and drugs containing sulfhydryl groups. Hypoglycaemia can occur inpostprandial or fasting state with variable severity. Normally there is physiological suppression of insulin, C peptide and proinsulin when plasma glucose levels go below 50 mg/dL. However in IAS, there is elevated insulin levels, while C peptide and proinsulin may or may not be increased (depends on the character of insulin antibody). As most cases present with postprandial symptoms, reactive hypoglycaemia is a close differential diagnosis. In India, so far only few cases have been reported. It is important to consider IAS in the differential diagnosis of endogenous hyperinsulinemic hypoglycaemia.

Case presentation

An elderly gentleman hypertensive, non-diabetic presented with recurrent episodes of hypoglycaemic symptoms over the past 1 week. His symptoms began with excessive sweating, palpitations, fatigability, tremulousness progressing to imbalance and blurring of vision noted predominantly in the postprandial period. The patient also had noticed similar episodes in early morning hours which were relieved with food intake. Patient denied history of access to insulin or insulin secretagogues. He was not on medications containing sulfhydryl group such as captopril, diltiazem, carbimazole or others reported to cause hypoglycaemia.

Family history was negative for similar complaints, any other endocrine or autoimmune disorder. There was no history suggestive of liver dysfunction, renal dysfunction, hypocortisolemia or other critical illness. No history of previous gastrointestinal surgeries.

Investigations

On examination, vitals and systemwise examinations were within normal limits. Lab parameters showed normal liver function tests, renal function tests and thyroid profile with HbA1C of 5.8. Critical blood sample collected during spontaneous hypoglycaemic episode showed random blood sugar (RBS) 32 mg/dL with corresponding insulin of >1000 μU/mL (N: 2.6–24.9 μU/mL) and C peptide levels >40 ng/mL (N: 1.1–4.4 ng/dL) and negative urine ketones. Markedly elevated insulin levels and non-suppressed C peptide along with corresponding insulin to C peptide molar ratio >1 were consistent with endogenous hyperinsulinemia. MRI abdomen and endoscopic ultrasound were negative for pancreatic lesion. Autoimmune insulin antibody syndrome was considered in view of markedly elevated insulin levels and postprandial hypoglycaemic symptoms. Autoimmune insulin antibody testing was positive with serum insulin autoanitibody level reported as 84.08 µ/mL.

Differential diagnosis

Differential diagnosis for hypoglycaemia in non-diabetic individuals includes patients with hepatic, cardiac or renal failure; sepsis; cortisol insufficiency; postgastric bypass surgery commonly called dumping syndrome; drug induced (factitious insulin and insulin secretagogue) and exposure to alcohol.

However in our patient, after ruling out above conditions, reactive hypoglycaemia was considered in the differential diagnosis in view of predominant postprandial occurrence of symptoms. Insulinoma was the second differential, considering the hyperinsulinemic state and the age of presentation.

Rare possibility of nesidioblastosis was also considered.

Treatment

Patient was treated with small frequent meals, along with alpha-glucosidase inhibitors.

Immunosuppressive therapy was given using oral prednisolone at doses of 1 mg/kg/day for 1 month which was gradually tapered over 3 months and stopped.

Outcome and follow-up

He did not experience any hypoglycaemic symptoms with treatment and prednisolone was gradually tapered and stopped. He is on routine follow-up on outpatient basis without hypoglycaemic episodes for the last 6 months. Repeat insulin autoimmune antibody levels were suppressed to 13.55 µ/mL.

Discussion

IAS is an uncommon clinical entity causing hyperinsulinemic hypoglycaemia. There are two variants of IAS. Type A variant—also known as Hirata’s disease—in which hypoglycaemic episodes are due to insulin autoantibodies. Type B variant—Flier’s disease—hypoglycaemia occurs secondary to antibodies directed against insulin receptors. It is common in individuals older than 60 years and rare among paediatric population.^2–4 There is strong genetic predisposition associated with HLA-DR4 antigen in Japanese population. Most of these cases are associated with other autoimmune diseases like Systemic Lupus Erythematosis (SLE), rheumatoid arthritis, Graves and systemic sclerosis.^5–7 About 50% cases of IAS patients report ingestion of drugs containing sulfhydryl group, most commonly implicated with methimazole. Other medication includes carbimazole, glutathione, tolbutamide, gold, interferon-alpha, captopril, diltiazem and imipenem.^8–10

Mechanism of hypoglycaemia in IAS is not completely understood. Most widely accepted theory is mismatch between blood glucose and free insulin levels. Following food intake, glucose levels increase, stimulating production of insulin. Autoantibodies bind to these insulin molecules, making them unavailable to exert their action. The resultant hyperglycaemia not only stimulates further insulin release but also explains elevated HbA1C, commonly observed in IAS patients. As glucose concentration eventually falls, insulin molecules spontaneously dissociate from antibodies, giving rise to elevated levels of free insulin which is inappropriate for glucose concentration.^{11 12} IAS is most commonly caused by IgG class of antibodies, but there are case reports with IgA and IgM antibodies.^{13 14} Striking feature of IAS is magnitude of insulin elevation generally more than 1000 pmol/L.¹⁵

In a study by Hirata et al, spontaneous remission was seen in 82% of cases.¹⁶ Insulin autoantibodies will disappear over a period of few months.¹⁷ Immunosuppressive therapy is needed in majority of the cases, which helps in achieving euglycaemia. Steroids are reported to reduce hypoglycaemic episodes and decreasing antibody titres.^{18 19} Plasmapheresis has been used in few cases for acute management.²⁰ Intravenous immunoglobulins are also proven to be effective in improving patient symptoms.^{20 21} Rituximab—an anti-CD20 antibody—was found to be effective in decreasing insulin receptor antibodies.^{22 23} Other drugs which are proven to be efficacious include cyclophosphamide, mycophenolate mofetil, cyclosporine and azathioprine.

Learning points.

• Insulin autoimmune syndrome (IAS) presents with predominant postprandial hypoglycaemic symptoms and it is an important differentials for reactive hypoglycaemia in non-diabetic individuals.

• IAS must be evaluated in patients with Hyperinsulinemic Hypoglycemia with negative imaging for localisation of tumour.

• Insulin levels more than >1000 pmol/L almost always suggest presence of insulin autoantibody.

• Clinicians must be aware of this rare endocrine disorders as it is easily treatable and has a good outcome.