Clinical Pearls & Morning Reports
Insulin autoimmune syndrome is often misdiagnosed as insulinoma or beta-cell hypertrophy, which can lead to unnecessary, invasive diagnostic procedures and, in some cases, unnecessary pancreatic surgery. Read the NEJM Clinical Problem-Solving Article here.
Q: What is insulin autoimmune syndrome?
A: Insulin autoimmune syndrome, or Hirata disease, is a rare cause of hyperinsulinemic hypoglycemia. This syndrome is characterized by the presence of autoantibodies directed against endogenous insulin in patients who have not had previous exposure to exogenous insulin and have no pathologic abnormalities of the pancreatic islet cells and is one of the two identified causes of autoimmune hypoglycemia (the other being type B insulin resistance syndrome, which is caused by autoantibodies against the insulin receptor). It can be associated with other autoimmune conditions, and certain medications are commonly associated with insulin autoimmune syndrome (e.g., drugs containing a sulfhydryl group).
Q: Is insulin autoimmune syndrome more common in some races than in others?
A: The prevalence of insulin autoimmune syndrome varies according to race. Higher rates are reported among Asians (with an estimated incidence among Japanese persons of 0.017 per 100) than among persons of other races; the HLA–DR4 allele, which is strongly associated with insulin autoimmune syndrome, is more common among Asians than among persons of other races. Underdiagnosis is common, particularly among non-Asians, and in the past decade, the number of reported cases among Whites has increased.
A: The presumed cause of hypoglycemia in insulin autoimmune syndrome is a disconnect between the glucose level and the free insulin concentration, which results from the formation of insulin–insulin autoantibody complexes after insulin is released postprandially. Owing to this binding, the insulin is ineffective, which leads to transient postprandial hyperglycemia; hyperglycemia triggers the production of more insulin by the pancreatic beta cells, causing profound hyperinsulinemia. When the binding capacity of insulin autoantibodies is exceeded, the glucose level falls. The remaining insulin–insulin autoantibody complexes form a reservoir of bound insulin, which is released randomly with respect to plasma glucose levels, resulting in spontaneous hypoglycemia. The insulin autoantibodies have both a high binding capacity and a low affinity for insulin, leading to a high spontaneous dissociation.
A: In 60 to 80% of patients, remission of insulin autoimmune syndrome occurs spontaneously within 3 to 6 months or after treatment of the underlying cause (e.g., Graves’ disease or rheumatoid arthritis) or discontinuation of the medication that provoked the syndrome, with a concurrent decrease in autoantibody levels. Therapy to manage symptoms is necessary during this period. The cornerstone of treatment is a diet consisting of frequent small, low-carbohydrate meals to prevent high insulin peaks. Other empirical treatments aimed at reducing the release of insulin include somatostatin analogues (octreotide), diazoxide, or partial pancreatectomy. Case reports suggest that high-dose glucocorticoids can alleviate hypoglycemia, possibly by lowering the insulin autoantibody titer, and that acarbose (an α-glucosidase inhibitor) in addition to glucocorticoid treatment can delay intestinal carbohydrate absorption and therefore lessen the postprandial rise in glucose and insulin in persons with insulin autoimmune syndrome. In addition, reductions in antibody titers and in hypoglycemic episodes have been described in patients who were treated with plasmapheresis or rituximab.