Autoimmune Hypoglycemia: Diagnosis, Evaluation, and Treatment
Autoimmune hypoglycemia, also known as Insulin Autoimmune Syndrome (IAS) or Hirata's disease, is a rare condition characterized by spontaneous hypoglycemic episodes due to the presence of high titers of insulin autoantibodies that cause inappropriate insulin secretion independent of blood glucose levels. This condition must be distinguished from other causes of hyperinsulinemic hypoglycemia to avoid unnecessary invasive procedures.
Pathophysiology
Autoimmune hypoglycemia develops through a two-phase mechanism:
- Initial phase: Insulin autoantibodies bind to insulin, preventing it from binding to receptors, potentially causing mild hyperglycemia in the postprandial period
- Later phase: Insulin spontaneously dissociates from antibodies regardless of blood glucose levels, causing hypoglycemia
Clinical Presentation
- Spontaneous hypoglycemic episodes (often severe)
- Symptoms predominantly occurring in the postprandial period
- No history of exogenous insulin administration
- May be associated with other autoimmune disorders
- More common in Asian populations but can occur in any ethnicity
Diagnostic Approach
Laboratory Evaluation
Document hypoglycemia with Whipple's triad:
- Low blood glucose (<70 mg/dL)
- Symptoms of hypoglycemia
- Resolution of symptoms with glucose administration
Critical laboratory tests during hypoglycemic episode:
- Elevated total immunoreactive insulin levels (often extremely high)
- Elevated C-peptide levels (distinguishes from exogenous insulin administration)
- Presence of insulin autoantibodies (IAA) in high titer - gold standard for diagnosis 1
Additional testing:
- Glutamic acid decarboxylase (GAD) autoantibodies
- Islet cell autoantibodies
- Insulin receptor autoantibodies (to rule out Type B insulin resistance syndrome)
- 75-gram oral glucose tolerance test (OGTT) showing a typical pattern of delayed hypoglycemia 2
Differential Diagnosis
- Insulinoma
- Exogenous insulin administration
- Sulfonylurea use
- Other forms of endogenous hyperinsulinism
- Type B insulin resistance syndrome
Treatment Approach
Treatment should follow a stepwise approach based on severity:
First-line Management
- Dietary modifications:
- Frequent small meals
- Low carbohydrate diet to prevent postprandial insulin surges
- Avoidance of simple sugars
- Continuous glucose monitoring to detect and prevent hypoglycemic episodes 3
Second-line Management (for persistent symptoms)
- Corticosteroids (prednisone): Often effective in reducing antibody production
- Medications to reduce insulin secretion:
- Diazoxide
- Somatostatin analogs (octreotide)
Third-line Management (for severe, refractory cases)
- Plasmapheresis: Rapidly reduces insulin antibody levels in severe cases 4
- Rituximab: Effective for cases refractory to steroids by selectively suppressing insulin autoantibodies 3
- Other immunosuppressants: Azathioprine may be considered in resistant cases
Monitoring and Follow-up
- Regular blood glucose monitoring, preferably with continuous glucose monitoring systems
- Periodic measurement of insulin autoantibody titers
- Monitoring for other autoimmune conditions
- Most cases spontaneously resolve within months to years, but some may require prolonged therapy
Prognosis
Autoimmune hypoglycemia is frequently a self-limiting disease with good prognosis 1. Most patients achieve remission within several months with appropriate management, though some may require more aggressive immunosuppressive therapy for persistent symptoms.
Key Points to Remember
- Always consider autoimmune hypoglycemia in patients with spontaneous hypoglycemia, elevated insulin levels, and no history of exogenous insulin use
- Detection of insulin autoantibodies is diagnostic
- Avoid unnecessary invasive procedures such as pancreatic imaging or surgery
- Treatment should be tailored to symptom severity, starting with conservative measures
- Most cases resolve spontaneously, but severe cases may require immunosuppressive therapy