What is autoimmune hypoglycemia syndrome?

Autoimmune Hypoglycemia Syndrome

Autoimmune hypoglycemia syndrome is a rare condition characterized by spontaneous hypoglycemia caused by the presence of autoantibodies against insulin or the insulin receptor, occurring in patients who have never received exogenous insulin. 1, 2

Types of Autoimmune Hypoglycemia

There are two main types of autoimmune hypoglycemia:

1. Anti-insulin antibody syndrome (Insulin autoimmune syndrome or IAS):

   • Characterized by the presence of autoantibodies against endogenous insulin 3, 4
   • Typically presents with reactive hypoglycemia occurring several hours after meals 1
   • Features extremely high insulin levels during hypoglycemic episodes 4, 5
   • More commonly reported in Japanese populations 1

2. Anti-insulin receptor antibody syndrome:

   • Characterized by autoantibodies that bind to insulin receptors 1
   • These antibodies mimic insulin action, causing primarily fasting hypoglycemia 1
   • Often associated with other autoimmune diseases 1, 6
   • Laboratory findings may be confusing as anti-receptor antibodies can inhibit insulin clearance, elevating plasma insulin levels 1

Clinical Presentation

• Hypoglycemic symptoms: Neuroglycopenic symptoms that can be severe 2
• Timing of hypoglycemia:
  • Anti-insulin antibody syndrome: Predominantly postprandial or reactive hypoglycemia, occurring several hours after meals 3, 1
  • Anti-insulin receptor antibody syndrome: Primarily fasting hypoglycemia 1
• Associated conditions: Often occurs with other autoimmune disorders 6, 1

Diagnostic Features

• Extremely high insulin levels during hypoglycemic episodes 4, 5
• Presence of insulin autoantibodies in patients never exposed to exogenous insulin 3, 4
• Oral glucose tolerance test (OGTT) showing a typical pattern with postprandial hyperglycemia followed by reactive hypoglycemia 3, 4
• C-peptide levels:
  • Normal or elevated in anti-insulin antibody syndrome 4
  • Low in anti-insulin receptor antibody syndrome (despite high insulin levels) 1
• Negative imaging studies for insulinoma 3, 4, 5

Differential Diagnosis

• Insulinoma: Most important differential diagnosis; autoimmune hypoglycemia must be distinguished to avoid unnecessary surgical interventions 3, 2
• Surreptitious insulin injection: May be confused with anti-insulin receptor antibody syndrome due to high insulin but low C-peptide levels 1
• Other causes of hyperinsulinemic hypoglycemia 6

Management

For anti-insulin antibody syndrome:

• Dietary management:
  • 1,600-calorie diet containing approximately 40% carbohydrates 4
  • Diet restricted in simple sugars 4, 5
  • Frequent small meals (6 per day) 4, 1
• Medication options:
  • Acarbose may be helpful in some cases 5
  • Prednisone for cases not responding to dietary management 1, 5

For anti-insulin receptor antibody syndrome:

• Prednisone therapy: Rapidly alleviates hypoglycemia, usually within 24 hours 1
• Immunosuppressive therapy: May be required in severe cases 2

Prognosis

• Anti-insulin antibody syndrome: Often resolves spontaneously within months 3
• Anti-insulin receptor antibody syndrome: Antibodies typically disappear over several months to years 1
• Conservative management is generally preferred as the condition is usually self-limiting 2

Clinical Pearls

• Consider autoimmune hypoglycemia in all cases of hyperinsulinemic hypoglycemia to avoid unnecessary surgical interventions 2
• Insulin antibody measurements should be performed in unexplained cases of hypoglycemia 4
• The polyethylene glycol precipitation test can be useful in diagnosis by demonstrating antibody-bound insulin 5