What is autoimmune hypoglycemia?

Autoimmune Hypoglycemia: Diagnosis and Management

Autoimmune hypoglycemia is a rare condition characterized by hypoglycemic episodes due to the presence of autoantibodies that interact with insulin or insulin receptors, resulting in dysregulated glucose metabolism. There are two main types: Insulin Autoimmune Syndrome (IAS, also known as Hirata disease) and Type B Insulin Resistance Syndrome (TBIRS) 1.

Types of Autoimmune Hypoglycemia

1. Insulin Autoimmune Syndrome (IAS/Hirata Disease)

• Pathophysiology: Characterized by high titers of insulin autoantibodies (IAA) that bind to endogenous insulin 1
• Mechanism: Involves a biphasic process:
  • Initial phase: IAA bind to insulin, preventing it from interacting with insulin receptors, potentially causing mild hyperglycemia
  • Later phase: Insulin spontaneously dissociates from antibodies regardless of blood glucose levels, causing hypoglycemia 1, 2
• Genetic predisposition: More common in individuals with specific HLA types 3
• Triggers: Often precipitated by medications (particularly those containing sulfhydryl groups) or viral infections 1, 4

2. Type B Insulin Resistance Syndrome (TBIRS)

• Pathophysiology: Caused by autoantibodies against insulin receptors (IRAbs)
• Clinical presentation: Can cause a spectrum from hypoglycemia to severe insulin-resistant hyperglycemia 3

Clinical Presentation

• Recurrent episodes of hypoglycemia, often occurring postprandially
• Neuroglycopenic symptoms (confusion, altered consciousness, seizures)
• Autonomic symptoms (sweating, tremor, palpitations)
• In severe cases, patients may present with hypoglycemic coma
• Symptoms may be particularly severe due to the unpredictable nature of insulin release from antibody complexes 1, 5

Diagnostic Approach

1. Laboratory findings:

   • Hyperinsulinemic hypoglycemia (high insulin levels during hypoglycemic episodes)
   • Elevated C-peptide levels (distinguishing from exogenous insulin administration)
   • Positive insulin autoantibodies (IAA) - the gold standard for diagnosis 1
   • In TBIRS: presence of insulin receptor autoantibodies

2. Differential diagnosis:

   • Insulinoma
   • Exogenous insulin administration
   • Other causes of reactive hypoglycemia
   • Medications causing hypoglycemia 5

3. Additional testing:

   • Scatchard analysis to determine antibody binding characteristics
   • Imaging studies to exclude insulinoma when clinically indicated 2

Management

Acute Management of Hypoglycemia

• Treat hypoglycemic episodes with 15-20g of fast-acting carbohydrates when blood glucose is <70 mg/dL 6
• For severe hypoglycemia (altered mental status requiring assistance), administer glucagon via injection or intranasal route 6
• Recheck blood glucose after 15 minutes and repeat treatment if hypoglycemia persists 6

Long-term Management

1. Conservative approach:

   • Dietary modifications:
     • Frequent small meals
     • Low carbohydrate content to prevent large insulin responses
     • Complex carbohydrates rather than simple sugars 6, 1
   • Regular glucose monitoring

2. Pharmacological interventions (for severe or persistent cases):

   • First-line: Medications that reduce pancreatic insulin secretion
     • Somatostatin analogs
     • Diazoxide
   • Second-line: Immunosuppressive therapy
     • Glucocorticoids (prednisone)
     • Azathioprine
     • Rituximab in refractory cases 1, 2

3. Plasmapheresis:

   • May be effective in rapidly reducing antibody levels in severe cases 2

4. Discontinuation of triggering agents:

   • Identify and discontinue any medications that may have triggered the condition (e.g., alpha-lipoic acid) 4

Prognosis

• IAS is frequently self-limiting, with spontaneous remission occurring in many cases within 3-6 months 1, 4
• More severe cases may require immunosuppressive therapy
• Monitoring for recurrence is recommended even after apparent resolution

Clinical Pearls and Pitfalls

• Key pitfall: Misdiagnosis as insulinoma, leading to unnecessary pancreatic surgery 5
• Important consideration: The severity of hypoglycemia can vary widely between patients - some may require only dietary modifications while others need aggressive immunosuppression 4
• Monitoring: Regular follow-up to assess antibody levels and adjust treatment as needed
• Patient education: Teaching patients to recognize and promptly treat hypoglycemic symptoms is crucial

Autoimmune hypoglycemia should be considered in the differential diagnosis of any patient presenting with hyperinsulinemic hypoglycemia, especially when there is no evidence of insulinoma or exogenous insulin administration.