What antibodies should be checked for in autoimmune hypoglycemia?

Antibody Testing for Autoimmune Hypoglycemia

For autoimmune hypoglycemia, the primary antibodies that should be tested are anti-insulin antibodies and anti-insulin receptor antibodies.

Types of Autoimmune Hypoglycemia

Autoimmune hypoglycemia can be classified into two main categories:

1. Insulin Autoimmune Syndrome (IAS)

   • Characterized by anti-insulin antibodies
   • Also known as Hirata disease
   • More common in Asian populations, particularly Japanese

2. Type B Insulin Resistance Syndrome

   • Characterized by anti-insulin receptor antibodies
   • Often associated with other autoimmune conditions

Specific Antibody Tests

For Insulin Autoimmune Syndrome:

• Anti-insulin antibodies (IAA) 1, 2, 3, 4, 5
  • Should be measured using both:
    • Radioimmunoassay (RIA) - more sensitive
    • ELISA - complementary method as some cases may be missed by RIA alone 5

For Type B Insulin Resistance:

• Anti-insulin receptor antibodies 1
  • Direct assay for antibodies directed against the insulin receptor

Diagnostic Approach

1. Initial laboratory evaluation:

   • Document hypoglycemia (plasma glucose <70 mg/dL)
   • Measure insulin and C-peptide levels during hypoglycemic episode
   • Calculate insulin to C-peptide molar ratio (elevated ratio >1 suggests insulin antibodies) 4

2. Confirmatory testing:

   • Polyethylene glycol (PEG) precipitation to detect antibody-bound insulin 5
   • Gel filtration chromatography (GFC) for definitive confirmation of antibody-bound insulin 5
   • Mass spectrometry for more accurate insulin quantification when antibodies are present 5

Clinical Pearls and Pitfalls

• Key distinguishing features:

  • In IAS: spontaneous hypoglycemia with extremely high insulin levels (often >100 μU/mL) and detectable C-peptide 3, 4
  • Insulin to C-peptide molar ratio is typically markedly elevated (>1) 4

• Common pitfalls:

  • Misdiagnosis as insulinoma leading to unnecessary invasive procedures 4
  • False interpretation of high insulin levels as exogenous insulin administration 1
  • Relying on a single antibody test method may miss some cases 5

• Timing considerations:

  • IAS typically causes reactive hypoglycemia (several hours after meals) rather than fasting hypoglycemia 1
  • Anti-insulin receptor antibodies typically cause fasting hypoglycemia 1

Additional Considerations

• Consider testing for other autoimmune conditions, as autoimmune hypoglycemia may be associated with other autoimmune disorders 6
• HLA typing may be helpful as IAS has been associated with specific HLA types, particularly HLA-DR4 2

By systematically testing for these antibodies and following the diagnostic approach outlined above, autoimmune hypoglycemia can be accurately diagnosed and distinguished from other causes of hypoglycemia.