What autoantibodies (autoimmune antibodies) should be tested for in patients suspected of having Latent Autoimmune Diabetes in Adults (LADA)?

Autoantibodies to Test in Latent Autoimmune Diabetes in Adults (LADA)

Recommended Autoantibody Panel

For patients suspected of having LADA, testing should include glutamic acid decarboxylase antibodies (GADA), islet antigen-2 antibodies (IA-2A), zinc transporter 8 antibodies (ZnT8A), and insulin autoantibodies (IAA), with GADA being the most important primary test. 1, 2

Primary Autoantibody Testing

• GADA (Glutamic Acid Decarboxylase Antibodies)

  • Most frequently detected autoantibody in LADA (~80% of cases) 2
  • Should be the first test performed when LADA is suspected 2
  • High sensitivity for identifying autoimmune diabetes in adults

• ZnT8A (Zinc Transporter 8 Antibodies)

  • Present in approximately 50% of LADA patients 2
  • Important complementary test, especially when GADA is negative but LADA is still suspected 3
  • Different variants should be tested (particularly ZnT8A-Arg-Trp325) 3

• IA-2A (Islet Antigen-2 Antibodies)

  • Present in approximately 60% of patients with autoimmune diabetes 2
  • Should be tested if GADA is negative but clinical suspicion remains high 2

• IAA (Insulin Autoantibodies)

  • Present in approximately 55% of patients with autoimmune diabetes 2
  • Important caveat: IAA testing is only valid in patients not previously treated with insulin, as insulin therapy induces antibody formation 1

Testing Considerations

Laboratory Requirements

• Islet autoantibodies should only be measured in accredited laboratories with established quality control programs and participation in proficiency testing 1
• Standardized assay methods are essential for accurate results 1

Interpretation of Results

• Multiple antibody positivity has a 70% predictive value for developing type 1 diabetes within 10 years 2
• Single antibody positivity has only 15% predictive value within 10 years 2
• Up to 1-2% of healthy individuals may have a single autoantibody and have a low risk of type 1 diabetes 2
• GADA is the most common single autoantibody found in LADA (90.5% of autoantibody-positive adult-onset diabetes) 4

Clinical Context

• Autoantibody testing is particularly important in adults who have phenotypic risk factors that overlap with type 1 diabetes:
  • Younger age at diagnosis (30-50 years)
  • Lower BMI (<30)
  • Unintentional weight loss
  • Personal or family history of autoimmune disorders
  • Early failure of oral hypoglycemic agents 1, 2

Additional Considerations

Titer Significance

• High-titer GADA (>200 WHO IU) is associated with a more type 1-like phenotype:
  • More likely to be female
  • Lower BMI
  • Higher insulin requirement 4

Complementary Testing

• C-peptide levels should be measured alongside autoantibodies:
  • Levels <200 pmol/L are consistent with type 1 diabetes
  • Levels 200-600 pmol/L are indeterminate
  • Levels >600 pmol/L are consistent with type 2 diabetes 2

Testing for Associated Autoimmune Conditions

• Consider testing for thyroid autoantibodies (anti-TPO, anti-thyroglobulin) as they are present in approximately 40% of LADA patients 2, 5
• Anti-parietal cell antibodies (APCA) are found in about 25% of LADA patients 5

Pitfalls and Caveats

• Relying solely on clinical presentation can lead to misdiagnosis, as up to 40% of adults with autoimmune diabetes are initially misdiagnosed as having type 2 diabetes 2
• Obesity does not rule out LADA, as obesity is increasingly common in the general population 2
• Single autoantibody testing (e.g., GADA only) may miss some LADA cases; consider testing for multiple antibodies when clinical suspicion is high 3
• IAA testing is invalid in patients already treated with insulin 1
• Laboratory variability in autoantibody testing can be substantial; use standardized assays and accredited laboratories 1