What is the appropriate workup and management for Latent Autoimmune Diabetes in Adults (LADA)?

LADA Workup and Management

Test for islet autoantibodies, particularly GADA, in adults presenting with diabetes who have clinical features suggestive of autoimmune diabetes—including younger age at diagnosis, unintentional weight loss, lean body habitus, rapid progression to insulin requirement, or personal/family history of autoimmune diseases. 1

When to Suspect LADA

LADA should be considered in approximately 5-10% of adults initially diagnosed with apparent type 2 diabetes who present with distinguishing features 1:

• Lower BMI and lean body habitus compared to typical type 2 diabetes patients 1
• Younger age at diagnosis (typically after age 30-35 years) 1
• Unintentional weight loss at presentation 1
• Fewer metabolic risk factors and better lipid profiles than type 2 diabetes 1
• Ketoacidosis or rapid progression to insulin requirement 1
• Personal or family history of autoimmune diseases 1, 2

Diagnostic Laboratory Workup

Primary Antibody Testing

Standardized islet autoantibody tests are recommended for classification of diabetes in adults with phenotypic overlap between type 1 and type 2 diabetes. 3

Order the following autoantibody panel 3:

• Glutamic acid decarboxylase antibodies (GADA) - the single best immune marker for LADA 2
• Islet antigen-2 antibodies (IA-2A) 3
• Zinc transporter 8 antibodies (ZnT8A) 3
• Insulin autoantibodies (IAA) 3

Key Diagnostic Criteria

• Presence of circulating islet autoantibodies distinguishes LADA from type 2 diabetes 1
• GADA is most commonly positive in LADA patients 2
• High titers of GADA and/or GADA directed toward COOH-terminal epitopes identify patients at very high risk of rapid progression to insulin dependency 2
• Low titers of GADA characterize patients with clinical features almost indistinguishable from type 2 diabetes 2

Additional Metabolic Assessment

Standard diabetes workup should include 3:

• Fasting plasma glucose (≥126 mg/dL diagnostic for diabetes) 3
• HbA1c (≥6.5% diagnostic for diabetes) 3
• C-peptide levels to assess beta-cell function 3

Staging and Prognosis

Use the staging system for autoimmune diabetes 3:

• Stage 1: Multiple islet autoantibodies + normoglycemia + presymptomatic 3
• Stage 2: Islet autoantibodies + dysglycemia (FPG 100-125 mg/dL, 2-h PG 140-199 mg/dL, or HbA1c 5.7-6.4%) + presymptomatic 3
• Stage 3: Islet autoantibodies + overt diabetes + symptomatic 3

Longitudinal follow-up of subjects with two or more islet autoantibodies is recommended to track disease progression through these stages. 3

Screening for Associated Autoimmune Conditions

LADA patients have increased risk for other organ-specific autoimmune diseases and should be screened accordingly. 2

Screen for 2:

• Thyroid autoimmune diseases (most frequently associated condition) 4, 2
• Autoimmune Addison's disease 2
• Pernicious anemia (present in approximately 4% of type 1 diabetes patients) 4
• Vitiligo 4

Order thyroid function tests, thyroid antibodies, and consider vitamin B12 levels with intrinsic factor antibodies. 4

Critical Pitfalls to Avoid

Antibody Testing Limitations

• Approximately 5-10% of autoimmune diabetes patients may be antibody-negative, so clinical features remain important even with negative antibody results 1
• Islet autoantibodies decrease with age and may not be detectable in all patients 1
• Single positive antibody (present in 1-2% of healthy individuals) has low predictive value for diabetes progression 3
• Antibody prevalence varies by race: 85-90% in white patients with type 1 diabetes versus only 19% in black or Hispanic patients 3

Clinical Recognition Errors

• Do not assume type 2 diabetes based solely on adult age at presentation—LADA typically manifests after age 30-35 1
• Do not delay antibody testing in lean adults with diabetes, as early identification allows for appropriate treatment planning 1
• Islet autoantibodies are not recommended for routine diagnosis of all diabetes cases—reserve testing for those with clinical features suggesting autoimmune etiology 3

Management Considerations

Beta-cell destruction in LADA progresses more slowly than classical type 1 diabetes, with insulin dependence typically developing over years rather than weeks to months, providing a wider window for intervention. 1, 5

The rate of progression correlates with autoantibody levels 2:

• High GADA titers indicate rapid progression similar to type 1 diabetes 2
• Low GADA titers indicate slower progression with features closer to type 2 diabetes 2