What are the recommended steps to diagnose Latent Autoimmune Diabetes in Adults (LADA)?

Diagnosing Latent Autoimmune Diabetes in Adults (LADA)

Standardized islet autoantibody tests are the cornerstone for diagnosing LADA in adults who have phenotypic overlap between type 1 and type 2 diabetes. 1

Clinical Features That Should Prompt LADA Testing

LADA should be suspected in adults with diabetes who present with:

• Age at diagnosis >35 years but with earlier onset than typical type 2 diabetes (especially <50 years) 2
• Normal or only mildly elevated BMI (<25 kg/m²) 2
• Acute symptoms of hyperglycemia (polyuria, polydipsia, weight loss) that are less severe than classic type 1 diabetes 2
• Personal or family history of autoimmune disease 2
• Suboptimal response to oral hypoglycemic agents within the first few years of diagnosis 3

Diagnostic Algorithm for LADA

1. Initial Clinical Assessment:

   • Calculate LADA clinical risk score (1 point for each): age <50 years, acute symptoms, BMI <25 kg/m², personal history of autoimmune disease, family history of autoimmune disease
   • If score ≥2, proceed with autoantibody testing (90% sensitivity, 71% specificity) 2

2. Autoantibody Testing:

   • Test for GAD65 antibodies (GADA) first - most common and persistent autoantibody in LADA 1, 4
   • If clinical suspicion remains high despite negative GADA, test for additional autoantibodies:
     • Islet cell antibodies (ICA)
     • Insulin autoantibodies (IAA)
     • Islet antigen-2 antibodies (IA-2A)
     • Zinc transporter 8 antibodies (ZnT8A) 1

3. C-peptide Assessment:

   • Measure fasting C-peptide or stimulated C-peptide (after glucagon)
   • Interpretation:
     • <0.6 ng/mL (<200 pmol/L): Type 1 diabetes pattern
     • 0.6-1.8 ng/mL (200-600 pmol/L): Indeterminate (consistent with LADA)

     • 1.8 ng/mL (>600 pmol/L): Type 2 diabetes pattern 5

4. Confirmation Criteria:

   • LADA diagnosis requires:
     • Age >35 years at diabetes onset
     • Presence of at least one islet autoantibody (preferably GADA)
     • No requirement for insulin for at least 6 months after diagnosis 6

Staging LADA

Once diagnosed, LADA can be staged according to the autoimmune diabetes staging system:

• Stage 1: Multiple islet autoantibodies with normoglycemia
• Stage 2: Islet autoantibodies with dysglycemia (IFG: FPG 100-125 mg/dL, IGT: 2-h PG 140-199 mg/dL, or A1C 5.7-6.4%)
• Stage 3: Overt hyperglycemia with diabetes by standard criteria 1

Pitfalls and Caveats

• False positives: Testing for islet autoantibodies in patients without clinical features suggestive of autoimmune diabetes may yield false-positive results 7
• Heterogeneity: LADA likely represents a mixed population of true autoimmune diabetes and non-autoimmune diabetes with false-positive antibody results 7
• Beta-cell function: Despite being classified as "latent," LADA patients already have impaired beta-cell function at diagnosis 3
• Progression: Multiple positive autoantibodies predict faster progression to insulin dependence (within 5 years), while single antibody positivity may take up to 12 years 3
• Renal impairment: C-peptide levels may be falsely elevated in patients with kidney disease due to reduced clearance 5

Clinical Implications

• Early identification of LADA is crucial as these patients have a higher risk of progression to insulin dependency than typical type 2 diabetes
• Most LADA patients will require insulin within 3 years of diagnosis 4
• Early insulin therapy may help preserve remaining beta-cell function, though this remains somewhat controversial 6
• Sulfonylureas should generally be avoided as they may accelerate beta-cell failure 5
• Screen for other autoimmune disorders (thyroid disease, celiac disease, Addison's disease) 5

By following this diagnostic approach, clinicians can identify LADA patients early and implement appropriate treatment strategies to preserve beta-cell function and improve long-term outcomes.