Management of Falsely Elevated HbA1c
When HbA1c appears falsely elevated, immediately repeat the test using the same methodology to rule out laboratory error, then verify with alternative glucose measurements (fasting plasma glucose, continuous glucose monitoring, or fructosamine) before making any treatment decisions. 1, 2
Initial Verification Steps
Repeat the HbA1c test without delay using the same laboratory method, as the American Diabetes Association guidelines emphasize that laboratory error must be ruled out before confirming any diabetes diagnosis. 1 If the repeat HbA1c remains elevated but discordant with clinical presentation, proceed to alternative testing rather than waiting 3-6 months. 1
Identify Conditions Causing False Elevation
Red Blood Cell Lifespan Disorders
- Iron deficiency anemia prolongs RBC lifespan, artificially increasing HbA1c independent of glycemic control. 2, 3
- Aplastic anemia similarly extends RBC survival, elevating HbA1c measurements. 2
- Measure erythrocyte creatine to estimate RBC lifespan if suspected (normal range: 55.1-66.7 days). 3
Hemoglobinopathies
- Hemoglobin variants (HbS, HbC, Hemoglobin Wayne, Hb Hirose) can cause falsely elevated results depending on the assay method used. 2, 4, 5
- Order hemoglobin electrophoresis when HbA1c is significantly elevated (>10%) but fasting glucose remains normal (80-100 mg/dL). 4, 5
- S-beta+-thalassemia specifically interferes with Bio-Rad Variant II Turbo HPLC assay, causing HbA1c readings of 25-30% when actual glycemic control corresponds to 4.7-5.8%. 5
Assay-Specific Interference
- Point-of-care A1C assays lack mandated proficiency testing and should not be used for diagnostic purposes. 1
- Different methodologies (HPLC, enzymatic, immunoassay) may yield discordant results in the same patient with hemoglobin variants. 3, 5
Alternative Glycemic Assessment
When HbA1c reliability is questioned, use these alternatives:
- Fasting plasma glucose (≥126 mg/dL diagnostic for diabetes) with proper sample handling—spin and separate immediately after drawing. 1, 6
- Continuous glucose monitoring provides comprehensive glycemic patterns over 7-14 days, revealing whether HbA1c correlates with actual glucose exposure. 2, 4
- Fructosamine reflects glycemic control over 2-3 weeks and is unaffected by RBC lifespan or hemoglobin variants. 2, 7
- Glycated albumin provides 2-4 week glycemic assessment independent of RBC disorders. 3
Diagnostic Algorithm for Discordant Results
If HbA1c ≥6.5% but fasting glucose <126 mg/dL:
- Repeat HbA1c immediately using the same laboratory method. 1
- If repeat confirms elevation, obtain fasting plasma glucose on a separate day. 1, 6
- If both tests remain discordant, order hemoglobin electrophoresis and complete blood count with RBC indices. 2, 4
- Consider continuous glucose monitoring to assess actual glycemic patterns. 2, 4
For conditions with abnormal RBC turnover (hemolytic anemia, chronic kidney disease, pregnancy, recent blood loss/transfusion), use only glucose-based criteria for diagnosis—HbA1c is unreliable. 1, 2
Treatment Implications
Do not initiate or intensify diabetes therapy based solely on an isolated elevated HbA1c that conflicts with glucose measurements. 4 A case report documented a patient maintained on metformin for two years based on HbA1c of 10.3-10.7% despite normal fasting glucose (80-100 mg/dL) and normal CGM—treatment was appropriately discontinued after hemoglobin Wayne was identified. 4
Critical Pitfalls to Avoid
- Never diagnose diabetes based on a single HbA1c without confirmation, especially when clinical presentation doesn't match. 1, 6
- Don't assume all assays are equivalent—hemoglobin variants may interfere with one methodology but not another. 3, 5
- Avoid using point-of-care HbA1c for diagnostic decisions due to lack of standardization. 1
- Don't delay alternative testing when HbA1c and glucose measurements are markedly discordant—investigate immediately rather than empirically treating. 2, 4