What should be done in cases of suspected Hemoglobin A1c (HbA1c) false errors?

Management of Suspected HbA1c False Errors

When HbA1c results appear discordant with clinical presentation or self-monitored blood glucose readings, immediately repeat the HbA1c test using the same laboratory method and simultaneously obtain fasting plasma glucose or perform glucose-based testing to confirm true glycemic status. 1

Initial Verification Algorithm

Step 1: Immediate Repeat Testing

• Repeat HbA1c without delay using the identical laboratory method to rule out laboratory error before making any diagnostic or treatment decisions 2, 3
• Simultaneously obtain fasting plasma glucose (FPG) or perform oral glucose tolerance test (OGTT) for comparison 1, 4
• Do not wait 3-6 months if results remain discordant—proceed immediately to alternative testing 2

Step 2: Assess for Conditions Affecting Red Blood Cell Turnover

The most common causes of falsely altered HbA1c involve conditions that change RBC lifespan, which affects HbA1c independent of actual glycemia 1, 3:

Conditions causing falsely LOW HbA1c:

• Hemolytic anemia (any cause) 1, 3
• Recent acute blood loss or transfusion 1
• Pregnancy 1, 3
• Chronic kidney disease (shortened RBC lifespan) 3
• Recovery from acute blood loss 1

Conditions causing falsely HIGH HbA1c:

• Iron deficiency anemia (prolongs RBC lifespan and glucose exposure) 1, 3
• Occult malignancies affecting bone marrow function 2, 5
• Chronic infections causing inflammatory RBC turnover changes 2, 5
• Aplastic anemia 2

Diagnostic Workup for Discordant Results

Essential Laboratory Tests:

• Complete blood count to assess for anemia 3, 5
• Iron studies (serum iron, ferritin, TIBC) to evaluate for iron deficiency 3, 5
• Reticulocyte count to assess RBC turnover 3
• Hemoglobin electrophoresis if hemoglobin variant suspected 1, 6

When to Suspect Hemoglobin Variants:

• HbA1c reading is surprisingly high or low 3, 5
• Significant change in HbA1c coincident with change in laboratory method 3, 6
• Discrepant HbA1c values when measured by different methods (e.g., HPLC vs immunoassay showing >2% difference) 6, 7
• Patient of African, Mediterranean, or Southeast Asian descent (higher prevalence of variants) 6, 8

Critical Decision Points

If HbA1c ≥6.5% but FPG <126 mg/dL:

• Repeat HbA1c immediately using same method 2
• If repeat HbA1c remains ≥6.5%, diabetes is confirmed even if FPG remains <126 mg/dL 1
• However, if clinical suspicion exists for interfering factors, proceed to evaluation for RBC disorders before confirming diagnosis 2, 3

Absolute contraindications to using HbA1c for diagnosis:

• Homozygous hemoglobin variants (HbSS, HbEE) - HbA1c cannot be measured and should not be reported 1, 3
• Conditions with abnormal RBC turnover (hemolytic anemia, recent blood loss/transfusion, pregnancy) - use only glucose-based criteria 1

Alternative Glycemic Markers

When HbA1c is unreliable, use:

• Fructosamine or glycated albumin - reflects 2-3 weeks of glycemic control, unaffected by RBC disorders 1, 3
• Continuous glucose monitoring (CGM) - provides comprehensive glycemic patterns and identifies missed excursions 2, 3
• Glucose testing exclusively for screening, diagnosis, and management 1

Common Pitfalls to Avoid

Never diagnose diabetes on a single HbA1c alone when clinical presentation doesn't match, especially without confirmation testing 2

Do not use point-of-care HbA1c for diagnostic decisions due to lack of standardization and systematic quality oversight 2, 5

Avoid mixing different HbA1c methods for sequential measurements, as this introduces additional measurement error 3, 4

Do not ignore discordance between HbA1c and self-monitored glucose - this warrants immediate investigation for interfering factors 2, 5

Sequential HbA1c values within 0.5% do not statistically differ unless assay coefficient of variation is <3%, so don't overinterpret small changes 3, 5

Special Populations Requiring Glucose-Based Testing

Mandatory use of glucose criteria only (not HbA1c):

• Pregnant women 1, 3
• Patients with hemolytic anemia of any cause 1
• Recent blood transfusion recipients 1
• Chronic kidney disease with shortened RBC lifespan 3
• Known homozygous hemoglobin variants 1, 3

Laboratory Quality Considerations

Ensure laboratory uses NGSP-certified methods traceable to DCCT reference standards 1

Laboratories must be aware of potential interferences in their specific patient population and select appropriate assay methods 1, 3

Whole blood samples are stable for up to 1 week at 4°C, but improper storage at high temperatures introduces large artifacts 1

Additional Interfering Factors

Medications and supplements potentially affecting HbA1c:

• Vitamins C and E may falsely lower HbA1c by inhibiting glycation 1, 3
• Chronic salicylate use may falsely increase results with some methods 1, 3
• Hypertriglyceridemia, hyperbilirubinemia, uremia may interfere with older assay methods 1

Age and race considerations:

• HbA1c increases approximately 0.1% per decade after age 30 in people without diabetes 3
• African Americans may have HbA1c values 0.4% higher than whites for equivalent glycemia 3