What conditions make HbA1c (Hemoglobin A1c) testing inappropriate or misleading?

Conditions Where HbA1c Testing is Inappropriate or Misleading

HbA1c testing should not be used for diabetes diagnosis or monitoring in patients with conditions affecting red blood cell turnover, including hemolytic anemias, recent blood loss or transfusion, pregnancy (second and third trimesters and postpartum), sickle cell disease, glucose-6-phosphate dehydrogenase deficiency, hemodialysis, and erythropoietin therapy—in these situations, only plasma glucose criteria should be used. 1

Conditions with Altered Red Blood Cell Turnover (Use Glucose Testing Only)

Conditions Causing Falsely Low HbA1c:

• Hemolytic anemias: Any condition that shortens red blood cell survival falsely lowers HbA1c regardless of assay method used 1
• Recent blood loss or transfusion: Within the past 2-3 months, HbA1c will not accurately reflect glycemic control 1, 2
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Increases red cell turnover, resulting in artificially low readings 1
• Erythropoietin therapy: Stimulates production of younger red blood cells, decreasing HbA1c values 1
• Hemodialysis and end-stage kidney disease: Affects red cell turnover and HbA1c reliability 1
• Pregnancy (second and third trimesters) and postpartum period: Increased red cell turnover makes HbA1c unreliable 1, 2

Conditions Causing Falsely Elevated HbA1c:

• Iron-deficiency anemia: Can falsely increase HbA1c results 1
• Prolonged red blood cell lifespan: Certain genetic conditions may extend RBC survival beyond the normal 55-67 days, artificially elevating HbA1c 3

Hemoglobinopathies and Hemoglobin Variants

Complete Inability to Measure HbA1c:

• Homozygous hemoglobin variants (HbSS, HbEE, HbCC): These patients lack HbA entirely, making HbA1c measurement impossible and reporting inappropriate 1
• Sickle cell disease (HbSS): Cannot measure HbA1c; must use glucose criteria exclusively 1

Hemoglobin Variants Causing Interference:

• Sickle cell trait (HbAS): May result in HbA1c values approximately 0.3% lower than actual glycemia in African American individuals 1, 4
• G6PD G202A variant: Can decrease HbA1c by 0.8% in homozygous men and 0.7% in homozygous women 1
• Hb Hirose and other rare variants: May cause falsely elevated or lowered HbA1c depending on the specific mutation and assay method used 3
• For patients with hemoglobin variants but normal red cell turnover: Use only HbA1c assays specifically validated to be free from interference with that particular variant 1, 2

Rapidly Evolving Diabetes

• Acute-onset type 1 diabetes: HbA1c may not be significantly elevated despite frank diabetes because the disease progresses too quickly for HbA1c to reflect hyperglycemia severity, particularly in children 5, 1
• Use plasma glucose measurements, not HbA1c, to diagnose acute-onset type 1 diabetes in individuals with hyperglycemic symptoms 5

Racial and Ethnic Considerations

• African American individuals: May have HbA1c levels 0.3-0.8% higher than non-Hispanic White individuals with identical glucose levels, independent of hemoglobin variants 1, 4, 2
• Populations with high prevalence of hemoglobinopathies: In regions like Tanzania with high rates of hemoglobinopathies in people with HIV, HbA1c may be lower than expected based on glucose 1

HIV and Certain Medications

• HIV treated with certain protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs): HbA1c is less reliable than blood glucose measurement 1

Transfusion-Dependent Conditions

• Transfusion-dependent thalassemia: HbA1c can be falsely elevated (often in diabetic range >6.4%) despite normal fasting glucose, making it inappropriate for diabetes screening or monitoring 6, 7
• In efficiently transfused patients: Circulating hemoglobin is from blood donors, not the patient, fundamentally altering the interpretation 7

Alternative Testing Approaches

When HbA1c is unreliable, use these alternatives:

• Plasma glucose criteria: Fasting plasma glucose ≥126 mg/dL, 2-hour OGTT ≥200 mg/dL, or random glucose ≥200 mg/dL with symptoms 1, 2
• Fructosamine or glycated albumin: Reflect shorter periods of glycemia (2-3 weeks) and are not affected by red cell turnover 1, 8
• 1,5-anhydroglucitol: Not affected by hemolysis or red cell age 8
• Continuous glucose monitoring: Provides direct glucose measurements independent of red cell factors 1

Critical Pitfalls to Avoid

• Never use point-of-care HbA1c assays for diagnostic purposes: They lack sufficient accuracy 1, 5
• Ensure adequate carbohydrate intake: At least 150 g/day for 3 days prior to glucose testing to avoid falsely low results 1, 2
• Marked discordance between HbA1c and plasma glucose: Should prompt consideration that the HbA1c assay may not be reliable for that individual 1
• Always use NGSP-certified assays: Standardized to the DCCT reference assay 1, 4