Does hereditary macrocytosis (a condition characterized by larger than normal red blood cells) affect Hemoglobin A1c (HbA1c) measurements?

Does Hereditary Macrocytosis Affect HbA1c?

Yes, hereditary macrocytosis can falsely lower HbA1c measurements because conditions that increase red blood cell size often involve increased red cell turnover or shortened erythrocyte lifespan, reducing the time available for hemoglobin glycation. 1, 2

Mechanism of HbA1c Interference

HbA1c reflects glycemia over the preceding 120 days, with glycation accumulating progressively as red blood cells age. 3 Any condition that shortens erythrocyte lifespan or increases red cell turnover decreases HbA1c values, since glycation of hemoglobin increases with the age of red blood cells. 1, 3

Hereditary macrocytosis is frequently associated with:

• Hemolytic anemias (including hereditary spherocytosis and hereditary stomatocytosis), which reduce red cell survival and falsely lower HbA1c 1, 4, 5
• Increased erythrocyte production, introducing younger cells with less accumulated glycation 1
• Conditions like G6PD deficiency, which can lower HbA1c by approximately 0.8% in homozygous men and 0.7% in homozygous women through increased red cell turnover 6, 1

Clinical Recognition and Diagnosis

Marked discrepancies between measured HbA1c and plasma glucose levels should prompt consideration that the HbA1c assay may not be reliable for that individual. 6, 2

Key diagnostic steps include:

• Obtain a complete blood count to assess mean corpuscular volume (MCV) and evaluate for hemolysis (elevated reticulocyte count, low haptoglobin) 2, 3
• Review peripheral blood smear for morphologic abnormalities suggesting hereditary hemolytic conditions 4, 5
• Compare HbA1c with fasting plasma glucose and/or 2-hour oral glucose tolerance test to identify discordance 2, 3
• Consider hemoglobin electrophoresis if hemoglobin variants are suspected (e.g., hereditary persistence of fetal hemoglobin) 7, 8, 9

Management When HbA1c is Unreliable

In conditions associated with increased red blood cell turnover, only plasma blood glucose criteria should be used to diagnose and monitor diabetes. 6

Alternative monitoring strategies include:

• Fasting plasma glucose and 2-hour post-prandial glucose measurements as the primary monitoring tools 6, 2, 3
• Fructosamine or glycated albumin, which reflect 2-4 weeks of glycemic control and are unaffected by red cell turnover 1, 2, 4
• Self-monitoring of blood glucose (SMBG) provides direct glucose measurements unaffected by RBC turnover 1, 3
• Continuous glucose monitoring (CGM) offers comprehensive glycemic assessment when available, with estimated HbA1c calculated from average glucose being more reliable than measured HbA1c 1, 5

Important Clinical Pitfalls

Do not rely on HbA1c alone when hereditary macrocytosis or hemolytic conditions are present, as this will underestimate true glycemic burden and lead to inadequate diabetes management. 6, 1

Specific scenarios requiring caution:

• Hereditary spherocytosis can cause significant discrepancy between HbA1c and actual glucose control 4
• Hereditary persistence of fetal hemoglobin may cause either falsely elevated or falsely lowered HbA1c depending on the assay used 7, 8, 9
• Compound hemoglobinopathies (e.g., homozygous hemoglobin S disease with hereditary persistence of fetal hemoglobin) can produce abnormally low HbA1c values 9

Laboratory Considerations

Use only NGSP-certified HbA1c assay methods traceable to the DCCT reference, and consider boronate affinity chromatography methods when interfering factors are suspected. 1, 3

When HbA1c appears discordant:

• Check the NGSP website (www.ngsp.org/interf.asp) for updated lists of assays with known interferences 6
• Switch to an assay without interference from hemoglobin variants if available 6, 2
• Abandon HbA1c monitoring entirely in favor of plasma glucose criteria if reliable assays are unavailable 6, 1