Hereditary Macrocytosis and HbA1c Measurement

Mechanism of HbA1c Interference

The American Diabetes Association notes that 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, which reduce red cell survival and falsely lower HbA1c 1
Increased erythrocyte production introduces younger cells with less accumulated glycation, affecting HbA1c measurements 1
Conditions like G6PD deficiency can lower HbA1c by approximately 0.8% in homozygous men and 0.7% in homozygous women through increased red cell turnover 4, 5, 1

The American College of Physicians recommends that marked discrepancies between measured HbA1c and plasma glucose levels should prompt consideration that the HbA1c assay may not be reliable for that individual 4, 5, 2
Obtaining a complete blood count to assess mean corpuscular volume (MCV) and evaluate for hemolysis is a key diagnostic step 2, 3
Comparing HbA1c with fasting plasma glucose and/or 2-hour oral glucose tolerance test can help identify discordance 2, 3

The American Diabetes Association suggests that in conditions associated with increased red blood cell turnover, only plasma blood glucose criteria should be used to diagnose and monitor diabetes 4, 5
Fasting plasma glucose and 2-hour post-prandial glucose measurements can be used as primary monitoring tools 4, 2, 3
Fructosamine or glycated albumin can reflect 2-4 weeks of glycemic control and are unaffected by red cell turnover 1, 2
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

The American College of Physicians advises against relying 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, 7, 1

The National Glycohemoglobin Standardization Program (NGSP) recommends using only NGSP-certified HbA1c assay methods traceable to the DCCT reference, and considering boronate affinity chromatography methods when interfering factors are suspected 1, 3
When HbA1c appears discordant, checking the NGSP website for updated lists of assays with known interferences is recommended 4, 5
Switching to an assay without interference from hemoglobin variants may be necessary if available 5, 2
Abandoning HbA1c monitoring entirely in favor of plasma glucose criteria may be necessary if reliable assays are unavailable 4, 1