Causes of Low HbA1c
Low HbA1c values are most commonly caused by conditions that shorten red blood cell lifespan or increase red blood cell turnover, resulting in falsely low measurements that do not accurately reflect true glycemic control. 1
Primary Causes Related to Red Blood Cell Turnover
Conditions That Shorten RBC Lifespan (Falsely Lower HbA1c)
- Hemolytic anemia of any etiology falsely lowers HbA1c by reducing the time available for hemoglobin glycation 1
- Recovery from acute blood loss decreases mean RBC age, leading to spuriously low results 1
- Recent blood transfusion introduces younger donor red blood cells with less accumulated glycation 1
- Chronic lymphocytic leukemia can cause hemolytic anemia or reduce RBC survival, producing falsely low readings 2
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency increases red cell turnover and can lower HbA1c by approximately 0.8% in homozygous men and 0.7% in homozygous women 1, 2
Conditions That Increase RBC Production
- Erythropoietin therapy stimulates production of younger red blood cells with less accumulated glycation 1, 2
- Iron supplementation and vitamin B12 therapy increase erythrocyte production, introducing younger cells into circulation 1
- Chronic liver disease with spleen enlargement can accelerate RBC turnover 1
Pregnancy-Related Changes
- Second and third trimesters of pregnancy show slightly lower HbA1c levels due to increased red blood cell turnover 1
- Postpartum period also demonstrates unreliable HbA1c measurements 1
Hemoglobin Variants and Genetic Factors
- Sickle cell trait (HbS heterozygosity) in African Americans lowers HbA1c by approximately 0.3% for any given level of mean glycemia 1
- Homozygous hemoglobin variants (HbSS, HbEE) prevent accurate HbA1c measurement entirely 1
- X-linked G6PD G202A variant (carried by 11% of African Americans) decreases HbA1c significantly 1
Medication and Supplement Interference
- Vitamins C and E are reported to falsely lower HbA1c results, possibly by inhibiting glycation of hemoglobin 1
- Chronic ingestion of salicylates may interfere with some assay methods 1
- Opiate addiction has been reported to affect certain measurement methods 1
End-Stage Renal Disease
- Hemodialysis patients demonstrate discrepancies between HbA1c and true mean glycemia due to altered RBC turnover 1
- End-stage kidney disease affects red blood cell survival independently 1
Clinical Implications and Management
When HbA1c is unexpectedly low or discordant with plasma glucose measurements, use plasma glucose criteria alone for diagnosis and monitoring. 1, 2
Alternative Glycemic Monitoring Options
- Fructosamine or glycated albumin should be used when abnormalities in red blood cell turnover compromise HbA1c interpretation, though they reflect a shorter period (2-4 weeks) of average glycemia 1, 2
- Self-monitoring of blood glucose (SMBG) provides direct glucose measurements unaffected by RBC turnover 2
- Continuous glucose monitoring (CGM) offers comprehensive glycemic assessment when available 2
Critical Diagnostic Pitfall
Iron-deficiency anemia paradoxically increases HbA1c (not decreases it) by creating an older red blood cell cohort with more time for glycation. 1, 2 This is the opposite effect of hemolytic conditions and must be distinguished clinically. 3, 4
Laboratory Considerations
- Laboratories must use only NGSP-certified HbA1c assay methods traceable to the DCCT reference 1
- Marked discrepancies between measured HbA1c and plasma glucose levels should prompt consideration that the assay may be unreliable for that individual 1
- Boronate affinity chromatography methods may be more reliable in the presence of interfering factors 2
Conditions Requiring Glucose-Only Diagnosis
In the following conditions, only plasma blood glucose criteria should be used for diabetes screening, diagnosis, and management: 1, 2
- Sickle cell disease
- Pregnancy (second and third trimesters)
- G6PD deficiency
- HIV (particularly with certain protease inhibitors and NRTIs)
- Hemodialysis
- Recent blood loss or transfusion
- Erythropoietin therapy
- Hemolytic anemia of any cause