What is the explanation for high Fasting Blood Sugar (FBS) but low Hemoglobin A1c (HbA1c)?

High Fasting Blood Sugar with Low HbA1c: Explanation and Clinical Approach

The most common explanation for high fasting blood sugar (FBS) with low HbA1c is a condition causing shortened red blood cell lifespan or increased red blood cell turnover, which artificially lowers HbA1c despite elevated glucose levels. 1

Primary Mechanisms to Consider

Conditions Affecting Red Blood Cell Turnover

The discordance between FBS and HbA1c occurs when red blood cells don't survive long enough to accumulate glycation proportional to actual glucose exposure:

• Hemolytic conditions including hemolytic anemia, sickle cell disease, or chronic lymphocytic leukemia reduce erythrocyte lifespan and falsely lower HbA1c 1, 2
• Recent blood loss or transfusion decreases the average age of circulating red blood cells, reducing glycation time 1
• Erythropoietin therapy stimulates production of younger red blood cells with less accumulated glycation 1
• Glucose-6-phosphate dehydrogenase deficiency can lower HbA1c by approximately 0.8% in homozygous individuals through increased red cell turnover 1

Assay Interference Issues

Technical problems with HbA1c measurement can produce falsely low results:

• Hemoglobin variants (such as HbS trait in African Americans) may lower HbA1c by approximately 0.3% compared to actual glycemia 1
• Certain medications including specific HIV protease inhibitors and nucleoside reverse transcriptase inhibitors can interfere with HbA1c reliability 1
• Cold agglutinins and other interfering substances may affect the assay, though warming specimens doesn't always correct the discrepancy 3

Clinical Evaluation Algorithm

Step 1: Verify the Discordance

• Confirm both measurements are accurate by repeating tests, ensuring FBS samples were spun and separated immediately after collection 1
• Calculate the expected HbA1c from the FBS level—a moderate positive correlation exists (r=0.65), though FBS typically underestimates average glucose compared to HbA1c-derived estimated average glucose 4

Step 2: Assess for Red Blood Cell Disorders

Look for these specific findings:

• Complete blood count abnormalities: anemia (hemoglobin <10 g/dL), elevated mean corpuscular volume, reticulocytosis 2, 3
• Hemoglobinopathy screening: particularly in African American patients or those with family history 1
• Markers of hemolysis: elevated indirect bilirubin, elevated LDH, decreased haptoglobin 3
• Underlying hematologic conditions: chronic lymphocytic leukemia (especially Binet stage C), other blood cancers 2

Step 3: Review Medical History for Interfering Conditions

• Chronic kidney disease (especially advanced CKD or dialysis patients) where anemia and uremia-related factors affect HbA1c 1
• Recent blood loss or transfusion within the past 3 months 1
• Medications: erythropoietin-stimulating agents, certain HIV medications, hydroxychloroquine 1, 3
• Pregnancy (second and third trimesters) where increased red cell turnover occurs 1

Alternative Glycemic Monitoring When HbA1c is Unreliable

When marked discordance exists between HbA1c and plasma glucose, use plasma glucose criteria alone to diagnose and monitor diabetes. 1

Recommended Alternative Measures

• Fructosamine or glycated albumin reflect 2-4 weeks of glycemic control and are less affected by red cell turnover 1, 2, 3
  • Caveat: Glycated albumin is biased low by hypoalbuminemia; fructosamine is biased high by hypoalbuminemia 1
• Self-monitoring of blood glucose with structured testing patterns provides real-time data 2
• Continuous glucose monitoring when available offers comprehensive glycemic assessment including time in range and glycemic variability 2, 5
• Serum albumin-adjusted glycated albumin may provide better accuracy in patients with hypoalbuminemia 1

Important Clinical Pitfalls

Don't Assume HbA1c is Always Accurate

• African Americans may have HbA1c levels 0.3-0.8% higher than non-Hispanic whites with identical glucose levels, but the reverse can occur with certain genetic variants 1
• Iron deficiency anemia paradoxically increases HbA1c by creating an older red blood cell cohort, opposite to hemolytic conditions 1, 2

Recognize When to Abandon HbA1c Entirely

In these conditions, only use plasma glucose criteria for diagnosis and monitoring 1:

• Active hemolysis or hemolytic anemia
• Pregnancy (second and third trimesters)
• Hemodialysis patients
• Recent significant blood loss or transfusion
• Erythropoietin therapy

Postprandial Glucose Contribution

• Postprandial glucose contributes more to HbA1c when overall control is good to fair (HbA1c <7.3% to <9.2%), while fasting glucose dominates at higher HbA1c levels (>9.3%) 6
• This means isolated high FBS with low HbA1c could theoretically reflect excellent postprandial control masking fasting hyperglycemia, though this is less common than red cell turnover issues

Laboratory Considerations

• Check the NGSP website (www.ngsp.org/interf.asp) for updated information on assay interferences 1
• Consider boronate affinity chromatography methods for HbA1c measurement when interference is suspected, as these may be more reliable 2
• Correlation with other glycemic measures (fasting glucose, postprandial glucose) is essential to establish true glycemic status 2