What could be causing elevated blood glucose levels with decreased Hemoglobin A1C (HbA1C) levels in a patient with diabetes?

Elevated Blood Glucose with Decreased A1C: Diagnostic Approach

Direct Answer

When you observe elevated blood glucose levels alongside a decreased or unexpectedly low A1C, you are most likely dealing with a condition that shortens red blood cell lifespan, preventing adequate time for hemoglobin glycation—the A1C is falsely low and does not reflect true glycemic burden. 1, 2

Primary Conditions Causing Falsely Low A1C

Hemolytic Conditions

• Hemolytic anemia of any etiology falsely lowers A1C by reducing the time available for hemoglobin glycation, making the A1C unreliable for assessing true glycemic control 1, 2
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency increases red cell turnover and can lower A1C by approximately 0.8% in homozygous men and 0.7% in homozygous women compared to actual glycemia 1, 2
• Sickle cell disease (homozygous HbSS) prevents accurate A1C measurement entirely due to markedly shortened RBC survival 1, 2
• Paroxysmal nocturnal hemoglobinuria (PNH) causes A1C to decline in parallel with worsening anemia, while fasting glucose, fructosamine, and glycated albumin remain elevated, confirming ongoing hyperglycemia 3

Blood Loss and Transfusion

• Recent blood loss decreases mean RBC age, leading to spuriously low A1C results that underestimate true glycemic control 1, 2
• Recent blood transfusion introduces younger donor red blood cells with less accumulated glycation, artificially lowering the A1C 1, 2

Increased RBC Production

• Erythropoietin therapy stimulates production of younger red blood cells with less accumulated glycation, causing A1C to underestimate average glucose 1, 2
• Iron supplementation and vitamin B12 therapy increase erythrocyte production, introducing younger cells into circulation and lowering A1C relative to actual glucose levels 2

Pregnancy

• Second and third trimesters of pregnancy show slightly lower A1C levels due to increased red blood cell turnover, making plasma glucose criteria more reliable for diagnosis 1, 2

End-Stage Renal Disease

• Hemodialysis patients demonstrate significant discrepancies between A1C and true mean glycemia due to altered RBC turnover, with A1C typically underestimating glucose control by approximately 0.74% 1, 2, 4
• In hemodialysis patients with type 2 diabetes, up to 49% have A1C-GMI discordance greater than 1%, with A1C underestimating average glucose 4

Hemoglobin Variants

• Sickle cell trait (HbS heterozygosity) in African Americans lowers A1C by approximately 0.3% for any given level of mean glycemia 1, 2
• X-linked G6PD G202A variant, carried by 11% of African Americans, is associated with decreased A1C despite normal glucose levels 1

Diagnostic Algorithm

Step 1: Verify the Discrepancy

• Repeat A1C testing using an NGSP-certified laboratory method to rule out measurement error 1, 5
• Obtain fasting plasma glucose (≥126 mg/dL confirms diabetes) and consider 2-hour OGTT (≥200 mg/dL confirms diabetes) 1, 5
• Marked discrepancy between A1C and glucose measurements (>0.5-1.0% difference) suggests A1C interference and warrants investigation 1, 6

Step 2: Evaluate for Conditions Affecting RBC Turnover

• Complete blood count with reticulocyte count to assess for anemia and increased RBC turnover 3
• Hemoglobin electrophoresis if hemoglobin variant suspected (particularly in African American patients) 1, 2
• G6PD enzyme activity if deficiency suspected based on ethnicity or clinical history 1, 2
• Iron studies, vitamin B12, and folate levels to identify recent supplementation or deficiency 2
• Review medication history for erythropoietin therapy, recent blood transfusions, or iron/B12 supplementation 1, 2
• Assess for pregnancy (second/third trimester) in women of childbearing age 1, 2
• Evaluate renal function (eGFR) as chronic kidney disease and hemodialysis significantly affect A1C reliability 1, 6, 4

Step 3: Use Alternative Glycemic Markers

• Fructosamine or glycated albumin should be used when abnormalities in red blood cell turnover compromise A1C interpretation, though they reflect a shorter period (2-4 weeks) of average glycemia 2, 3
• Self-monitoring of blood glucose (SMBG) provides direct glucose measurements unaffected by RBC turnover 2
• Continuous glucose monitoring (CGM) offers comprehensive glycemic assessment and glucose management indicator (GMI) when available 2, 4
• In hemodialysis patients specifically, GMI or mean glucose and time-in-range may be considered more appropriate glucose control markers than A1C 4

Critical Management Principles

When conditions affecting RBC turnover are identified, use plasma glucose criteria alone for diagnosis and monitoring—do not rely on A1C. 1, 2

Key Clinical Pitfalls to Avoid

• Never dismiss elevated glucose levels simply because A1C appears normal or low—the glucose measurements reflect true glycemic status while A1C may be artifactually decreased 1, 5, 3
• Do not delay diabetes treatment based on falsely reassuring A1C values when fasting or random glucose levels are consistently elevated 5, 3
• Ensure samples for plasma glucose are spun and separated immediately after they are drawn, as glycolysis can falsely lower glucose concentrations if samples are not processed promptly 1
• Recognize that relying on A1C alone when interfering conditions exist will underestimate true glycemic burden and lead to inadequate treatment 5, 2

Laboratory Considerations

• Laboratories must use only NGSP-certified A1C assay methods traceable to the DCCT reference to ensure accuracy 1, 2
• Boronate affinity chromatography methods may be more reliable in the presence of interfering factors compared to other assay methods 2
• Check the NGSP website (www.ngsp.org/interf.asp) for an updated list of A1C assays with known interferences from hemoglobin variants 1, 2

Additional Considerations

Pre-Test Preparation

• Ensure patients consume at least 150 g of carbohydrates daily for 3 days prior to oral glucose tolerance testing, as fasting and carbohydrate restriction can falsely elevate glucose levels during testing 1

Racial and Ethnic Factors

• African Americans may have A1C values 0.3-0.4% higher than non-Hispanic whites at identical glucose levels, independent of measured glycemia—this is the opposite scenario but important for complete understanding of A1C-glucose discordance 5, 2