Are there any medical conditions that can cause A1C (Hemoglobin A1C) and fasting blood glucose to read lower than actual glucose levels?

Medical Conditions That Falsely Lower A1C and Fasting Blood Glucose

Yes, several medical conditions can cause A1C to read falsely low, making it appear better than actual glycemic control, while fasting glucose is generally less affected by these conditions.

Conditions That Falsely Lower A1C

Increased Red Blood Cell Turnover

Any condition that shortens red blood cell lifespan will cause A1C to underestimate true glycemic exposure because hemoglobin has less time to become glycated 1:

• Hemolytic anemias (any cause) 1
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency 1
• Recent blood loss or hemorrhage 1
• Recent blood transfusion 1
• Sickle cell disease (A1C cannot be reliably measured at all) 1
• Erythropoietin therapy 1
• Hemodialysis 1
• End-stage kidney disease 1

Hemoglobin Variants (Hemoglobinopathies)

Certain genetic variants can interfere with A1C measurement or alter the relationship between A1C and actual glucose levels 1:

• Sickle cell trait (HbS heterozygous): Lowers A1C by approximately 0.3% for any given level of mean glycemia in African Americans 1, 2
• G6PD G202A variant: Decreases A1C by 0.8% in homozygous men and 0.7% in homozygous women (carried by 11% of African Americans) 1, 2
• Thalassemia 1, 3
• Other hemoglobin variants may interfere with specific A1C assays 1

Pregnancy-Related Changes

During the second and third trimesters of pregnancy and the postpartum period, A1C underestimates glycemia due to increased red blood cell turnover 1.

HIV Treatment

Certain antiretroviral medications can affect A1C reliability, particularly some protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) 1. In regions with high hemoglobinopathy prevalence among people with HIV (such as Tanzania), A1C may be lower than expected based on glucose 1.

Iron Deficiency Anemia

Iron-deficient anemia can make A1C less reliable as a measure of glycemic control 1.

Other Conditions

• Cirrhosis 1
• Splenectomy (can prolong red blood cell lifespan, but this would raise A1C) 1

Conditions Affecting Fasting Blood Glucose

Fasting glucose is generally more stable but can be affected by:

• Acute stress or illness (typically raises glucose) 1
• Recent carbohydrate restriction: Fasting and carbohydrate restriction for 3 days prior to testing can falsely elevate glucose levels 1
• Sample handling issues: If plasma is not separated immediately after blood draw, glycolysis will falsely lower glucose readings 1

Critical Clinical Recommendations

When to Avoid A1C for Diagnosis

Use only plasma glucose criteria (fasting glucose or oral glucose tolerance test) to diagnose diabetes in patients with 1:

• Any condition with increased red blood cell turnover
• Pregnancy (second/third trimester) and postpartum period
• G6PD deficiency
• Hemolytic anemias
• Recent blood loss or transfusion
• Hemodialysis
• Erythropoietin therapy

When A1C and Glucose Don't Match

Marked discordance between measured A1C and plasma glucose levels should prompt consideration of 1:

• Using an A1C assay without interference from hemoglobin variants (check www.ngsp.org/interf.asp for updated list) 1
• Switching to plasma glucose criteria for diagnosis and monitoring 1
• Evaluating for hemoglobin variants or conditions affecting red blood cell turnover 1

Race/Ethnicity Considerations

African Americans may have higher A1C levels than non-Hispanic whites with similar glucose levels, independent of hemoglobin variants 1. This means A1C may overestimate rather than underestimate glycemia in this population, though the relationship with complications appears similar 1.

Practical Algorithm

When A1C seems discordant with clinical picture 3:

1. Obtain fasting plasma glucose and/or 2-hour oral glucose tolerance test 3
2. Review complete blood count for anemia or conditions affecting red cell turnover 3
3. Consider hemoglobin electrophoresis if variant suspected 1
4. If interference confirmed, use glucose-based criteria for all future monitoring 1, 3