What conditions can cause A1c (Hemoglobin A1c) levels to appear artificially low?

Causes of Artificially Low A1c Levels

Conditions that shorten red blood cell lifespan are the primary causes of artificially low A1c values, as these conditions reduce the exposure time of hemoglobin to glucose, leading to falsely low readings that underestimate true glycemic status. 1

Primary Causes of Falsely Low A1c

Hemolytic Conditions

• Hemolytic anemias - any condition causing premature destruction of red blood cells 1, 2
• Glucose-6-phosphate dehydrogenase deficiency 1
• Sickle cell disease/trait - African Americans with sickle cell trait may have A1c values approximately 0.3% lower than expected 1
• Paroxysmal nocturnal hemoglobinuria 3

Genetic Variants

• X-linked glucose-6-phosphate dehydrogenase G202A variant - carried by 11% of African Americans, associated with A1c decreases of approximately 0.8% in homozygous men and 0.7% in homozygous women 1
• Hemoglobin variants - certain variants can interfere with A1c measurement depending on the assay used 1

Medications and Treatments

• Dapsone - can cause artificially low A1c values through hemolysis 4
• Ribavirin - used for hepatitis C treatment, causes reversible hemolytic anemia 5
• Erythropoietin therapy - stimulates production of new red blood cells, reducing mean erythrocyte age 1, 5

Other Clinical Conditions

• Recent blood transfusion - introduces new red blood cells with less glycation 1
• Recent blood loss - triggers production of new red blood cells 1
• Pregnancy (second and third trimesters) - increased red blood cell turnover 1
• End-stage kidney disease/hemodialysis - reduced erythrocyte lifespan from uremia and mechanical lysis during dialysis 1
• HIV treated with certain protease inhibitors and nucleoside reverse transcriptase inhibitors 1

Clinical Implications

Recognizing Discordance

• Marked discrepancies between measured A1c and plasma glucose levels should prompt consideration that the A1c assay may not be reliable for that individual 1
• When A1c is unexpectedly low despite elevated blood glucose readings, consider the possibility of shortened red blood cell lifespan 1

Alternative Monitoring Methods

1. Fructosamine - reflects glycemic control over 2-3 weeks; less affected by red blood cell lifespan but can be impacted by hypoalbuminemia 1, 2
2. Glycated albumin - more reliable in patients with hemolytic conditions; less likely to be affected by confounding factors except low albumin levels 1, 2
3. Self-monitoring of blood glucose (SMBG) - provides immediate glycemic information 2
4. Continuous glucose monitoring (CGM) - provides detailed glycemic patterns and can calculate estimated A1c 1, 2

Important Considerations

• Using an inappropriate A1c assay in patients with hemoglobin variants can lead to falsely elevated or lowered results; use an assay without interference when hemoglobin variants are present 1
• Misinterpreting artificially low A1c values may lead to undertreatment of diabetes and increased risk of complications 2
• In conditions with shortened red blood cell lifespan, only plasma blood glucose criteria should be used to diagnose diabetes 1
• When A1c cannot be reliably used, a combination of alternative glycemic markers and blood glucose monitoring should be employed for optimal diabetes management 1, 2

Remember that A1c is an indirect measure of average glycemia and should be interpreted with caution in patients with conditions affecting red blood cell turnover. When in doubt, use multiple methods to assess glycemic control.