Are there any medical conditions that can falsely elevate Hemoglobin A1C (HbA1C) levels?

Medical Conditions That Falsely Elevate A1C

Yes, iron deficiency anemia is the most clinically significant condition that falsely elevates A1C levels, while chronic kidney disease with uremia can also cause false elevation through hemoglobin carbamylation. 1, 2

Conditions That Falsely Elevate A1C

Iron Deficiency Anemia

• Iron deficiency anemia prolongs erythrocyte lifespan and exposes red blood cells to glucose for longer periods, causing falsely elevated HbA1c levels. 2
• This is one of the most common causes of falsely elevated A1C in clinical practice and should be suspected when A1C is discordant with glucose monitoring. 1, 2
• The American Diabetes Association specifically identifies iron-deficient anemia as making A1C less reliable than blood glucose measurement. 1

Chronic Kidney Disease (Advanced Stages)

• Carbamylation of hemoglobin in uremic patients can cause falsely increased A1C values. 1
• However, this effect is method-dependent and may not occur with all assay types. 1
• Important caveat: While advanced CKD can falsely elevate A1C through carbamylation, it can also falsely lower A1C through shortened red blood cell lifespan and hemolysis, making interpretation complex. 1, 2

Occult Malignancies Affecting Bone Marrow

• Malignancies affecting bone marrow function can alter red blood cell production and lifespan, leading to falsely elevated HbA1c. 2
• This should be considered when A1C is unexpectedly high without corresponding hyperglycemia. 2

Chronic Infections

• Inflammatory responses from chronic infections may affect red blood cell turnover, potentially resulting in higher HbA1c values than expected based on blood glucose levels. 2

Certain Medications and Substances

• Hypertriglyceridemia, hyperbilirubinemia, chronic alcoholism, chronic ingestion of salicylates, and opiate addiction can interfere with some assay methods, falsely increasing results. 2
• The clinical significance varies by assay method used. 2

Hemoglobin Variants (Can Elevate OR Lower A1C)

Method-Dependent Effects

• Hemoglobin variants (HbS, HbC) can result in falsely elevated or falsely lowered HbA1c levels depending on the specific assay method used. 2
• Marked discrepancies between measured A1C and plasma glucose levels should prompt consideration that the A1C assay may not be reliable for that individual. 1
• An updated list of A1C assays with interferences is available at www.ngsp.org/interf.asp. 1

Specific Variant Example

• Hemoglobin Wayne is a rare variant that falsely elevates A1C when measured using cation-exchange high-performance liquid chromatography, but shows normal values with boronate affinity method. 3
• Some variants increase hemoglobin antigenicity, contributing to falsely high levels particularly with immunoassay methods. 4

Race/Ethnicity Considerations

African Americans

• African Americans may have higher A1C levels than non-Hispanic Whites with similar fasting and postglucose load glucose levels. 1
• African Americans with prediabetes have HbA1c values that are 0.4% higher than white persons for any given level of glycemia, unexplained by measured differences in glycemia or clinical factors. 2
• However, African Americans heterozygous for HbS (sickle cell trait) may have lower A1C by about 0.3% compared with those without the trait. 1

Clinical Algorithm for Suspected False Elevation

When to Suspect False Elevation

1. A1C is surprisingly high or significantly changed coincident with a change in laboratory method. 2
2. Discrepancy between A1C and self-monitored blood glucose readings. 2
3. A1C does not correlate with patient's symptoms or clinical presentation. 1, 2

Diagnostic Workup

• Obtain complete blood count to assess for anemia. 2
• Order iron studies to evaluate for iron deficiency. 2
• Check for hemoglobin variants if discrepancy persists (hemoglobin electrophoresis or genetic analysis). 1, 3
• Consider erythrocyte creatine measurement to assess red blood cell lifespan if available. 4

Alternative Testing Options

• Use fructosamine or glycated albumin when A1C reliability is questioned, though these reflect a shorter period of average glycemia than HbA1c. 2, 5
• Consider continuous glucose monitoring (CGM) to better understand glycemic patterns. 2
• Use plasma glucose criteria exclusively for diagnosis in patients with conditions affecting red blood cell turnover. 1, 2

Critical Pitfalls to Avoid

• Never base treatment decisions solely on a single HbA1c measurement without consideration of glucose monitoring results, as this may lead to unnecessary initiation or intensification of therapy. 2
• Do not use A1C for diagnosis in conditions with increased red blood cell turnover (sickle cell disease, pregnancy second/third trimesters, G6PD deficiency, hemodialysis, recent blood loss/transfusion, erythropoietin therapy). 1
• Remember that sequential HbA1c values within 0.5% do not statistically differ from one another unless the assay coefficient of variation is less than 3%. 2