What can falsely elevate Hemoglobin A1c (HbA1c) levels?

Conditions That Falsely Elevate HbA1c

Iron deficiency anemia is the most clinically significant condition that falsely elevates HbA1c by prolonging red blood cell lifespan and increasing glucose exposure time. 1, 2

Primary Causes of False HbA1c Elevation

Iron Deficiency Anemia

• Iron deficiency anemia prolongs erythrocyte lifespan, exposing red blood cells to glucose for extended periods, resulting in falsely elevated HbA1c levels. 3, 1, 2
• This is one of the most common causes of falsely elevated HbA1c encountered in clinical practice. 2
• The American Diabetes Association specifically identifies iron-deficient anemia as making HbA1c less reliable than direct blood glucose measurement. 2

Chronic Kidney Disease with Uremia

• Carbamylation of hemoglobin in uremic patients causes falsely increased HbA1c values, though this effect is method-dependent and may not occur with all assay types. 3, 2
• Advanced CKD presents a complex picture: it can falsely elevate HbA1c through carbamylation AND falsely lower it through shortened red blood cell lifespan and hemolysis, making interpretation challenging. 3, 2
• Acidosis in kidney disease contributes to falsely increased values. 3

Hemoglobin Variants

• Hemoglobin variants (HbS, HbC, Hb Okayama, Hb Wayne, Hb Hirose) can result in falsely elevated HbA1c levels depending on the specific assay method used. 3, 1, 2
• Hemoglobin Wayne is a rare variant that can cause false elevation of HbA1c. 4
• Hb Hirose (β-37Trp→Ser) with β-198A→G promoter mutation has been associated with falsely elevated HbA1c across multiple measurement methods (HPLC, enzymatic, and immunoassay). 5
• Increased hemoglobin antigenicity due to gene mutations may contribute to particularly high HbA1c levels when measured by immunoassay. 5

Secondary Factors

Prolonged Red Blood Cell Lifespan

• Any condition that increases red blood cell lifespan beyond the normal range (55.1-66.7 days) will falsely elevate HbA1c by extending glucose exposure time. 5
• Differences in mean red cell half-life (ranging from 48 to 68 days) may explain some interindividual variability in the relationship between measured average glucose and HbA1c. 3

Medications and Substances

• Hypertriglyceridemia, hyperbilirubinemia, chronic alcoholism, chronic ingestion of salicylates, and opiate addiction interfere with some assay methods, falsely increasing results. 3, 4
• These interferences are based on older studies and may not pertain to modern methods. 3

Age-Related Factors

• Age-related increases in mean HbA1c occur at approximately 0.1% per decade after age 30 years in people without diabetes. 3, 1

Race-Related Variations

• 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. 1, 2

Clinical Recognition Algorithm

When to Suspect Falsely Elevated HbA1c

Suspect false elevation when: 1, 2

• HbA1c is surprisingly high relative to self-monitored blood glucose readings
• Significant discrepancy exists between HbA1c and continuous glucose monitoring data
• HbA1c does not correlate with patient's symptoms or clinical presentation
• HbA1c changed significantly coincident with a change in laboratory method

Diagnostic Workup

When false elevation is suspected: 1, 2

1. Obtain complete blood count to assess for anemia
2. Order iron studies (serum iron, ferritin, TIBC, transferrin saturation) to evaluate for iron deficiency
3. Consider erythrocyte creatine measurement to assess red blood cell lifespan if available
4. Order hemoglobin electrophoresis or variant analysis if hemoglobin variant is suspected
5. Measure fructosamine or glycated albumin as alternative glycemic markers (though these reflect a shorter period of average glycemia than HbA1c)
6. Implement continuous glucose monitoring to better understand glycemic patterns

Alternative Testing Strategies

When HbA1c is Unreliable

• Use fructosamine or glycated albumin in clinical settings where abnormalities in red blood cell turnover, hemoglobin variants, or other interfering factors compromise HbA1c interpretation. 3, 1, 2
• Use plasma glucose criteria exclusively for diagnosis in patients with conditions affecting red blood cell turnover. 2
• Consider boronate affinity methods for HbA1c measurement when hemoglobin variants are suspected, as they are less susceptible to interference. 1

For Ongoing Monitoring

• Use boronate affinity HbA1c exclusively for ongoing monitoring if hemoglobin variants are confirmed. 1
• Supplement HbA1c monitoring with self-monitoring of blood glucose and continuous glucose monitoring to capture glycemic patterns and variability. 1

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. 1, 2
• Do not use HbA1c for diagnosis in conditions with increased red blood cell turnover. 2
• Avoid averaging discordant HbA1c results, as this provides no clinically useful information and may lead to inappropriate treatment decisions. 1
• Do not dismiss a higher value as laboratory error without investigation. 1
• Avoid switching between different HbA1c methods for serial monitoring once a reliable method is established, as this introduces additional measurement variability. 1