What can cause a falsely elevated Hemoglobin A1c (HbA1c)?

Causes of Falsely Elevated Hemoglobin A1c (HbA1c)

Multiple conditions can cause falsely elevated HbA1c values, including iron deficiency anemia, hemoglobin variants, carbamylation in uremia, acidosis, prolonged red blood cell lifespan, and certain medications. 1, 2

Conditions That Falsely Elevate HbA1c

Red Blood Cell Lifespan Alterations

• Prolonged red blood cell lifespan conditions:
  • Iron deficiency anemia (most common) 1, 2
  • Vitamin B12 or folate deficiency anemia
  • Asplenia (absence of spleen function)
  • Reduced erythropoiesis 1

Hemoglobin Variants and Hemoglobinopathies

• Over 700 hemoglobin variants can interfere with HbA1c measurements 1, 2
• Specific variants like Hemoglobin Wayne 3, Hemoglobin Okayama 4, and Hemoglobin Hirose 5 can cause falsely elevated results
• Method-specific interferences (some variants affect certain assay methods more than others) 2

Biochemical Interferences

• Carbamylation of hemoglobin in uremia/kidney disease 1
• Acidosis 1
• Hypertriglyceridemia 1
• Hyperbilirubinemia 1

Medications and Substances

• Chronic alcoholism 1
• Chronic ingestion of salicylates 1
• Opiate addiction 1

Other Factors

• Advanced age (approximately 0.1% increase per decade after age 30) 1
• Racial/ethnic differences (African Americans may have higher HbA1c levels independent of glycemia) 2

Detection and Management of Falsely Elevated HbA1c

Warning Signs of Potentially Inaccurate HbA1c

• Discordance between HbA1c and blood glucose measurements 2
• Unexpectedly high HbA1c despite good glucose control on self-monitoring 3
• Significant change in HbA1c coincident with a change in laboratory method 1
• History of anemia, kidney disease, or known hemoglobinopathy 2

Alternative Testing Methods

When HbA1c is unreliable, consider:

1. Plasma glucose criteria 2:

   • Fasting plasma glucose
   • 2-hour plasma glucose during oral glucose tolerance test
   • Random plasma glucose with symptoms

2. Alternative glycemic markers 1, 2:

   • Fructosamine (reflects 2-3 week glycemic control)
   • Glycated albumin (more reliable in hemolytic conditions)
   • Continuous glucose monitoring (provides detailed glycemic patterns)

Laboratory Considerations

• Use HbA1c assays certified by the National Glycohemoglobin Standardization Program (NGSP) 2
• For patients with known hemoglobin variants, select an assay method without interference from that specific variant 2
• Boronate affinity chromatography methods may be more reliable for patients with suspected hemoglobin variants 1

Clinical Implications

Potential Consequences of Falsely Elevated HbA1c

• Misdiagnosis of diabetes or prediabetes 2
• Inappropriate treatment intensification 2
• Unnecessary medication side effects
• Patient anxiety and decreased quality of life

Best Practices

• Consider alternative testing in patients with conditions that may affect HbA1c accuracy
• Correlate HbA1c results with other glycemic measures (blood glucose monitoring, fructosamine)
• Maintain awareness of common interferences based on your patient population 1
• When in doubt about HbA1c accuracy, use multiple methods to assess glycemic control 2

By understanding these factors that can falsely elevate HbA1c, clinicians can avoid misdiagnosis and inappropriate treatment decisions, ultimately improving patient outcomes.