What causes a low Hemoglobin A1c (Hgb A1c) level?

Causes of Low Hemoglobin A1c (HbA1c) Levels

Low HbA1c values are primarily caused by conditions that shorten red blood cell lifespan or alter hemoglobin structure, resulting in decreased glycation despite normal blood glucose levels. 1

Common Causes of Falsely Low HbA1c

Conditions Affecting Red Blood Cell Lifespan

• Hemolytic anemias: Any condition causing premature destruction of red blood cells 1, 2
  • Autoimmune hemolytic anemia
  • Sickle cell disease/trait
  • Glucose-6-phosphate dehydrogenase deficiency
  • Mechanical hemolysis (e.g., heart valve prosthesis)

Recent Blood Loss or Transfusions

• Blood loss leads to production of new red blood cells with less time for glycation
• Recent transfusions introduce non-glycated donor red blood cells 1

Medical Treatments and Conditions

• Hemodialysis/end-stage kidney disease: Shortened red cell survival
• Erythropoietin therapy: Increases production of new red blood cells
• Pregnancy (second and third trimesters): Increased red cell turnover
• HIV treated with certain medications: Some protease inhibitors and nucleoside reverse transcriptase inhibitors affect red cell lifespan 1

Genetic Factors

• Hemoglobin variants: Over 700 variants can interfere with HbA1c measurements 1, 3
  • Hemoglobin Wayne (rare variant that can actually cause falsely elevated HbA1c)
  • Other hemoglobinopathies that affect red cell survival or structure

Medications and Substances

• Chronic alcoholism: Interferes with HbA1c assay methods
• Chronic ingestion of salicylates: Can affect measurement accuracy
• Opiate addiction: May interfere with assay results 1

Clinical Implications and Assessment

When to Suspect Falsely Low HbA1c

• Discrepancy between HbA1c and plasma glucose measurements
• Patient with known hemoglobinopathy or hemolytic condition
• Unexpectedly low HbA1c in a patient with clinical signs of hyperglycemia
• HbA1c values that don't correlate with other glycemic measures (fasting glucose, post-prandial glucose) 4, 1

Diagnostic Approach

1. Compare HbA1c with estimated A1c from glucose monitoring
2. Evaluate for hemolysis with complete blood count, reticulocyte count, haptoglobin, and LDH
3. Consider hemoglobin electrophoresis if hemoglobinopathy is suspected
4. Review medication history for drugs that might affect red cell lifespan 1

Alternative Testing Methods

• Fructosamine: Reflects glycemic control over 2-3 weeks (less affected by red cell lifespan)
• Glycated albumin: More reliable in patients with hemolytic conditions
• Continuous glucose monitoring (CGM): Provides comprehensive glycemic assessment
• Self-monitoring of blood glucose (SMBG): Can help validate HbA1c results 1

Clinical Recommendations

• In patients with conditions affecting red blood cell turnover, use plasma glucose criteria exclusively for diabetes diagnosis 4, 1
• When HbA1c is suspected to be inaccurate, use alternative methods to assess glycemic control
• Be aware that treating based on falsely low HbA1c may lead to undertreatment of diabetes and increased risk of complications 1
• Use multiple monitoring methods for comprehensive assessment in patients with conditions that may affect HbA1c accuracy 1

Special Considerations

• Patients on hemodialysis may have falsely low HbA1c values despite hyperglycemia 4
• Patients with recent blood loss or transfusion should have HbA1c interpreted with caution for 2-3 months 1
• In patients with hemoglobin <10 g/dL, consider alternative testing methods 1

Understanding these factors is crucial for accurate interpretation of HbA1c results and appropriate management of diabetes or suspected diabetes in patients with conditions affecting red blood cell lifespan or hemoglobin structure.