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

Conditions That Can Cause Falsely Elevated HbA1c

Iron deficiency anemia is the most common condition that causes falsely elevated HbA1c values despite normal blood glucose levels. 1 Several other conditions can also lead to inaccurate HbA1c measurements, which can significantly impact diabetes diagnosis and management.

Conditions That Falsely Elevate HbA1c

Anemias

• Iron deficiency anemia: Causes falsely elevated HbA1c despite normal glucose levels 1
• Vitamin B12 or folate deficiency: Can increase HbA1c values 1

Red Blood Cell Lifespan Alterations

• Prolonged red blood cell lifespan: Leads to higher HbA1c as hemoglobin has more time to become glycated 2
• Asplenia: Reduced clearance of older red blood cells

Hemoglobin Variants and Hemoglobinopathies

• Hemoglobin variants: Over 700 variants can interfere with HbA1c measurements 1
• S-beta+-thalassemia: Can cause falsely elevated HbA1c with certain assay methods, particularly Bio-Rad Variant II Turbo cation-exchange HPLC assay 3
• Transfusion-dependent thalassemia: 85.7% of patients show HbA1c in diabetic range despite normal fasting glucose 4
• Multiple beta globulin gene mutations: Can cause falsely elevated HbA1c regardless of measurement method 2

Other Factors

• Hypertriglyceridemia: May interfere with some assay methods 5
• Hyperbilirubinemia: Can falsely increase results with certain methods 5
• Uremia: Historical interference (may not affect modern methods) 5
• Chronic alcoholism: May interfere with some assay methods 5
• Chronic ingestion of salicylates: Can affect some measurement methods 5
• Opiate addiction: Reported to interfere with some assay methods 5

Conditions That Falsely Lower HbA1c

While not the focus of the question, it's important to note conditions that cause falsely decreased HbA1c:

• Hemolytic anemia: Shortened red cell lifespan 5, 1
• Sickle cell disease/trait: Approximately 0.3% lower HbA1c than expected 5, 1
• Glucose-6-phosphate dehydrogenase deficiency: Affects red cell survival 5, 1
• Recent blood loss or transfusion: Alters red cell population 5, 1
• Pregnancy (second and third trimesters): Increased red cell turnover 5
• Hemodialysis/end-stage kidney disease: Affects red cell survival 1
• Erythropoietin therapy: Increases production of new red cells 5, 1
• HIV treated with certain protease inhibitors and nucleoside reverse transcriptase inhibitors: Affects red cell dynamics 5, 1

Clinical Implications and Management

When to Suspect HbA1c Inaccuracy

• Marked discrepancies between measured HbA1c and plasma glucose levels 5
• Significant change in HbA1c coincident with a change in laboratory method 1
• HbA1c values in diabetic range with normal fasting glucose levels 4

Alternative Testing Methods

1. Use plasma glucose criteria exclusively for diagnosis in patients with conditions affecting red blood cell turnover 5
2. Fructosamine: Reflects glycemic control over 2-3 weeks; less affected by red cell lifespan but impacted by hypoalbuminemia 1
3. Glycated albumin: More reliable in patients with hemolytic conditions 1
4. Continuous glucose monitoring (CGM): Provides detailed glycemic patterns 1
5. Self-monitoring of blood glucose (SMBG): Helps validate HbA1c results 1

Laboratory Considerations

• Use A1c assays certified by the National Glycohemoglobin Standardization Program (NGSP) 5, 1
• For patients with suspected hemoglobin variants, boronate affinity chromatography methods may be more reliable 1, 6
• Check NGSP website (www.ngsp.org/interf.asp) for updated list of A1c assays with interferences 5, 1

Algorithm for HbA1c Interpretation

1. Assess for risk factors for falsely elevated HbA1c:

   • Check complete blood count for anemia
   • Review patient history for hemoglobinopathies or ethnic background with higher risk
   • Note any medications that may interfere with results

2. If hemoglobin ≥10 g/dL: HbA1c can be used with caution 1

3. If hemoglobin <10 g/dL or suspected interference:

   • Use alternative testing methods
   • Consider HPLC method initially to identify or rule out common variant hemoglobins 6
   • Use plasma glucose criteria for diagnosis 5

4. When discrepancy is detected:

   • Compare HbA1c with estimated A1c from glucose monitoring
   • Consider alternative glycemic markers (fructosamine, glycated albumin)
   • Use multiple methods to assess glycemic control

Failing to recognize these interferences can lead to inappropriate diabetes treatment decisions, including overtreatment that may cause dangerous hypoglycemia or undertreatment that increases risk of complications 1.