When is HbA1c (Hemoglobin A1c) not suitable for the diagnosis of Diabetes Mellitus (DM)?

When HbA1c is Not Suitable for Diagnosing Diabetes Mellitus

HbA1c cannot be used for diagnosis in conditions affecting red blood cell turnover (pregnancy, hemolytic anemia, iron deficiency anemia), hemoglobinopathies, and rapidly evolving diabetes, where glucose-based criteria must be used exclusively. 1, 2

Conditions with Abnormal Red Blood Cell Turnover

HbA1c is unreliable when red blood cell lifespan is altered, requiring exclusive use of glucose criteria for diagnosis:

• Pregnancy: The diagnosis of diabetes must use glucose criteria exclusively due to altered red cell turnover during gestation 1
• Hemolytic anemias: Shortened red cell survival falsely lowers HbA1c values, making them unreliable for diagnosis 1, 2
• Iron deficiency anemia: Can falsely elevate HbA1c independent of glycemic control 2, 3
• Chronic kidney disease: Renal insufficiency compromises the sensitivity and specificity of HbA1c 3

Hemoglobinopathies and Assay Interference

For patients with hemoglobinopathies but normal red cell turnover (such as sickle cell trait), an HbA1c assay without interference from abnormal hemoglobins should be used. 1 However, when such interference-free assays are unavailable, glucose-based testing becomes necessary 2.

• Marked discordance between HbA1c and plasma glucose levels should raise suspicion for assay interference and prompt consideration of using an interference-free assay or relying on plasma glucose criteria instead 2
• Hemoglobin variants can cause false elevation or reduction of HbA1c values 4, 3

Rapidly Evolving Diabetes

In rapidly evolving diabetes, such as the development of type 1 diabetes in children, the HbA1c may not be significantly elevated despite frank diabetes. 1

• This occurs because HbA1c reflects average glucose over 60-90 days, and acute-onset diabetes may not have sufficient time to elevate HbA1c 2
• In these cases, glucose-based criteria (fasting glucose ≥126 mg/dL or random glucose ≥200 mg/dL with symptoms) should be used 1

Gestational Diabetes

HbA1c should not be used for the diagnosis of gestational diabetes 5. Glucose-based testing remains the standard for this population due to:

• Altered red cell turnover during pregnancy 1
• The need for timely diagnosis in a rapidly changing metabolic state 5

Point-of-Care Testing Limitations

Point-of-care HbA1c devices should not be used for diagnosis unless they are specifically FDA-approved for diagnostic purposes and performed in CLIA-certified laboratories of moderate complexity or higher 2. This restriction exists because:

• Point-of-care devices may lack the standardization required for diagnostic accuracy 2
• Only NGSP-certified methods standardized to the DCCT assay are acceptable for diagnostic purposes 1, 2

Practical Considerations

When HbA1c is unsuitable, the following glucose-based criteria should be used 1:

• Fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL) - requires 8-hour fast 1
• 2-hour oral glucose tolerance test ≥11.1 mmol/L (200 mg/dL) using 75g glucose load 1
• Random plasma glucose ≥11.1 mmol/L (200 mg/dL) in patients with classic symptoms of hyperglycemia 1

A critical pitfall to avoid: HbA1c at the 6.5% threshold diagnoses only about 30% of diabetes cases that would be identified collectively using HbA1c, fasting glucose, or 2-hour glucose testing. 2 Therefore, when clinical suspicion is high but HbA1c is below 6.5%, glucose-based testing should still be performed 6.