Undetectable HbA1c: Causes and Clinical Approach

Primary Cause

The American College of Cardiology is not mentioned in this article, however, the article states that undetectable HbA1c in a diabetic patient is most commonly caused by homozygous or compound heterozygous hemoglobin variants that lack HbA, making HbA1c measurement impossible regardless of the assay method used 1, 2

HbA1c cannot be measured and should not be reported in individuals with homozygous hemoglobin variants such as HbSS or HbEE; glycated proteins like fructosamine or glycated albumin must be used instead 1, 2

Hemolytic anemia, characteristic of beta-thalassemia, results in falsely low HbA1c because red blood cells have less time for glucose exposure and glycation 2
Acute blood loss recovers with falsely low HbA1c by reducing mean RBC age 1
Chronic kidney disease can shorten erythrocyte lifespan, resulting in falsely low values 1
Pregnancy (second and third trimesters) alters RBC turnover, lowering usual HbA1c concentrations 1, 3
Any condition that shortens RBC survival or decreases mean RBC age produces falsely low HbA1c results regardless of the assay method used 1, 2

Order hemoglobin electrophoresis or variant analysis to identify structural hemoglobin abnormalities 1
Obtain complete blood count to assess for anemia and hemolysis 1, 4
Check reticulocyte count to evaluate red blood cell turnover 1
Glucose testing will be necessary for screening, diagnosis, and management in individuals with disorders that affect red blood cell turnover, as HbA1c may provide spurious results 1, 2
Use fructosamine or glycated albumin as alternative markers, though these reflect a shorter period of average glycemia than HbA1c 1, 2
Implement continuous glucose monitoring (CGM) to better understand glycemic patterns 1, 4
Use plasma glucose criteria exclusively for diagnosis in patients with conditions affecting red blood cell turnover 4

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, 4
Do not average discordant HbA1c results or dismiss undetectable values as laboratory error without investigation 1
Do not switch between different HbA1c methods for serial monitoring once a reliable method is established 1
HbA1c should be interpreted with caution when there is a discrepancy with self-monitored blood glucose readings, especially in patients with suspected hemoglobinopathy 1, 2
Marked discrepancies between measured A1C and plasma glucose levels should prompt consideration that the A1C assay may not be reliable for that individual 3, 4

The ability to identify samples harboring Hb variants that preclude the utility of HbA1c may be beneficial in high prevalence populations, particularly in Southeast Asian populations with a higher prevalence of HbE variants 1
Mediterranean populations have a higher prevalence of beta-thalassemia 2