What causes undetectable Hemoglobin A1c (HbA1c) levels in an adult patient with a history of diabetes?

Undetectable HbA1c: Causes and Clinical Approach

Primary Cause

Undetectable HbA1c in a diabetic patient is most commonly caused by homozygous or compound heterozygous hemoglobin variants (HbSS, HbSC, HbEE, or S-β-thalassemia) that lack HbA, making HbA1c measurement impossible regardless of the assay method used. 1, 2, 3

Hemoglobin Variants Causing Undetectable HbA1c

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

Specific Variants That Prevent Detection:

• Homozygous sickle cell disease (HbSS) - the most common cause in clinical practice 3
• HbSC disease (compound heterozygous) 3
• HbS-β-thalassemia (compound heterozygous) 3
• Homozygous HbEE 1
• Hereditary persistence of fetal hemoglobin (HPFH) - can cause inconsistent or undetectable HbA1c levels 4
• Hemoglobin D Punjab - may cause undetectable HbA1c with certain ion-exchange HPLC methods 5

Critical Mechanism:

Modern HbA1c platforms with improved analytic specificity have eliminated interferences from heterozygous variants, but this creates the unintended consequence of reporting no value (or falsely reporting a value) in the presence of homozygous and compound heterozygous variants that lack HbA 3

Assay-Specific Technical Failures

Some hemoglobin variants cause method-dependent interference where certain assay platforms cannot detect or report HbA1c, while other methods may inappropriately report a value. 5

Method-Dependent Issues:

• Ion-exchange HPLC methods may fail to detect HbA1c in patients with specific variants like Hb D Punjab, while immunoturbidimetric methods successfully measure it 5
• Three of four major instrument platforms are known to report HbA1c values even in the absence of HbA, creating dangerous clinical scenarios 3
• Laboratories should be aware of potential interferences including hemoglobin variants that may affect HbA1c test results depending on the method used 1, 2

Conditions Affecting Red Blood Cell Lifespan

While these conditions typically cause falsely low (not undetectable) HbA1c, severe cases may approach undetectable levels:

Shortened RBC Lifespan (Falsely Low Values):

• 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 - recovery from acute blood loss falsely lowers 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 6, 1

Any condition that shortens RBC survival or decreases mean RBC age produces falsely low HbA1c results regardless of the assay method used. 1, 2

Diagnostic Algorithm When HbA1c Is Undetectable

Step 1: Immediate Laboratory Investigation

• Order hemoglobin electrophoresis or variant analysis to identify structural hemoglobin abnormalities 1
• Obtain complete blood count to assess for anemia and hemolysis 1, 7
• Check reticulocyte count to evaluate red blood cell turnover 1

Step 2: Alternative Glycemic Monitoring

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 (2-3 weeks) of average glycemia than HbA1c 1, 2
• Implement continuous glucose monitoring (CGM) to better understand glycemic patterns 1, 7
• Use plasma glucose criteria exclusively for diagnosis in patients with conditions affecting red blood cell turnover 7

Step 3: Ongoing Management Strategy

• If hemoglobin variants are confirmed, use boronate affinity HbA1c exclusively for ongoing monitoring if this method can detect the variant 1
• Supplement with self-monitoring of blood glucose and continuous glucose monitoring to capture glycemic patterns and variability 1
• In conditions with increased red blood cell turnover, only plasma blood glucose criteria should be used to diagnose diabetes 6

Critical Clinical Pitfalls to Avoid

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, 7

• 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 6, 7

High-Risk Populations Requiring Vigilance

The ability to identify samples harboring Hb variants that preclude the utility of HbA1c may be beneficial in high prevalence populations, particularly:

• African Americans - higher prevalence of sickle cell disease and trait 3
• Southeast Asian populations - higher prevalence of HbE variants 1
• Mediterranean populations - higher prevalence of beta-thalassemia 2