What is the management approach for a patient with normal fasting and postprandial glucose levels but elevated Hemoglobin A1c (HbA1c) and fructosamine levels, potentially indicating diabetes mellitus?

Discordant Glycemic Markers: Elevated HbA1c and Fructosamine with Normal Glucose Levels

Primary Diagnostic Consideration

When HbA1c and fructosamine are markedly elevated despite normal fasting and postprandial glucose levels, the most likely explanation is a condition that prolongs red blood cell lifespan or slows erythropoiesis, causing falsely elevated glycated markers. 1, 2

Conditions That Falsely Elevate HbA1c and Fructosamine

Red Blood Cell Lifespan Prolongation

• Iron deficiency anemia is the most common cause, prolonging erythrocyte lifespan and exposing cells to glucose for longer periods, causing falsely elevated HbA1c levels 2
• Iron deficiency creates an older red blood cell cohort, paradoxically increasing HbA1c despite normal glucose levels 3
• This mechanism affects both HbA1c and fructosamine since both reflect cumulative glycation over time 2

Occult Malignancies and Bone Marrow Disorders

• Occult malignancies affecting bone marrow function can alter red blood cell production and lifespan, leading to falsely elevated HbA1c 2
• Chronic lymphocytic leukemia can affect HbA1c measurements, though typically causes falsely low values when hemolytic anemia is present 3
• Myelodysplastic syndrome can cause discordance between HbA1c and actual glucose control 4

Chronic Inflammatory States

• Chronic infections may cause inflammatory responses affecting red blood cell turnover, potentially resulting in higher HbA1c values than expected based on blood glucose levels 2

Diagnostic Algorithm

Step 1: Confirm the Discordance

• Repeat both HbA1c and fasting/postprandial glucose measurements to verify the discrepancy 1
• Ensure glucose samples were collected properly (spun and separated immediately after collection) 3
• Verify HbA1c was performed using an NGSP-certified method standardized to the DCCT assay 1

Step 2: Evaluate for Red Blood Cell Disorders

• Order complete blood count (CBC) to assess for anemia, mean corpuscular volume (MCV), and red blood cell distribution width 2
• Obtain iron studies including serum iron, total iron-binding capacity, ferritin, and transferrin saturation 2
• Consider hemoglobin electrophoresis if hemoglobinopathy is suspected based on ethnicity or family history 1, 3

Step 3: Alternative Glycemic Markers

• Measure glycated albumin as it reflects 2-4 weeks of glycemic control and is less affected by red cell turnover 3, 5
• In patients with end-stage kidney disease, glycated albumin provides better assessment than HbA1c or fructosamine 5
• Fructosamine reflects glycemia over approximately 2-3 weeks but has variable reliability 1

Step 4: Consider Continuous Glucose Monitoring

• CGM provides direct assessment of glycemic patterns independent of red blood cell factors 1, 5
• Glucose Management Indicator (GMI) calculated from CGM mean glucose may be more reliable than laboratory HbA1c when red blood cell turnover is abnormal 1
• CGM is particularly valuable when HbA1c reliability is questioned 2

Management Approach

When Iron Deficiency is Identified

• Treat the underlying iron deficiency with oral or intravenous iron supplementation as clinically indicated 2
• Use plasma glucose criteria exclusively for diabetes diagnosis and monitoring until iron stores are repleted 1
• Recheck HbA1c 3-4 months after iron repletion to allow for red blood cell turnover 2

When Other Red Blood Cell Disorders are Present

• Rely on plasma glucose measurements (fasting and 2-hour post-OGTT) for diagnosis and monitoring 1
• Consider boronate affinity chromatography method for HbA1c measurement, which is less susceptible to interference 3, 2
• Use glycated albumin or fructosamine as adjunctive markers, recognizing their shorter timeframe of glycemic reflection 3, 5

When No Clear Cause is Identified

• Implement structured self-monitoring of blood glucose with preprandial, postprandial, and bedtime measurements 1
• Consider 7-point or 8-point daily glucose profiles to capture glycemic variability 1
• Evaluate for occult conditions including chronic kidney disease, liver disease, or malignancy 2

Critical Pitfalls to Avoid

Do Not Average Discordant Results

• Never average discordant HbA1c and glucose values, as this provides no clinically useful information and may lead to inappropriate treatment decisions 2
• Do not dismiss elevated HbA1c as laboratory error without thorough investigation 2

Do Not Rely Solely on HbA1c

• Treatment decisions based solely on a single HbA1c measurement without consideration of glucose monitoring results may lead to unnecessary therapy intensification 2
• In conditions with abnormal red blood cell turnover, HbA1c may provide spurious results regardless of the method used 2

Do Not Switch Assay Methods Without Reason

• Avoid switching between different HbA1c methods for serial monitoring once a reliable method is established, as this introduces additional measurement variability 2
• Sequential HbA1c values within 0.5% do not statistically differ unless the assay coefficient of variation is less than 3% 2

Race and Ethnicity Considerations

• African Americans may have HbA1c levels 0.3-0.4% higher than non-Hispanic whites with identical glucose levels 1
• Glucose-6-phosphate dehydrogenase deficiency (G6PD), carried by 11% of African Americans, can lower HbA1c by approximately 0.8% in homozygous individuals 1, 3
• Despite these variations, the association of HbA1c with risk for complications appears similar across racial groups 1

When to Use Plasma Glucose Criteria Exclusively

The American Diabetes Association recommends using only plasma blood glucose criteria for diagnosis and monitoring in the following conditions: 1, 3

• Conditions with increased red blood cell turnover (sickle cell disease, hemolytic anemia)
• Pregnancy (second and third trimesters)
• Glucose-6-phosphate dehydrogenase deficiency
• Hemodialysis
• Recent blood loss or transfusion
• Erythropoietin therapy
• Iron deficiency anemia (until repleted)