What is a more accurate way to check Hemoglobin A1C (HbA1c) in a patient with diabetes mellitus and severe anemia?

Glycemic Monitoring in Severe Anemia

In patients with severe anemia, HbA1c is unreliable and should not be used; instead, use fructosamine or glycated albumin for monitoring glycemic control, or rely exclusively on plasma glucose measurements for diagnosis. 1

Why HbA1c Fails in Severe Anemia

Severe anemia causes falsely low HbA1c values due to shortened red blood cell lifespan, making it a poor marker of glycemic control. 1 The mechanism is straightforward: HbA1c reflects glucose exposure over the 2-3 month lifespan of red blood cells, but when red cells turn over more rapidly (as in hemolytic anemia, iron deficiency anemia, or blood loss), the hemoglobin has less time to accumulate glucose, resulting in artificially low readings that underestimate true glycemic burden. 2, 3

Additional conditions that invalidate HbA1c include: 1

• Hemolytic anemia of any cause
• Iron deficiency anemia
• Recent blood transfusions
• Erythropoietin therapy
• Pregnancy (second and third trimesters)
• End-stage kidney disease

Recommended Alternative: Fructosamine

Fructosamine is the preferred alternative marker because it measures glycated serum proteins rather than hemoglobin, making it completely unaffected by red blood cell disorders. 4, 2

Key advantages of fructosamine: 2, 5

• Reflects glycemic control over 2-3 weeks (albumin half-life), not months
• Unaffected by hemoglobin variants or red cell turnover
• Inexpensive and widely available
• Particularly useful when HbA1c and glucose measurements are discordant

Important caveat: Fructosamine can be falsely low in patients with hypoalbuminemia (common in severe illness, nephrotic syndrome, or malnutrition), so check serum albumin levels and interpret accordingly. 5

Alternative Option: Glycated Albumin

Glycated albumin is superior to both HbA1c and fructosamine in patients with chronic kidney disease and may be preferred in severe anemia with concurrent renal disease. 1, 6

Evidence supporting glycated albumin: 6

• Correlates better with continuous glucose monitoring than HbA1c in CKD patients (r=0.54 vs r=0.38)
• More accurately predicts hospitalization and mortality in dialysis patients
• Less affected by low albumin levels than fructosamine

The GA/HbA1c ratio >2.5 suggests HbA1c is underestimating glycemic control due to altered red cell turnover. 6

For Diagnosis: Use Glucose Criteria Exclusively

The American Diabetes Association explicitly states that in conditions with abnormal red cell turnover, diabetes diagnosis must employ glucose criteria exclusively—never HbA1c. 1, 4

Diagnostic glucose thresholds: 1

• Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L)
• 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during oral glucose tolerance test
• Random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic hyperglycemic symptoms

Critical technical requirement: Glucose samples must be processed immediately (spun and separated within 30 minutes) to prevent falsely low readings from ongoing glycolysis in the tube. 4

Practical Algorithm for Severe Anemia

1. Confirm the diagnosis of severe anemia and identify the type (hemolytic, iron deficiency, blood loss, etc.). 1

2. For ongoing glycemic monitoring: Order fructosamine (preferred) or glycated albumin, checking serum albumin level simultaneously to interpret results correctly. 4, 2, 6

3. For diabetes diagnosis: Use only fasting plasma glucose, 2-hour OGTT, or random glucose with symptoms—never HbA1c. 1

4. If fructosamine/glycated albumin unavailable: Rely on frequent self-monitoring of blood glucose or continuous glucose monitoring to assess glycemic patterns. 1, 4

Common Pitfalls to Avoid

Never assume HbA1c is accurate just because it's "normal" in a patient with known diabetes and severe anemia—the anemia may be masking poor control. 2, 3 A case report documented a patient with myelodysplastic syndrome whose HbA1c was falsely normal (even below normal range) despite consistently elevated glucose values; fructosamine revealed the true poor control. 2

Do not use point-of-care HbA1c devices in anemic patients—these are even less reliable than laboratory HbA1c assays in conditions affecting red cells. 1

When marked discrepancies exist between HbA1c and glucose measurements, immediately suspect assay interference and switch to alternative markers. 1, 4 Don't waste time repeating HbA1c tests hoping for concordance.

Special Consideration: Sickle Cell Disease vs. Trait

Distinguish between sickle cell disease and sickle cell trait, as management differs. 4

• Sickle cell disease: HbA1c is completely unreliable; use fructosamine or glucose measurements exclusively. 4
• Sickle cell trait: HbA1c can be measured using assays validated to be free from HbS interference (check NGSP website for approved assays), but values may still read ~0.3% lower than actual glycemic burden. 7, 4