Recognizing the Limitations of A1c

Case

A patient with a history of ESRD on HD has serial A1c levels over the past year measuring 6.5 on average while home blood glucose measurements vary considerably, often in the 200s-300s. Why the disparity?

Background

Hemoglobin A1c has an integral role in managing diabetes, but it’s not without limitations. In contrast to the major hemoglobin components—the paired α and β chains (α2β2) that constitute 97% of hemoglobin, A1c is a minor component formed by the chemical condensation of hemoglobin and glucose. This process occurs slowly and continuously over the typical 120-day lifespan of RBCs.

Weighted Mean

A1c measurements represent a weighted mean of glucose levels during the preceding 3-month period. In other words, glucose levels during the most recent 6 week period will have a greater influence on the A1c result compared to levels from the prior 6 weeks. Thus, if the patient has experienced a recent acute change in glycemic control (i.e., treatment with systemic steroids), the A1c value will be disproportionately affected by the most recent glucose levels.

Falsely Elevated A1c

Any condition that prolongs the life of the erythrocyte or is associated with decreased red cell turnover (e.g., iron/folate/B12 deficiency, asplenia) exposes the cell to glucose for a longer period of time, resulting in higher A1c levels.

Other less common causes of falsely elevated A1c levels include severe hypertriglyceridemia (concentrations >1,750 mg/dL), severe hyperbilirubinemia (concentrations >20 mg/dL), uremia, lead poisoning, and chronic alcohol use.

Falsely Low A1c

Any condition that shortens the life of the erythrocyte or is associated with increased red cell turnover (e.g., ESRD, pregnancy and the initial postpartum period, blood loss, hemolytic anemia, splenomegaly) shortens the exposure of the cell to glucose, resulting in lower A1c levels. ESRD is particularly complex, owing to multiple factors including anemia, erythropoietin therapy, and the presence of uremia.

Other less common causes of falsely low A1c levels include vitamin E supplementation, ribavirin, and interferon-alpha.

Hemoglobin Variants

In general, A1c measurement is not reliable in patients with homozygous hemoglobin variants (i.e., HbS or HbC), whereas A1c measurement can be used in patients with heterozygous hemoglobin variants (i.e., HbAS, HbAC) as long as an appropriate assay is used. The presence of a hemoglobin variant may be suspected in a variety of situations including a discordance between the patient’s self-monitoring glucose measurements and the A1c value, an A1c result >15 %, a markedly different A1c result compared to the previous value when a different method is used to measure A1c, or the presence of anemia with abnormal red cell indices on a complete blood count.

Alternatives to Using A1c

In situations where A1c may not accurately reflect glycemic control, using an alternative index is desirable. Potential indices at Lifespan include fructosamine and continuous glucose monitoring; other options that might be obtained as send-out labs include glycated albumin (a specific form of fructosamine) and 1,5-anhydroglucitrol. 

Source: Radin MS. J Gen Intern Med. 2014

Case Follow-up

The patient’s fructosamine level is 451, suggesting prior A1c levels were falsely low.

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