TRIP

When Is Hemoglobin A1c Inaccurate In Assessing Glycemic Control?

Clinical Correlations, 2012

Hemoglobin A1C (HbA1c) is an invaluable tool for monitoring long-term glycemic control in diabetic patients.
However, many clinicians managing diabetics have encountered the problem of HbA1c values that do not agree with fingerstick glucose logs.
Before suspecting an improperly calibrated glucometer or poor patient record keeping, it is useful to consider the situations in which HbA1c may be spuriously elevated or depressed.
These issues are best understood after reviewing how HbA1c is defined and measured–topics fraught with considerable confusion.
Glycosylation is a non-enzymatic, time-dependent chemical reaction in which glucose binds to the amino groups of proteins.[1] Historically, and long before its precise chemistry was discovered, glycosylated Hb was defined as an area of an elution chromatogram containing hemoglobin glycosylation products.
This elution peak was labeled as HbA1, in keeping with the existing nomenclature (HbA, HbA2, HbF, etc.
Later it was recognized that the chromatographic HbA1 region is not homogeneous and consists of several component peaks, designated A1a, A1b and A1c, with HbA1c being the dominant one.[1] The HbA1c fraction also turned out to correlate best with mean serum glucose concentrations, ie, to be a better index of long-term glycemia.
Relatively recently HbA1c was redefined chemically: now glycohemoglobin refers to hemoglobin glycosylated at any of its amino groups, while HbA1c is defined as glycohemoglobin with glucose bound specifically to the terminal valine of the beta-globin chain.
Consequently, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) has developed a standard reference method for HbA1c in which hemoglobin is cleaved with a specific peptidase into multiple oligopeptides, including a terminal hexapeptide containing the site of glycosylation in HbA1c.
Glycosylated and non-glycosylated hexapeptides are separated by high-performance liquid chromatography (HPLC) and quantified.
The ratio of concentrations of HbA1c to total Hb A is then reported.[2,3] All methods currently in use at NYU-affiliated hospitals are calibrated against that new IFCC standard.