The 4 most common hemoglobin (Hb) variants worldwide and in the US are Hb S, Hb E, Hb C, and Hb D. In addition, there are many other less common variants. These variants frequently go unrecognized in the heterozygous form (e.g., the Hb S trait) because they are usually clinically silent, but such a variant might still be clinically important if its presence can lead to erroneous test results. A large number of patients with diabetes have clinically silent Hb variants that may interfere with Hb A1c measurement by some methods. Most of the commonly used Hb A1c methods have been evaluated with the 4 most common Hb variant traits (see http://www.NGSP.org), and although one or more of these variants interfere with some methods, others do not. When an Hb variant causes a change in the erythrocyte life span or actually produces a change in Hb glycation, Hb A1c measurement may not give clinically useful results, regardless of the assay methodology. In the case of the patient described by Sofronescu et al., there were actually 2 Hb variants present, Hb S and Hb Raleigh. Because there is no Hb A, one cannot directly measure Hb A1c. One could consider using boronate affinity to measure the total glycated Hb, which would include glycated Hb S and Hb Raleigh, except that Hb Raleigh is glycated to much less of an extent (compared with Hb A) because of the specific amino acid substitution. A small number of cases require other measures of glycemic control, such as fructosamine or continuous glucose monitoring, instead of Hb A1c measurement, but such cases are rare. For the vast majority of patients with diabetes (and for those being tested for the presence of diabetes), Hb A1c measurement is the best way to assess long-term glycemic control, as long as an appropriate methodology is used. It is the responsibility of all manufacturers to clearly state their methods' limitations, and it is up to each laboratory to know—and to convey to their clinicians when appropriate—these limitations for the methods they use to measure Hb A1c.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
- Received for publication October 12, 2010.
- Accepted for publication October 20, 2010.
- © 2010 The American Association for Clinical Chemistry