Is it time for your HbA1c method check-up?

Take a moment to consider the following:

• Today there are approximately 200 million people worldwide suffering from diabetes; by 2030, that number is expected to increase to 365 million.¹
• HbA1c levels play a major part in determining diabetic treatment options, and many physicians use HbA1c as a diagnostic tool as well as for treatment and monitoring.
• Certain hemoglobin variants have been proven to cause interference in HbA1c readings using some ion-exchange and immunoassays, leading to inaccurate results and incorrect treatment of patients.^{2,3,4,5,6,7,8}
• Chemically-modified hemoglobin can cause interference in HbA1c methods such as ion exchange and electrophoresis which separate hemoglobin species on the basis of charge differences. Examples include carbamylated hemoglobin due to kidney disease, acetylated hemoglobin due to high aspirin use, and acetaldehyde-bound hemoglobin due to alcohol abuse.⁷
• Boronate Affinity methodology is essentially free from Hb variant interference and free from chemically-altered hemoglobin interference, leading to highly precise and accurate results.^2,7,8
• The possible long-term complications of diabetes include retinopathy, nephropathy, neuropathy, cardiovascular disease, cerebrovascular disease, gangrene and amputation, complications during pregnancy, and death.

Figure 1.
Global Prevalence of Diabetes

Diabetes is a worldwide epidemic today, affecting more than 200 million people—a number that is only expected to increase (see Figure 1). When considering a disease that is so globally prevalent and that has no cure, proper treatment becomes vitally important. In order to provide appropriate support to physicians’ efforts in maintaining good glycemic control in their patients, manufacturers and laboratories will want to provide the most precise and most accurate performance from their instruments and methodology.

Diabetes can be a particularly debilitating and life-threatening condition. From the 10-year Diabetes Complications Control Trials (DCCT)⁹, we know that intensive therapy and keeping HbA1c levels as near to normal as possible can reduce the development and/or the progression of long-term complications. For example, intensive therapy and good HbA1c control dramatically reduced both the development and/or the progression of the conditions described in Table 1.

Both manufacturers and laboratories have generally kept pace with the demand for improved precision. There is, however, still an urgent need for further improvement. This becomes clear when one considers that if a physician uses the American Diabetes Association (ADA) recommended cut-off point of 6.5% HbA1c to assist in the diagnosis of diabetes and the A1c method used has a 3.0% coefficient of variation, the possible error with 95.0% confidence could be as much as +/-0.4% A1c. The result reported could be anywhere between 6.1 and 6.9%. That is an enormous potential error when the results will be used to help determine how a patient is treated. As you check your current HbA1c method, you should ask the question: “What kind of precision can I expect from this method?”

An additional concern, and one of great importance, has to do with the influence of abnormal hemoglobin species that can provide significant interference to HbA1c test results. More than 1,000 known hemoglobinopathies have been described to date. While many of these may be rather rare, others, such as HbS, C, D and E, occur with considerable frequency. To provide a more specific example, HbS is estimated to occur in one of 500 individuals in the United States. Reports of significant interference providing false high or low HbA1c levels using ion-exchange or immunoassay methodologies have been described in several recent publications. Some of these reports cite interference from HbS, HbC, HbD or HbE using methods commonly used in clinical laboratories, including some high throughput chemistry analyzers.

Some of the specific characteristics of the HPLC Boronate Affinity method are as follows:

• It is highly precise.
• It is highly accurate.
• It is free from interference from chemically-modified hemoglobin.
• It is essentially free from interference from common hemoglobin variants.
• It has a rapid, two-minute injection-to-injection time, with a 59-second assay to be released soon.

Jim Noffsinger, PhD, is Vice President of Research and Development for the hemoglobin business unit of Trinity Biotech.

References

1. Wild,S, Roglic,G, Green,A, Sicree,R,King,H. Global Prevalence of Diabetes, Estimates for the year 2000 and projections for 2030. Diabetes Care 27(5):1047-1053.
2. Little, RR, Roberts, WL. A Review of Variant Hemoglobins Interfering with Hemoglobin A1c. J Diabetes Sci Technol. 2009 May; 3(3):446-451.
3. Roberts WL, De, BK, Brown, D, Handbury, MC, Hoyer, JD, John, WG, Lambert, TL, Lundell, RB, Rohlfing,C, Little, RR. Effects of Hemoglobin C and S Traits on Eight Glycohemoglobin Methods. Effects of Hemoglobin C and S Traits on Eight Glycohemoglobin Methods. Clin Chem 2002;48(2}:383-385.
4. Little, RR, Rohlfing, CL, Hanson, S, Connolly, S, Higgins, T, Weykamp,CW, D’Costa,M, Luzzi, V, Owen, WE, Roberts, WL. Effects of Hemoglobin (Hb) E and HbD, Traits on Measurements of Glycated Hb (HbA1c) by 23 Methods. Clin Chem 2008;54(8):1277-1282.
5. Roberts, WL, Frank,EL, Moulton,L, Papadea,C, Noffsinger, JK, Ou, CN. Effects of Nine Hemoglobin Variants on Five Glycohemoglobin Methods. Clin Chem 2000;46(4):569-572.
6. Tsai, LY, Tsai, SM, Lin, MN, Liu, SF. Effect of Hemoblobin Variants (Hb) J, Hb G, and Hb E on HbA1c Values as Measured by Cation-Exchange HPLC (Diamat). Clin Chem 2001;47(4):756-757.
7. Bry,L, Chen, PC, Sacks, DB. Effects of Hemoglobin Variants and Chemically Modified Derivatives on Assays for Glycohemoglobin. Clin Chem 2001;47(2);153-163.
8. Sacks,DB. Hemoglobin Variants and Hemoglobin A1c Analysis: Problem Solved? Clin Chem 2003;49(8):1245-1247.
9. Diabetes Control and Complications Trial Research Group. The effect of instnsive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329(14):977-986.
10. Roberts, WL, Safar-Pour,S, De,BK, Rohlfing,CL,Weykamp,CW, Liffle,RR, Effects of Hemoglobin C and S Traits on Glycohemoglobin Measurements by Eleven Methods. Clin Chem 2005;51(4):776-778.