The global prevalence of diabetes mellitus is increasing rapidly. Diabetes currently affects 246 million people worldwide and is expected to affect 380 million by 2025 . Measurement of glycated hemoglobin, predominantly HbA1c, is fundamental to the management of patients with diabetes. HbA1c is used to monitor long-term glycemic control, adjust therapy, assess the quality of diabetes care and predict the risk for the development of complications [2–4]. Accurate and reliable methods to measure HbA1c are necessary for optimal use.
Glycation of hemoglobin
Glycated hemoglobin is derived from the nonenzymatic addition of glucose to amino groups of hemoglobin. HbA1c is a specific glycated hemoglobin that results from the attachment of glucose to the N-terminal valine of the hemoglobin β-chain . Total glycated hemoglobin includes all glycated fractions, comprising HbA1c as well as hemoglobin glycated at sites other than the N-terminus of the beta chain e.g., epsilon amino groups on lysine residues. The concentration of HbA1c depends on both the concentration of glucose in the blood and the life span of the erythrocyte. Because erythrocytes are in the circulation for approximately 120 days, HbA1c represents the integrated glucose concentration over the preceding 8–12 weeks . It is, therefore, free of the large fluctuations that occur daily in blood glucose concentrations.
Measurement of HbA1c
The existence of several forms of hemoglobin has been known for over 50 years and ‘an unusual hemoglobin’ was described in patients with diabetes in 1969 . Numerous assays were subsequently developed to measure glycated hemoglobins. The principle of all methods is to separate the glycated and nonglycated forms of hemoglobin. This can be accomplished based on differences in charge (usually by HPLC) or structure (usually immunoassays or boronate affinity chromatography). There was minimal assay standardization initially and results varied widely among methods . Programs were developed in the 1990s in a few countries, most notably Sweden, Japan and the USA, to standardize HbA1c measurements .
The most widely adopted system is that of the National Glycohemoglobin Standardization Program (NGSP), which standardizes glycated hemoglobin test results so that values reported by clinical laboratories are comparable to those reported in the two largest clinical trials on the effects of intensive diabetes treatment, namely the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) . NGSP-certified methods are used worldwide. The NGSP standardization process has significantly reduced the variation in glycated hemoglobin measurement among laboratories . Despite the considerable improvement, intermethod variability is reported to still be a potential source of inaccuracy . Efforts to further enhance the accuracy of HbA1c measurements are being actively pursued .
The International Federation for Clinical Chemistry (IFCC) developed a reference method for measuring HbA1c. An N-terminal hexapeptide is cleaved from the β-chain of hemoglobin by the enzyme endoproteinase Glu-C. Glycated and nonglycated hexapeptides are separated from one another by high performance liquid chromatography and separately quantified by either mass spectrometry or capillary electrophoresis. The IFCC reference system produces values that are 1.5–2.0% absolute HbA1c units lower than those measured by the NGSP , presumably due to the greater specificity of the IFCC method. A network of 13 reference laboratories has been established to form an IFCC reference system [12•]. The main function of the IFCC system is to serve as an ‘anchor’ for HbA1c and allow manufacturers to calibrate their instruments to a higher level reference method. The IFCC method is time consuming, technically complex and carries higher cost, thus is not designed to be used for routine analysis of patient samples.
How is HbA1c reported?
HbA1c is usually reported as a percentage of total hemoglobin. The NGSP values, which are equivalent to those reported in the DCCT and UKPDS, have been used most widely. This enables a patient's results to be directly compared with those clinical outcomes studies. To avoid confusion with the widely used NGSP/DCCT/UKPDS units and to conform with Systeme International (SI) Units, IFCC numbers are now reported as mmol/mol [13•,14]. For example, an HbA1c result of 7% (in NGSP/DCCT/UKPDS units) is equivalent to 53 mmol/mol (in IFCC units). A consensus paper on worldwide standardization of HbA1c[15•] recommends that HbA1c values be reported in IFCC (mmol/mol) and NGSP (%) units, as well as average glucose. Although a uniform system for reporting HbA1c is desirable, it is likely that different formats will be adopted in different countries.
As mentioned earlier, HbA1c reflects blood glucose concentrations over the preceding 8–12 weeks and is commonly used as an indication of average blood glucose concentration. Retrospective analysis of data in the DCCT indicates a linear correlation between HbA1c and average glucose . However, the DCCT was limited to patients with type 1 diabetes and was not designed to measure average glucose. A multinational study (termed A1c Derived Average Glucose or ADAG) was recently performed to ascertain the relationship between HbA1c concentrations and long-term glucose values [17••]. The 507 study participants comprised patients with type 1 or type 2 diabetes as well as nondiabetic individuals. Broad ethnic and racial representation was obtained by recruiting individuals at 10 centers in the USA, Europe, Africa and Asia. To evaluate average glucose, participants performed a combination of continuous glucose monitoring and regular self-monitoring of blood glucose using portable meters. Over the course of the 12-week study, each participant had approximately 2700 glucose measurements. Comparison of HbA1c and average glucose results reveals a linear correlation [AGmg/dl = 28.7 × Hb A1c – 46.7 (AGmmol/l = 1.59 × Hb A1c – 2.59)] [17••]. For example, an HbA1c value of 6% (42 mmol/mol) (equivalent to the upper limit of the reference interval) translates into average glucose of 126 mg/dl (7.0 mmol/l). The regression equation produces values approximately 11% lower than those obtained from the DCCT, perhaps because average glucose was measured more accurately in the ADAG study. A smaller study (22 participants) that included continuous glucose monitoring for 3 months derived a relationship similar to that in the ADAG study .
The ADAG study has some limitations. For example, the average glucose varies among individuals with the same HbA1c concentration. Several factors could account for the scatter. These include measurement error, interindividual variation, differences in glycation or differences in red cell turnover rates. In addition, the study enrolled only diabetic patients with stable glycemic control, few Asians and no children or pregnant women. Notwithstanding these limitations, the regression equation can be used to calculate an eAG (estimated average glucose) based on the HbA1c result. This eAG value would not replace the measured HbA1c concentration, which would still be reported, but could be provided in addition to the HbA1c. The eAG, reported in familiar glucose units (i.e., mg/dl or mmol/l), could be used to help patients understand the meaning of HbA1c and how to use it appropriately to improve their glycemic control. This postulate is supported by the demonstration that improving patients' knowledge of the relationship between HbA1c and average glucose improves glycemic control . However, the concept of expressing HbA1c in terms of average glucose is not accepted by all and remains controversial [20–22].
Limitations of HbA1c testing
For the vast majority of patients with diabetes, HbA1c provides an excellent measure of glycemic control. However, there are situations where HbA1c may be unreliable. These include any condition that alters the erythrocyte life span (e.g., hemolytic anemia), severe iron-deficiency anemia, and certain hemoglobin variants or adducts, or recent red blood cell transfusions. Factors such as race or age are also reported to influence HbA1c.
The intraindividual variation of HbA1c in nondiabetic individuals is very low (<2%) [23,24], but substantial interindividual (between individuals) variation occurs. Moreover, there are published reports of diabetic individuals who appear to have HbA1c values that are higher or lower than expected based on their clinical presentation, blood glucose results, glycated plasma proteins (e.g., fructosamine), or home glucose monitoring data [25•,26]. Since obtaining accurate mean blood glucose (MBG) is problematic, it has been difficult to determine the cause(s) of these discrepancies and to verify that these differences are independent of MBG. This disparity between HbA1c and other measures of glycemia, termed the ‘glycation gap’ or ‘hemoglobin glycation index’, has a genetic component [25•]. Some authors have proposed a theory of high and low glycators [25•,26], whereby individuals with the same MBG may have different HbA1c concentrations. However, there is currently no reliable way to directly measure glycation rates in vivo and the hypothesis of different glycation rates is not substantiated by data.
Differences in erythrocyte life span might account for some of these disparities. Although the ‘average’ erythrocyte life span is 120 days, there is a range of values among individuals. For example, a recent study in a very small group of individuals (n = 12) showed that erythrocyte survival varies sufficiently among ‘hematologically normal’ people to cause clinically important differences in HbA1c; this would infer variability in HbA1c that is not related to glycemic control. Notwithstanding these observations, long-term clinical outcomes studies have clearly demonstrated very strong correlations between HbA1c concentrations and risks for complications in patients with diabetes [28,29]. Moreover, HbA1c predicts risk of cardiovascular disease even within the ‘normal’ HbA1c range . Therefore, although parameters independent of glycemia may influence the variability of HbA1c, these appear to be much less clinically significant than the impact of glycation on diabetes complications.
Race might influence HbA1c. Statistically significant differences in HbA1c concentrations among races have been reported in those with diabetes [31–33], even after adjustment for covariates such as quality of care. For example, in the TRIAD study, Latinos, Asians, and African–Americans had absolute HbA1c values 0.4, 0.4, and 0.2%, respectively, higher than whites . Although these studies adjusted for factors likely to affect glycemia, one cannot exclude the possibility that the differences among these populations may be due to differences in glycemic control. Herman et al.[34•] analyzed a cohort of adults with impaired glucose tolerance and identified differences in HbA1c among different racial groups. Racial differences in HbA1c have also been observed in nondiabetic populations [35,36], which suggest that there are heritable variations in HbA1c. The underlying mechanism is not known. Possibilities include differences in rates of glucose entry into erythrocytes, rates of glucose attachment to or release from hemoglobin, or erythrocyte survival. Regardless of the cause, the variations in HbA1c found among racial/ethnic groups are relatively small (≤0.4% HbA1c) and may not be clinically significant.
HbA1c increases with age by approximately 0.03% per year in nondiabetic individuals [37•,38]. Some conclude that the increase in HbA1c independent of the well documented decline in glucose tolerance with age is minimal . The small increase is unlikely to necessitate a change in treatment goals for different age groups.
Factors that interfere with the measurement of HbA1c
Hemoglobin variants affect some HbA1c measurements. The most common variants worldwide (in descending order of prevalence) are HbS, HbE, HbC and HbD. (In the USA, HbC is more common than HbE.) In addition, HbF may be increased in some conditions (e.g., leukemia, anemia) or hereditary persistence of fetal hemoglobin . No HbA1c method is appropriate for assessment of glycemic control in patients homozygous for HbS or HbC, with HbSC disease, or with any other condition that alters erythrocyte survival. Generally, individuals heterozygous for hemoglobin variants do not have shortened erythrocyte survival and HbA1c can be measured accurately if an appropriate assay method is used. Several publications have analyzed the effects of these hemoglobins on HbA1c results [41•–43•] (reviewed in ). The published findings are summarized in Table 1 and on the NGSP website (http://www.ngsp.org). The interferences are usually method specific. In general, HbAS and HbAC interfere with some immunoassays, whereas HbAE and HbAD interfere with some HLPC methods (Table 1). If an HPLC method is used, careful inspection of chromatograms usually reveals aberrant peaks produced by the variants, enabling detection of unacceptable results. As with any test, results that contradict the clinical picture should be investigated further.
Factors that affect the interpretation of HbA1c results
Iron deficiency anemia, a major public health problem in developing countries, is associated with higher HbA1c and higher fructosamine concentrations . Consistent with these observations, iron replacement therapy lowers both HbA1c and fructosamine concentrations in diabetic and nondiabetic individuals [40,45,46]. Similarly, HbA1c, but not glycated albumin, is increased in late pregnancy in nondiabetic individuals owing to iron deficiency [47•]. Insight into the mechanism was recently obtained by the observation that malondialdehyde, which is increased in patients with iron deficiency anemia , enhances the glycation of hemoglobin . Alternative measures of glycemic assessment (e.g., glucose monitoring) must be used in the presence of significant iron deficiency anemia, at least until the iron deficiency has been successfully treated.
Chronic renal failure develops in many diabetic patients. Almost half of all individuals with end stage renal disease in the USA have diabetes . The role of glycemic control and the value of HbA1c in diabetic individuals with renal disease are controversial. Although some studies detect no correlation between HbA1c and survival in dialysis patients [50,51], others observe that higher HbA1c is incrementally associated with increased risk of death in diabetic patients undergoing maintenance hemodialysis . Lower HbA1c is associated with improved survival in these patients, provided the decreased HbA1c does not result from malnutrition or anemia , suggesting that better glycemic control is important for this population. A recent report suggests HbA1c underestimates glycemic control in diabetic patients on dialysis and that glycated albumin is a more robust indicator of glycemic control [53•]. Further studies are needed to clarify the role of HbA1c in diabetic patients with chronic renal failure.
HbA1c for screening and diagnosis of diabetes
It is estimated that 25% of people with diabetes in the USA have not been diagnosed . Moreover, at the time of diagnosis, 25% of patients have diabetic retinopathy or microalbuminuria . Earlier diagnosis of diabetes could prevent or delay these complications.
The use of HbA1c for screening and diagnosis of diabetes has been debated extensively for over 25 years [16,56–58]. Advantages and disadvantages for HbA1c are listed in Table 2. A review of the literature (published in 2007) concluded that HbA1c is as effective a screen as fasting plasma glucose for the detection of type 2 diabetes [59••]. A committee of experts recently recommended that HbA1c be incorporated into criteria for screening and diagnosis of diabetes [60••]. The panel suggested that HbA1c, at least 6.5%, would be diagnostic of diabetes if confirmed by an increased blood glucose value. Moreover, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) have established a joint committee to reevaluate the diagnosis of diabetes; HbA1c is under consideration (David Nathan, personal communication). Appropriate cutoffs would have to be established and it is possible that thresholds for screening and diagnosis could differ [60••]. Nevertheless, it seems likely that HbA1c will soon be recommended as a screening/diagnostic test for diabetes.
HbA1c measurement is integral to the management of individuals with diabetes. Both the variability among methods that measure HbA1c and the interference produced by variant hemoglobins have been significantly reduced. Ongoing efforts are being directed towards further improving the accuracy of HbA1c measurement. This progress may enable HbA1c to be used for screening and diagnosis of diabetes.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 192–193).
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