FEATURE Haematology
Table 1. Advantages and Disadvantages of using HbA1c as a diagnostic test for diabetes
Disadvantages
Test more expensive than glucose Haemoglobin traits may interfere
Advantages No need for timed/fasting samples Better index of overall glycaemic exposure
States of altered erythrocyte turnover may interfere Less biological variability Certain races (African Americans) have higher levels Relatively unaffected by acute events Glucose assay less standardized
Less pre-analytical instability Currently used to guide and adjust therapy Test standardized to DCCT/UKPDS
Table 2. Differences between NGSP and IFCC methods NGSP
Based on a method (DCCT) Trials using HPLC
IFCC Based on the true method of standardization
True definition of the molecule and then established according to a reference method
May overestimate as substances may co-elute No interference or overestimation
nondiabetics and an ideal of 7% in well- controlled diabetics. Levels of 10-12% are indicative of poorly controlled diabetes mellitus. Up until recently, diabetes mellitus was diagnosed using either fasting blood glucose above 7 mmol/l or aq post glucose challenge level of ≥ 11.1 mmol/l. However, in 2009, the ADA International Expert Committee published new guidelines for the diagnosis of diabetes. They found a strong correlation between the common diabetic complication retinopathy and HbA1c, and found an HbA1c level of 6.5% predicted at least moderate retinopathy and could be used as a diagnostic cut-off for diabetes. Levels of 6-6.5% classified individuals at an increased risk of developing diabetes. Table 1 lists the advantages and disadvantages of using HbA1c instead of the traditional glucose results as a diagnostic test for diabetes mellitus.
HBA1CAND CARDIOVASCULAR RISK IN DIABETICS Several trials have shown an association between HbA1c levels and cardiovascular risk in diabetics. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) Trial examined patients with type 2 diabetes and found that they die of cardiovascular disease (CVD) at rates 2-4 times higher than nondiabetics. They found that each 1% increase in HbA1c was associated with an 18% increase in CVD. The Kumamoto trial
in Japan found the insulin-based intensive control of diabetics was associated with a decreased CVD event rate. The EPIC (European Prospective Investigation into Cancer)-Norfolk Trial found that every 1% increase in HbA1c was associated with a 24% increase in CVD risk and that HbA1c levels were found to be elevated well in advance to the clinical development of type 2 diabetes. But, the two most quoted trials that highlighted the importance of HbA1c as a predictor of risk in diabetics are the DCCT (Diabetes Control and Complications Trial) and the UKPDS (United Kingdom Prospective Diabetes Study) Trial. The former found that the relative risk of retinopathy or nephropathy in type 1 diabetics was reduced by 39% for each 10% relative decrease in HbA1c. The latter trial found that intensive glycaemic control as measured by HbA1c levels in type 2 diabetics’ reduced clinical outcomes. It was these two landmark trials that documented the benefit of tight glycaemic control as measured by HbA1c and improved clinical outcomes, which led to the standardization of the HbA1c assay.
“HbA1c is formed when haemoglobin A, the major component of adult haemoglobin, is modified by the covalent attachment of glucose to the amino terminus of the β-globin chain”
ASSAY STANDARDIZATION The goal of the laboratory is to provide information that is useful for clinical decision-making, but the foremost problem is lack of comparability of analytical results between laboratories. The many different analytical platforms using different methodologies contribute to this variability. Ideally, if two or more laboratories anywhere in the world tested the same patient specimen, equivalent values would be reported. Standardization refers to the process where assay manufacturers calibrate their instruments to certified reference materials and reference measurement procedures, leading to the transfer of measurement values from hierarchal levels to those available for routine use. Figure 1 shows the standardization procedure. Harmonization refers to the interim solution whilst waiting for the standardization procedure to be completed, where assays are recalibrated to give the same results, leading to comparable results.
HBA1C HARMONIZATION AND STANDARDIZATION In 1993, after the publication of the DCCT Trial, HbA1c was placed in the spotlight, HbA1c for the trial was determined using high performance liquid chromatography (HPLC), but there were many different methods being used to measure HbA1c other than HPLC. These were uncalibrated, had unacceptably large biases, had very high imprecision’s and some measured other fractions leading to over- or underestimation of levels. In short, the state of HbA1c assay standardization
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