Figure 1: The reference measurement system for standardization
Primary reference material
(pure substance)
Reference procedure (reference laboratory)
was in disarray. Separate standardization programs were implemented in Japan, Sweden, USA and by the International Federation of Clinical Chemistry (IFCC). The National Glycohemoglobin Standardization Program (NGSP) was formed in 1996 to standardize HbA1c test results so that the results reported were comparable to those reported in the DCCT and UKPDS trials. Laboratories needed to submit to the proficiency program conducted by the NGSP and in 2007 a College of American Pathologists (CAP) survey found that 99% of all laboratories used an NGSP-certified method. This harmonization process significantly reduced the interlaboratory variation, but the method was still not truly standardized. In 1995, the IFCC HbA1c working
group was established with the objective of standardizing the HbA1c assay by defining the actual molecule and establishing a true reference method according to standardization guidelines. The analyte was defined as an adduct of glucose to the N-terminal amino group of
Secondary reference material (analyte in human serum)
the β-chain of HbA0 and renamed N-[1- deoxyfructosyl] Hb. The reference method was HPLC-MS/HPLC-CE. Table 2 shows the difference between the NGSP and IFCC methods of HbA1c determination. However, there was now a clear
problem: IFCC measurements read 1.5-2% lower, which will be potentially confusing to patients and clinicians and may lead to deterioration of glycaemic control. In 2007, a Consensus Document was issued by various organizations that stated that the IFCC method was the only valid anchor to implement HbA1c standardization and that results should be reported in SI units mmol/mol (mmol HbA1c/mol total Hb). However, whilst awaiting the results of a further study, the ADAG (A1C Derived Average Glucose) Trial, values would be reported using both units with a master equation to relate these 2 values.
The purpose of the ADAG study was to establish the feasibility of expressing HbA1c as mean blood glucose. It was a multinational study examining 507 well- controlled type 1 and 2 diabetics and normal controls. HbA1c was determined using both DCCT and IFCC-
methods at baseline and then at monthly
visits. Continuous monitoring of blood glucose (CMBG) was performed within a 48-hour period at 4,8 and 12 weeks and self-monitoring of blood glucose (SMBG) was performed, giving a total of 2700 glucose measurements per patient and more than 1 million glucose results in total. The
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www.lifesciencesmagazines.com Calibration of routine methods
Measurement of clinical samples by commercial assays
HbA1c values were then compared to the weighted results of CMBG and SMBG and a linear regression model established a relationship between these parameters. The conclusion of this study was that HbA1c can be expressed as estimated average glucose (eAG) for most patients with type 1 or 2 diabetes.
CONCLUSION With the advances in assay standardization, HbA1c can now be used as not only an indicator of glycaemic control, but also as a diagnostic tool, provided a well-standardized reproducible assay is used and the erythrocyte lifespan is normal. Two dilemmas now exist: which HbA1c should be reported? Should eAG be reported with HbA1c? It is recommended that laboratories use NGSP-certified assay methods and that they participate in proficiency testing programs. HbA1c assay manufacturers need to show traceability to the IFCC reference method. The ADA and the American Association of Clinical Chemistry (AACC) advocated the reporting of eAG as well as HbA1c, but as of July 2010 this was no longer recommended. The Association of Clinical Biochemists recommended the reporting of both IFCC and NGSP HbA1c values with IFCC only from July 2011. However, due to clinician and patient confusion, this transition has been postponed until October 2011. At present, each country has their own guidelines for how to report HbA1c until a practical international consensus is reached. ■
ML LEARN MORE
The Haematology track at the Medlab Congress takes place on January 26th
2012
as part of the Arab Health Exhibition & Conference in Dubai. The exhibition is the largest healthcare event in the region and takes over the Dubai World Trade Centre for four days, 23-26th
January. For more
information about the Medlab Congress and all the tracks, visit the wesbite
www.arabhealthonline.com and click on the Medlab tab.
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