Glycated haemoglobin (HbA1c) has been used for monitoring patients with established diabetes for many years but its diagnostic application is a more recent development. This article provides some background to the test, explains dual reporting of results and discusses the use of HbA1c in the diagnosis and monitoring of diabetes.

What is HbA1c?

Adult haemoglobin is predominantly (97% of total) HbA. HbA1c is formed when a glucose molecule non-enzymatically attaches to the N-terminal valine of the β-chain of HbA. The amount of HbA1c formed is directly proportional to the average plasma glucose concentration during the 120-day life span of the erythrocyte, with recent plasma glucose contributing more than earlier concentrations. HbA1c is therefore a reflection of the average glycaemia over roughly the preceding 6–8 weeks and has a vital role in assessing the risk of an individual developing the complications of diabetes.¹

HbA1c for the diagnosis of diabetes mellitus

A 2012 position statement of the Australian Diabetes Society, the Royal College of Pathologists of Australasia (RCPA) and the Australasian Association of Clinical Biochemists (AACB)² contains the following:

• HbA1c levels ≥6.5% (≥48 mmol/mol) are acceptable for diagnosing diabetes so long as the test is done in a laboratory and no conditions exist which preclude its accuracy.
• In an asymptomatic patient with a positive result, the test should be repeated to confirm the diagnosis.
• The existing criteria based on fasting and random glucose levels and on the oral glucose tolerance test remain valid and are the diagnostic tests of choice for gestational diabetes, type 1 diabetes and in the presence of conditions that interfere with HbA1c measurement.

The use of HbA1c simplifies the diagnostic process and may facilitate the detection of diabetes diagnosis. The test can be performed at any time of the day, does not require special pre-test preparation, such as a diet or fasting, and is stable when collected in the appropriate specimen tube. Testing should be restricted to patients at high risk of undiagnosed diabetes and who are asymptomatic.³ If one or more symptoms suggestive of diabetes are present in a low-risk patient, blood glucose tests should be used, because patients with rapidly evolving diabetes can have normal HbA1c. HbA1c <6.5% (<48mmol/mol) indicates that diabetes is unlikely but (since the patient is high-risk) the test should be repeated in 12 months. Patients should be given appropriate lifestyle advice and other modifiable cardiovascular risk factors should be assessed.³ There is uncertainty about the use of HbA1c to diagnose prediabetes. While patients with HbA1c above normal but below 6.5% (48 mmol/mol) are more likely to develop diabetes than is suggested by their AUSDRISK score alone, they have minimal risk of developing microvascular complications. Management is the same as for those at high risk of type 2 diabetes with HbA1c within the normal range.³ HbA1c ≥6.5% (≥48 mmol/mol) should be confirmed by another test (glucose or repeat HbA1c). Repeat HbA1c should be performed on a different day but as soon as possible, before any lifestyle or pharmacological interventions are initiated.³ It is important that clinicians state clearly the indication for the test when requesting HbA1c testing, with wording such as ‘diabetes monitoring’ or ‘diabetes screening’. This will allow the correct Medicare item number and interpretative comments to be used.

Individualisation of HbA1c treatment targets

In monitoring patients with established diabetes, the general target is ≤7.0% (≤53 mmol/mol). Individualisation of target HbA1c, taking into account patient-specific factors, such as type of diabetes and its duration, pregnancy, diabetes medication used, existing cardiovascular disease, risk of hypoglycaemia and comorbidities, may modify the target range from ≤6.0% (≤42 mmol/mol) to ≤8.0%(≤64 mmol/mol).⁴

Dual reporting of HbA1c

There are many assays for measuring HbA1c. For many years, the NGSP in the US and other national and regional programs harmonised HbA1c methods. This allowed valid, interlaboratory comparison of results. The NGSP uses percentage (%) units. The IFCC standardised glycated haemoglobin measurement by making it traceable to an international standard.⁵ The IFCC uses mmol/mol (mmol HbA1c per mol total Hb). The improved specificity of IFCC-HbA1c is reflected in results which are consistently 1.5%–2.0% lower than NGSP values.¹ A 2007 consensus statement from the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), IFCC and International Diabetes Federation (IDF) was adopted and implemented by Australasian laboratories.⁵ It recommended that HbA1c results be reported in both IFCC units (mmol/mol) and derived NGSP units (%) to allow clinicians to become familiar with IFCC results before reporting of NGSP % units is withdrawn. Currently, there is no agreement on when dual reporting will cease and hence HbA1c results are still reported with two units.

Conditions affecting HbA1c results

As HbA1c is simply haemoglobin with the addition of a glucose molecule, conditions that affect red blood cells or their survival time, such as haemoglobinopathies or anaemia, will affect the HbA1c result.³ Patients with abnormal haemoglobins may form other glycated products which may form at different rates to that of normal haemoglobin. Haemolytic anaemia can reduce HbA1c by decreasing red cell survival, leading to reduction in the availability of haemoglobin for glycation. This occurs with autoimmune haemolytic anaemia, haemoglobinopathies and chronic renal failure. Any drugs that give rise to haemolytic anaemia will have the same effect. Red cell survival time is also reduced in severe liver disease, anaemia of chronic disease, vitamin B12 and folic acid deficiencies, and regular phlebotomy. Interestingly, iron deficiency anaemia can increase HbA1c by up to 2%.¹ There are alternative ways of monitoring diabetes treatment in these patients, including the use of closer glucose monitoring and fructosamine testing. Any discordance between glucose and HbA1c levels should alert the clinician so that other testing options should be considered.

Key points

When requesting HbA1c it is vital that the clinician specify clearly the indication for the test, for example, ‘diabetes monitoring’ or ‘diabetes screening’.

• HbA1c ≥6.5% (≥48 mmol/mol) can be used to diagnose diabetes in asymptomatic, high-risk patients. HbA1c ≥6.5% should be confirmed with glucose or another HbA1c performed on a different day but as soon as possible, before any intervention has commenced.
• The recommended treatment target is HbA1c ≤7.0% (≤53 mmol/mol). Treatment targets may need to be individualised to between ≤6.0% (≤42 mmol/mol) to ≤8.0% (≤64 mmol/ mol), depending on patient-specific factors, such as type and duration of diabetes and risk of hypoglycaemia.
• Currently, HbA1c is reported in both National Glycohemoglobin Standardization Program (NGSP) units (%) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) units (mmol/mol), with the aim of eventually reporting in IFCC units only.
• A number of medical conditions affect HbA1c results and preclude its use in both monitoring and diagnosis of diabetes mellitus.

References

1. Kilpatrick ES. Haemoglobin A1c in the diagnosis and monitoring of diabetes mellitus. J Clin Pathol 2008;61(9):977-982
2. d’Emdem MC. et al. The role of HbA1c in the diagnosis of diabetes mellitus in Australia. MJA 2012;197(4):1-3
3. d’Emdem MC. et al. Guidance concerning the use of glycated haemoglobin (HbA1c) for the diagnosis of diabetes mellitus – A position statement of the Australian Diabetes Society. MJA 2015;203(2):89-91
4. Cheung NW. et al. Position statement of the Australian Diabetes Society: individualisation of glycated haemoglobin targets for adults with diabetes mellitus. MJA 2009;191(6):339-344
5. Jones G. et al. Consensus Statement on the Worldwide Standardisation of the Haemoglobin A1c Measurement – An Australasian Update. The Clinical Biochemist Newsletter 2008;14-18. Available online: https://www.aacb.asn.au/documents/item/1213

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General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.