The need to identify haemoglobinopathies when using HbA1c as a diagnostic test
The Haemoglobin A1c (HbA1c) test is a blood test which is commonly used to help diagnose and monitor people with diabetes. Although the test is formally endorsed in many countries as a form of diagnosing and monitoring type 2 diabetes, there remains some debate regarding its applicability for diagnosis. We spoke with Associate Professor Chris Florkowski to discuss the cautions and caveats regarding using HbA1c as a diagnostic test.
“Haemoglobin is the protein in red blood cells which carries oxygen throughout your body. HbA1c is the term used to describe haemoglobin which is joined together with glucose, specifically at one particular site; the N-terminal valine of the beta chain. HbA1c gives a measure of what the average blood glucose level has been in the previous 2-3 months, reflecting the life span of the red blood cell,” said A/Prof Florkowski.
The HbA1c test is useful in both diagnosis and monitoring the quality of glucose control in diabetes, and also assists in making treatment decisions such as adjusting insulin doses. For those people without diabetes, normal HbA1c is between 4% and 5.6%. HbA1c levels of 6.5% or higher are seen in those people with diabetes.
“HbA1C testing offers a number of advantages over other diagnostic tests for type 2 diabetes such as a glucose test. The HbA1c test is a single blood test which does not require any particular preparation such as fasting, which is required prior to a glucose test or an oral glucose tolerance test, which has until recently been the preferred way of diagnosing diabetes. HbA1c also gives a stable reading and is not subject to the short-term variations that are seen with blood glucose. The diagnostic cut-offs relate to clinical outcomes, namely the risk of developing complications,” said A/Prof Florkowski.
Laboratory methods for HbA1c are accurate and precise. In Australia, a HbA1c level of 48 mmol/mol (6.5%) is endorsed as the cut-off for diagnosing diabetes in asymptomatic individuals at high risk of diabetes. In New Zealand, the adoption of HbA1c as a diagnostic test was coordinated with the adoption of exclusively molar units with the higher diagnostic cut-off rounded up to ≥50 mmol/mol (≥6.7%), and with repeat testing on a second occasion in individuals without symptoms.
“In New Zealand, part of the rationale for the rounded cut-off for HbA1c was to make the molar units more memorable, although also to maximise the specificity for the diagnosis of diabetes. It may be argued that some cases of diabetes (maybe 20-30%) will be ‘missed’ by using a higher cut-off, although such individuals will usually have HbA1c close to the cut-off (41–49 mmol/mol), will be re-tested in 6–12 months and enter a lifestyle programme,” said A/Prof Florkowski.
In conditions where the life span of the red blood cell is shortened, such as in regular blood donors, the HbA1c will be lowered and therefore will not accurately reflect underlying glucose control. HbA1c can also be confounded by the presence of haemoglobin variants due to their effects on red cell survival and/or analytical interference with the laboratory method. In these cases, a HbA1c test may also reveal haemoglobinopathies. Dr Helen Moore, haematologist at Waikato District Health Board, explains that further tests may be required if haemoglobinopathy is suspected.
“Haemoglobinopathy encompasses all genetic diseases of haemoglobin and is among the most common inherited diseases in the world. The condition falls into two main groups; thalassemia syndromes and structural haemoglobin variants, however the terms are often used interchangeably. We often pick up haemoglobinopathies incidentally, for example in young women who may not have had a Complete Blood Count (CBC) done before, we may pick them up during pregnancy.”
“A HbA1c test will often pick up an abnormal haemoglobin peak, however it won’t tell you what it is. What we would do then is look at the patient’s ethnicity, look at their blood parameters and then, particularly if they are pregnant, we would then do a haemoglobinopathy screen to try and determine if this is something that is significant or not,” said Dr Moore.
Patients may be known to have a haemoglobin variant. The laboratory may suspect a haemoglobin variant by detecting an abnormal chromatogram when measuring HbA1c by certain methods or clinicians may suspect a variant through results that are discordantly high or low compared with prevailing blood glucose results. In these situations, the laboratory can investigate further with haemoglobin electrophoresis, mass spectrometry or DNA based diagnostic tests. In many situations, however a variant may be present without any significant effect on the HbA1c result.
Increasingly, with the adoption of HbA1c as a diagnostic test, accurate results are vitally important and awareness of possible confounding factors such as haemoglobin variants has increased. Hence the recognition of such variants appears to be gaining in pace.
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This article appeared in the July 2019 Edition of ePathWay which is an online magazine produced by the Royal College of Pathologists of Australasia (http://www.rcpa.edu.au/Library/Publications/ePathway).
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