Bruce Campbell

GLYCATED haemoglobin, specifically HbA_1c, long used to monitor control of diabetes, has also recently been approved as a diagnostic test for diabetes in asymptomatic patients at high risk.

HbA_1c usually works well in monitoring the management of diabetes since HbA_1c levels in the plasma reflect the average blood glucose levels over the past several months in most patients. However, practitioners need to be aware that HbA_1c levels do not always reflect average blood glucose levels in some patients and this can be a trap.

While guidelines such as those produced by the RACGP give a good description of the potential problems with HbA_1c, it is very easy to forget this when confronted with a patient who seems completely well except for possibly elevated blood glucose levels.

Two examples of patients where HbA_1c measurements gave misleading results illustrate the need to sometimes consider uncommon problems. In one of these cases none of the doctors involved detected the problem over a period of more than 20 years!
    
Case 1

In a case we recently reported in Pathology, a middle-aged man was given a diagnosis of diabetes after he experienced symptoms and had several elevated blood glucose levels measured in the laboratory.

He was started on dietary management and medication. HbA_1c measurements were commenced and were always in the normal range, so his medications were ceased. However, the patient continued home blood glucose monitoring and these measurements usually showed elevated levels. These home blood glucose results over a period of many years were dismissed by a series of doctors, both GPs and specialists, because of his “good” HbA_1c results and otherwise normal pathology test results.

Eventually, one doctor became suspicious and investigated further, demonstrating that the patient had a low-grade haemolytic anaemia that was lowering his HbA_1c levels because of the shortened red cell lifespan. Serum fructosamine levels were elevated and HbA_1c testing was abandoned as inappropriate for this particular patient.

Case 2

The second patient* was again a middle-aged male with repeatedly elevated blood glucose levels but with a normal HbA_1c. Other routine biochemistry tests were normal. Because his blood glucose results were consistently high he was referred to a diabetes educator and dietitian.

Home blood glucose monitoring was started and this showed lower but still elevated blood glucose levels. A repeat HbA_1c 3 months after the initial test was again normal.

In this case the discrepancy was investigated earlier than in Case 1. Haematological investigations showed the presence of haemoglobin C disease, which is associated with shortened red cell survival and thus falsely low HbA_1c levels.

Again, HbA_1c testing was abandoned as being not suitable for this particular patient.

As with many other things in medicine, it pays to have a high index of suspicion where there are discrepancies in the expected pattern of results or clinical findings. The section on glycaemic monitoring and control in the 2014–2015 RACGP clinical guidelines describes these and other potential problems with HbA_1c measurements.

There are a variety of methods in use to measure HbA_1c in pathology laboratories. They do not all respond in the same manner to different haemoglobinopathies.

Depending on the type of abnormal haemoglobin present in the patient sample, some may show falsely low or high HbA_1c levels. However, if the red blood cell (RBC) survival is shortened for any reason, HbA_1c levels will be lower than expected because in vivo glycosylation is a slow process and haemoglobin in young RBCs is always less glycosylated than in older RBCs.

There is also potential for pathology laboratories to do more to assist doctors. For example, by calculating and reporting an estimated average glucose (eAG) as a comparator with measured blood glucose, or by detecting and flagging discrepancies between concurrent serum glucose and HbA_1c levels, and even scanning other available results for clues as to the cause.

Laboratories may be reluctant to do this because it is an uncommon problem and doctors are already burdened with the volume of data from investigations.

For best patient care, we would advise doctors to not rely blindly on the HbA_1c test result being “always” correct. If the “pattern” of results does not look right, be alert to the possibility of shortened RBC lifespan as a possible explanation for discrepancies between glucose and HbA_1c levels.

 

Dr Bruce Campbell is the Editor-in-Chief of Lab Tests Online Australasia and a retired chemical pathologist.
Professor Leslie Burnett is past chair of the board of directors of Lab Tests Online Australasia, and clinical professor in pathology and genetic medicine, University of Sydney.

* Thanks to Dr Mona Botros, chemical pathology registrar, for identifying the second case.