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Monday, May 1st,
The methods currently used to estimate glycated hemoglobin do not recognise
hemoglobin variants resulting in very low glycated hemoglobin values.
A new Brazilian study published in
the latest edition of Journal of Clinical Pathology shed new lights on
the accuracy of interpreting glycated hemoglobin levels in a
The glycated hemoglobin test (often
called the glycosylated hemoglobin test) or hemoglobin (A1C) is a
measurement of the overall control of the diabetic for the previous
two to three months. Most diabetic specialists feel it is now the
single most important blood test for known diabetics. The American
Diabetes Association recommends that if you are a diabetic, this test
be taken every 3 months and values should be maintained below 7% to
prevent and/or decrease the risk of chronic complications.
The fasting blood sugar (FBS) test,
which is still the mostly commonly performed test for Diabetes, does
not reflect the true picture of diabetic control over a long period of
time. The FBS only measures the level of sugar in the blood at the
moment it is taken from your finger or arm.
How it works
The glycated hemoglobin test was
introduced as a routine test in the late 1970s and early 1980s. It
measures how much glucose is attached to hemoglobin cells, the part of
the blood that carries oxygen. As the hemoglobin floats around in the
blood, it picks up glucose in about the same proportion as the glucose
that exists in the bloodstream. If your blood glucose is generally
running high, the hemoglobin will have more "glucose coating" (glycosylization).
If your glucose generally runs low, it will have less. Since the red
blood cells have about a two to three month life span in the body
before they are recycled, we can measure the "glucose coating" of a
sample of hemoglobin. This gives you an approximate average of glucose
control over the last two to three month period.
Every person, whether or not he or she
has diabetes, has a certain amount of glycosylization present. Because
of more sugar in their blood, people with diabetes have a greater
amount of glycosylization present. A low result on the glycated
hemoglobin test is a good result. If your test is in the good control
category, you can be satisfied that your diabetes management plan is
working well. If results are in the marginal category, some fine
tuning of your treatment plan may be needed. A poor result can be
improved. This test gives you valuable feedback on how well you are
controlling your diabetes. It can also let you know when to work on
improving your diabetes management.
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Glycated hemoglobin is formed in vivo
by a reaction between glucose and the N-terminal region of haemoglobin
(Hb) or ?chains. This irreversible non-enzymatic reaction between
glucose and haemoglobin A, the main type of hemoglobin in normal
adults, occurs over the life span of the erythrocyte. The resulting
HbA1c (glycated haemoglobin) is a stable glycated hemoglobin
containing primarily glycated N-terminal chains, and its total amount
depends directly on the average glucose concentration over the two to
three months before the measurement.
The clinical usefulness of the test
was supported especially by two major trials: Diabetes Control and
Complications Trial (DCCT) in type 1 diabetes4 and the United Kingdom
Prospective Diabetes Study (UKPDS) in type 2 diabetes. These trials
showed that improved glycaemic control, as assessed by HbA1c, could
lead to substantial reductions in the risk of developing the
microvascular complication of diabetes such as retinopathy,
nephropathy, and neuropathy. The UKPDS trial findings also suggested
that the risk of myocardial infarction (the main cause of premature
death in diabetes) could be improved by reducing HbA1c values.
Limitations of glycated hemoglobin
Several limitations have been known to
interpreting glycemic control with glycated hemoglobin. The presence
of hemoglobin variants may falsely lower glycated hemoglobin values.
The prevalence of the most common hemoglobin variants (HbS, HbC, and
HbD) depends on the genetic background of the population being
analyzed. Although relatively rare in white individuals, these
variants are common in populations with heterogeneous ethnic
backgrounds. In such populations, misleadingly low glycated hemoglobin
values have been identified by some methods, but not by others.
addition, several other factors besides the presence of genetic
variants or chemically modified derivatives of haemoglobin, such as
drugs, anaemia, uraemia, and alcoholism, may falsely lower glycated
hemoglobin results. Nevertheless, the impact of the effects of these
interferences in routine clinical practice has not yet been well
Evidence of the usefulness of glycated
hemoglobin in preventing diabetic complications stems mainly from the
two studies mentioned above. This creates further limitations; namely,
how applicable are findings from these studies to patients from parts
of the world outside the USA and the UK where these studies were
To address these limitations a study
was performed by Camargo and Gross and published in the latest issue
of Journal of Clinical Pathology. They investigated the causes of spuriously low HbA1c values in their Brazilian patients with
From August 1996 to December 2001, 29 657 samples from patients with
diabetes attending the outpatient diabetic clinic at Hospital de
Cl?icas de Porto Alegre, Brazil, were collected for glycated
hemoglobin determination. The study population were classified as white, 8.4% as mulatto, 4.0% as
black, and 0.9% as native, yellow, or not defined. They found that the presence of haemoglobin variants and
undiagnosed anaemia accounted for most of these cases. The
cosmopolitan nature of their population (in comparison to those in the DCCT and UKPDS
studies) probably contributed to the prevalence of
Among the patients presenting glycated hemoglobin values below 4.7%, 56% (70% of whom
were classified as white) of the results may be accounted for by the
presence of the hemoglobin variant. Although the number of samples showing
low values was
small (130 patients from 29 657 samples) this is certain to be just
the tip of the iceberg because they defined a very low HbA1c as being
below the normal (non-diabetic) lower reference limit of just 4.7%. Thus,
there may have been many other cases where the effect on the HbA1c
value was much more subtle but still clinically relevant.
Even when patients have no
abnormalities, the fact that HbA1c measures average glycaemia
and says nothing about swings in blood glucose can result in some
individuals only achieving their treatment goal at the expense of a
poor quality of life, as a result of frequent, disabling, and
unpredictable hypoglycaemia. The methods currently used to estimate
glycated hemoglobin do not recognise hemoglobin variants and the calculation for the glycated
component is only related to HbA1c, not to HbS1c, HbC1c, or to HbD1c,
resulting in very low glycated hemoglobin values.
Camargo JL, Gross JL. Conditions
associated with very low values of glycohemoglobin measured by an HPLC
method. J Clin Pathol 2004;57:346?9.
The Diabetes Control and Complications
Trial Research Group. The effect of intensive treatment of diabetes on
the development and progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977?86.
UK Prospective Diabetes Study (UKPDS)
Group. Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837?53.