ANALYSIS
susumu nishinaga/spl
Is haemoglobin A 1c
a step forward for
diagnosing diabetes?
Eric Kilpatrick, Zachary Bloomgarden, and Paul Zimmet
question proposals to diagnose diabetes by raised glycated
haemoglobin concentration rather than glucose testing
Currently, diabetes is diagnosed by ­measuring
plasma glucose concentration fasting (threshold
≥7 mmol/l) or after a oral glucose tolerance
test (≥11.1 mmol/l). However, an international expert committee ­comprising members appointed by the American ­Diabetes
­Association, the European ­Association for
the Study of Diabetes, and the International
­Diabetes Federation recently recommended
replacing these tests with one for glycated haemoglobin A1c (HbA1c).1 The committee stated
that type 2 diabetes should be diagnosed in
anyone with a confirmed HbA1c value ≥6.5%
(48 mmol/mol) without glucose testing,
although the glucose criteria will continue to
be used in people in whom measurement of
HbA1c may be inappropriate. Measurement of
HbA1c has several advantages over glucose but
its exclusive use could present problems, as we
discuss here.
mia over the preceding few weeks or months,
HbA1c could provide a more complete view
of glycaemia than a single fasting glucose
measurement or the “artificial” conditions
of a glucose tolerance test, which the expert
committee refers to as the “common sense”
rationale for its use. HbA1c measurement is
also the most common means of guiding
management of diabetes and adjusting treatment, so its use for diagnosis would simply
be an extension of this role.
A previous hurdle to even considering use
of HbA1c for diagnosis has been the lack of
standardisation in the assay, meaning that
results could vary depending on the laboratory method used. This is being overcome
through standardisation led by the International Federation of Clinical Chemistry and
Laboratory Medicine (IFCC) and should now
be less of a problem.3
Advantages of haemoglobin A1c
The expert committee document gave no
specific reasons for dispensing with glucose
criteria in favour of HbA1c, but it did highlight many of the advantages of using HbA1c
(table). These include the undoubted benefits
of requiring a single blood sample and being
able to test in the non-fasting state. The day to
day variability of HbA1c within an individual
is also smaller than that of fasting glucose and
considerably less than glucose concentration
after a glucose tolerance test (coefficient of
variation 3.6% v 5.7% v 16.6% in one study2),
so repeated measurements should be more
consistent with HbA1c. There is also the argument that, by giving an estimate of glycae-
Disadvantages
The case to move to HbA1c for diagnosis
seems compelling. However, there are some
real difficulties. Indeed, the expert committee accepts many of the inherent problems in
using HbA1c for diagnosis but does not discuss
the likely practical effects of these limitations.
For example, the presence of any abnormal
haemoglobin may affect HbA1c measurement
and give misleading results. How and if it will
affect the result depends on the analyser used.
One instrument might identify and account
for certain haemoglobinopathies but not others, and a different analyser could pick up
(or miss) a completely different spectrum of
abnormal haemoglobins.4
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The prevalence of haemoglobinopathies
varies widely between countries and races,
but an indication of the magnitude of the
problem is given by looking at people in
the United States with either sickle cell or
haemoglobin C trait. At least 10% of the 26
million African American citizens have these
traits,5 which can cause incorrect results in
at least a third of HbA1c analysers routinely
used there.4 Just how, therefore, are we going
to be sure that someone does not have a
­haemoglobinopathy that is causing them to
be diagnosed with diabetes (or not) inappropriately? In patients already known to have
diabetes, the National Institutes of Health
in the United States recommends that this
­possibility should be considered in people
of African, Mediterranean, or South East
Asian heritage when glucose measurements
are discrepant with HbA 1c results, when
the HbA1c result is unexpected, when the
result is greater than 15%, or when a value
changes drastically after a change in laboratory method.6 But if HbA1c is the sole means
of diagnosis and there is encouragement not
to self monitor glucose concentrations until
diabetes requires insulin treatment, we cannot identify wrongly diagnosed patients without the ­additional expense, ­interpretation,
and consent required for concurrent
­haemoglobinopathy ­screening.
Iron deficiency anaemia (a condition which
affects 3.3 million US women7) can also cause
HbA1c to be 1-1.5% higher than usual before
iron treatment.8 9 Should we be testing for this
as well as haemolytic anaemia and any other
condition that can alter red cell survival in
BMJ | 5 december 2009 | Volume 339
ANALYSIS
Advantages
Disadvantages
Glucose
Established as the current means of diagnosing diabetes
Directly measures the molecule thought to cause diabetes complications
Not subject to misleading results due to non-glycaemic factors
Smaller differences in results between laboratories than HbA1c
More feasible than HbA1c to be measured globally
Requires patient to be tested in the fasting state and for the sample to be analysed promptly
May require a glucose tolerance test for diagnosis
A single time point of glucose measurement
Higher within individual variability than that of HbA1c
Oral glucose tolerance test may be unreliable in patients with gastric surgery
Haemoglobin A1c
Established for monitoring patients known to have diabetes
Does not require a fasting sample and is more stable after sample
collection than glucose
Marker of glucose control over the previous weeks or months
Lower within person variability than with glucose
anyone with suspected diabetes? What about
patients with renal failure, which can have
a variable effect on HbA1c concentrations
(through haemolytic and iron deficient processes as well as the formation of carbamylated
haemoglobin), and conditions such as HIV,
where HbA1c appears 1% lower in patients
taking antiretroviral drugs?
The committee mentions the effect of ageing (HbA1c is 0.4% higher in 70 year olds
than 40 year olds with the same glucose tolerance)10 and ethnicity (0.4% higher in AfroCaribbeans than Europids)11 but thinks that
their “etiology and significance are unclear.”
So in the meantime we do not know if we
will wrongly identify older and non-Europid
people as having diabetes. Indeed, the committee fails to consider whether there is
important within patient variability in the
relation between HbA1c concentration and
mean glycaemia.12 13
Even the move to standardisation of HbA1c
measurement, although necessary, will not
instantly improve the performance of assays.
If we make an analogy between laboratory
HbA1c analysers and wristwatches, then international standardisation is the equivalent to
setting our watches to an atomic clock rather
than Big Ben. This will not, in itself, make
our watches more accurate. This was shown
in June 2009 when the UK National External Quality Assessment Service found that
251 laboratories sent standard samples with
an HbA1c concentration of 6.5% (48 mmol/
mol) reported values varying between 5.8%
and 7.2% (40 mmol/mol and 55 mmol/mol).
Variation could be even higher in countries
Measurement can be misleading in patients with haemoglobinopathies,
anaemia, or renal failure
May differ between patients of different ages and ethnicity
Larger differences in results between laboratories than glucose
Cost restricts access to test in many counties
Surrogate marker of hyperglycaemia with between individual discrepancies
between glucose and HbA1c
with fewer resources to measure HbA1c and
less experience with harmonisation of methods. These issues, and the potential list of
tests required in addition to HbA1c to ensure
its accuracy, make the idea of simply fasting overnight for a glucose test much more
appealing.
The aim of diagnosing type 2 diabetes is
to identify people at high risk of developing the microvascular complications of the
disease. As HbA1c will identify diabetes in
different groups of people than would glucose tests, there remains concern about
how well HbA1c compares with glucose in
predicting microvascular risk, even after
people in whom measuring HbA1c is likely
to pose a problem are excluded. The main
figure in the expert ­committee’s report shows
three studies (in Pima Indian, Egyptian, and
US ­populations) that found that the risk of
­retinopathy increases with rising fasting
plasma glucose, two hour glucose, and HbA1c
levels in roughly the same decile, implying
that the tests are interchangeable. However,
this would be expected within a population
no matter how poorly one of the tests ­predicts
risk compared with another. What is not
mentioned is that in all three studies receiver
operating characteristic curves show fasting or
two hour glucose measurement to be better
than HbA1c.14 One study cited to justify the
6.5% HbA1c cut-off even found that random
glucose testing provided “similar results.”15
The report presents new data showing HbA1c
to be at least as predictive of retinopathy as
glucose measurement, but these data have yet
to be fully published.
BMJ | 5 december 2009 | Volume 339 Before considering any change, we also
need to know how the current WHO recommendation of measuring two hour glucose
in patients with impaired fasting glucose
results,16 as practised in many countries,
compares to measuring only fasting plasma
glucose or HbA1c. Also, in large population
studies HbA1c is often measured by the same
method, or even the same instrument, in a
central laboratory. This removes the between
laboratory differences in HbA1c results already
mentioned and may give a false impression of
how well the test will perform routinely.
Lastly, there is the HbA1c cut-off of 6.5%
(48 mmol/mol) itself. Any threshold is
likely to be arbitrary to some extent, but
a proposed aim of using HbA1c is to help
reduce the time between onset of diabetes
and diagnosis and to pick up the third of
patients who have diabetes but do not know
it.17 However, according to data from the US
National Health and Nutrition ­Examination
Survey, 50-60% of patients with a fasting
plasma glucose ­concentration above the
current threshold of 7 mmol/l will have an
HbA1c ­concentration below 6.5%.17 Thus, use
of a 6.5% HbA1c threshold will add patients
to the missing third. What this ­presumably
means is that in people for whom HbA1c
measurement is known to be unreliable, the
use of glucose criteria will make them two
to three times as likely to be diagnosed with
diabetes as someone in whom HbA1c testing can be used. We also have the problem
of whether to diagnose diabetes in someone
with a fasting glucose of 10 mmol/l and an
HbA1c of 6.4% (47 mmol/mol).
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ANALYSIS
Conclusion
When new diagnostic criteria for any disease are proposed it is assumed they will be
demonstrably superior to existing criteria.
There are advantages and disadvantages
to using either plasma glucose or HbA1c
to diagnose diabetes, as summarised in the
table. However, measuring glucose may
present less of a risk of complete misdiagnosis than measuring HbA1c alone. Rather
than being a step forward, a move to HbA1c
only diagnosis could be a step too far.
Eric S Kilpatrick consultant in chemical pathology,
Department of Clinical Biochemistry, Hull Royal Infirmary and
Hull York Medical School, Hull HU3 2JZ
Zachary T Bloomgarden clinical professor of medicine,
Department of Medicine, Mount Sinai School of Medicine, New
York, USA
Paul Z Zimmet director emeritus, Baker IDI Heart and
Diabetes Institute, Caulfield South 3162, Australia
Correspondence to: Eric S Kilpatrick
[email protected]
Contributors and sources: ESK is honorary professor in
clinical biochemistry with a 20 year clinical interest in
diabetes and assessment of glycaemic control. ZTB is a
clinician treating diabetic patients. PZZ has clinical, molecular,
and epidemiological research interests. All authors drafted
and amended the article. ESK is the guarantor.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally
peer reviewed.
1
2
3
4
5
6
7
8
9
International Expert Committee. International expert
committee report on the role of the A1c assay in the
diagnosis of diabetes. Diabetes Care 2009;32:132734.
Selvin E, Crainiceanu C, Brancati F, Coresh J. Short-term
variability in measures of glycemia and implications
for the classification of diabetes. Arch Intern Med
2007;167:1545.
Miedema K. Towards worldwide standardisation of
HbA1c determination. Diabetologia 2004;47:1143-8.
National Glycohemoglobin Standardization
Programme. HbA1c methods and hemoglobin variants
(HbS, HbC, HbE and HbD traits). 2009. www.ngsp.org/
prog/index2.html.
Roberts WL, De BK, Brown D, Hanbury CM, Hoyer JD,
John WG, et al. Effects of hemoglobin C and S traits
on eight glycohemoglobin methods. Clin Chem
2002;48:383-5.
National Diabetes Information Clearinghouse. Sickle
cell trait and other hemoglobinopathies and diabetes:
important information for physicians. http://diabetes.
niddk.nih.gov/dm/pubs/hemovari-A1C/index.htm.
Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson
CL. Prevalence of iron deficiency in the United States.
JAMA 1997;277:973-6.
El-Agouza I, Abu SA, Sirdah M. The effect of iron
deficiency anaemia on the levels of haemoglobin
subtypes: possible consequences for clinical
diagnosis. Clin Lab Haematol 2002;24:285-9.
Coban E, Ozdogan M, Timuragaoglu A. Effect of iron
deficiency anemia on the levels of hemoglobin A1c in
nondiabetic patients. Acta Haematol 2004;112:126-8.
10 Pani L, Korenda L, Meigs J, Driver C, Chamany S, Fox
C, et al. Effect of aging on A1c levels in individuals
without diabetes: evidence from the Framingham
Offspring Study and the National Health and Nutrition
Examination Survey 2001-2004. Diabetes Care
2008;31:1991.
11 Herman W, Ma Y, Uwaifo G, Haffner S, Kahn S, Horton
E, et al. Differences in A1c by race and ethnicity
among patients with impaired glucose tolerance
in the diabetes prevention program. Diabetes Care
2007;30:2453.
12 Bloomgarden ZT, Inzucchi SE, Karnieli E, Le Roith D. The
proposed terminology ‘A(1c)-derived average glucose’
is inherently imprecise and should not be adopted.
Diabetologia 2008;51:1111-4.
13 Gallagher E , Le Roith D, Bloomgarden Z. Review of
hemoglobin A1c in the management of diabetes.
J Diabetes 2009;1:9-17.
14 Expert Committee on the Diagnosis and Classification
of Diabetes Mellitus. Report of the expert committee on
the diagnosis and classification of diabetes mellitus.
Diabetes Care 1997;20:1183-97.
15 Sabanayagam C, Liew G, Tai E, Shankar A, Lim S,
Subramaniam T, Wong T. Relationship between glycated
haemoglobin and microvascular complications: is there
a natural cut-off point for the diagnosis of diabetes?
Diabetologia 2009;52:1279-89.
16 WHO. Definition, diagnosis and classification of
diabetes mellitus and its complications: report of a
WHO consultation. Part 1. Diagnosis and classification
of diabetes mellitus. WHO, 1999.
17 Saudek C, Herman W, Sacks D, Bergenstal R,
Edelman D, Davidson M. A new look at screening and
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Cite this as: BMJ 2009;339:b4432
answers to endgames, p 1319. For long answers go to the Education Channel on bmj.com
Picture Quiz
An 80 year old woman who fell in her home
Statistical
question
Random
allocation III
a, b, and c
1 She has a hip fracture—specifically, a displaced fracture of the femoral
neck. The fracture is intracapsular or medial (fig).
2 An arthroplasty (hip replacement), usually a cemented hemiarthroplasty,
is the recommended surgical treatment for displaced femoral neck
fractures in elderly people. Internal fixation produces a poorer functional
result and an unacceptably high risk (30-40%) of repeat surgery.
3 Effective ways of reducing the risk of a new fracture should have been
implemented in 2004 after her first hip fracture. Medication, with vitamin
D and calcium along with alendronate 70 mg weekly as the first choices,
should have been started. In addition, strategies for reducing the risk of
falling again should have been implemented.
Anteroposterior radiograph of the right hip taken
at admission showing a displaced intracapsular
fracture of the femoral neck. The white arrow shows
the fracture line in the proximal (head) fragment;
note that the fracture is subcapital. The black arrow
notes the sharp bone fragment from the relatively
dense bone of the calcar femorale, the inner turn of
the femoral neck. This is where the “corner” marked
by the white arrow should have continued, and the
clinical shortening of the leg represents the distance
between these two points
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4 Yes. The typical patient is a woman of 75 years or more, living in western
Europe or North America, who sustains a hip fracture after a low energy
fall—that is, from standing height while walking.
5 In the short term, the main concerns are surgical complications
(periprosthetic fracture, deep wound infection, or dislocated arthroplasty)
which lead to repeat surgery in 5-10% of cases, pressure sores, pulmonary
embolism, cardiovascular complications, and infections (mainly urinary
and respiratory tract). In the medium or long term, other concerns include
reduced hip function, loss of independence, more fractures, and death.
BMJ | 5 december 2009 | Volume 339