Commentary
WHEN ARE HBA1C VALUES MISLEADING?
Richard Hellman, MD, FACP, FACE
In this issue of AACE Clinical Case Reports, Drs.
Arakari and Chongcharoen have authored a very interest-
ing article (1) which describes how glycated hemoglo-
bin (HbA1c) levels may be misleading as a measure of
glycemic control. They provide a case report regarding
a patient with diabetes who remained undiagnosed for
several years and then, despite moderately elevated fasting
glucose levels, received suboptimal therapy for his diabe-
tes, probably because his HbA1c levels were still in the
normal range. By the time the patient obtained endocrine
consultation, his urine showed evidence of microalbumin-
uria, a complication that may have been preventable had
treatment not been delayed. The patient who was the basis
of the case report had a rare hemoglobin variant (hemoglo-
binopathy), hemoglobin Leiden, which is associated with
a mild hemolytic anemia and splenomegaly, resulting in a
shortened red cell survival and thus normal HbA1c values
in the face of continuing hyperglycemia. The authors point
out that other hemoglobin variants and hemolytic anemi-
as may also contribute to lowering of HbA1c levels and
lessen the value of HbA1c levels for both diagnosis and
glycemic monitoring.
Submitted for publication January 14, 2016
Accepted for publication January 31, 2016
From the University of Missouri-Kansas City School of Medicine, Kansas
City, Missouri.
Address correspondence to Dr. Richard Hellman, Heart of America
Diabetes Research Foundation, 2790 Clay Edwards Drive, Suite 1250, North
Kansas City, MO 64116.
E-mail: rhellman@nkcendo.com.
DOI: 10.4158/EP161209.CO
To purchase reprints of this article, please visit: www.aace.com/reprints.
Copyright © 2016 AACE.
See accompanying article, p. e307.
Copyright © 2016 AACE
The importance of this well-done report goes far
beyond just the discussion of a fascinating but rare hemo-
globin variant. There are many clinical situations in which
the use of HbA1c levels alone for either diagnosis of diabe-
tes or as a measure of glycemic control is unwise and may
lead to serious errors. In fact, whenever a clinician notes
that the glycemic control of their patient, as estimated either
from continuous glucose monitoring system data, point-
of-care (POC) glucose readings, or a glycated albumin,
is discordant with their HbA1c level, the discordant data
should prompt an investigation as to whether the patient has
a condition in which HbA1c data are misleading.
So where to start? One method is to first examine the
source of the HbA1c value you are evaluating. Although
the majority of HbA1c methods used in larger clinical
chemistry laboratories are not falsely affected by hemo-
globin variants (2), some are, and a visit to the National
Glycohemoglobin Standardization Program website (3)
may identify those methods which may yield a falsely low
or falsely elevated HbA1c value in the presence of one of
the many hemoglobin variants. In addition, POC HbA1c
methods are in wide use clinically and more often are less
accurate. One problem is that several of the POC HbA1c
methods in wide use show significant biases and may report
falsely low HbA1c values and also are prone to interfer-
ence with hemoglobin variants (4). An even more common
issue is that although proficiency testing for those perform-
ing the POC testing is recommended by most experts,
many of those who regularly perform the tests have not
had adequate training or proficiency testing, and the results
are more likely to be inaccurate.
The problem of hemoglobin variants is a global one.
About 7% of the world population may have a hemoglo-
bin variant (5), and although many of the more than 1,175
different variants (5) are innocuous, some, as for example
hemoglobin Leiden, are not. Also, some hemoglobin vari-
ants, such as hemoglobins S, C, F, E, and D, are found in
AACE CLINICAL CASE REPORTS Vol 2 No. 4 Autumn 2016 e377
e378 Commentary on Misleading HbA1c, AACE Clinical Case Rep. 2016;2(No. 4)
many patients worldwide. In Southeast Asia, up to 30% of
the population may have at least a heterozygous hemoglo-
bin variant, often S, E, and D, but also F. About 10% of
the African American population has a hemoglobin variant.
Consequently, when caring for a patient with an ethnic or
racial background which is associated with a higher inci-
dence of hemoglobin variants, it is reasonable to consider
whether the patient has a hemoglobin variant that needs to
be factored into the evaluation of their HbA1c data.
In the case study, the mechanism by which a hemoglo-
bin variant caused a falsely low HbA1c in the case reported
was by causing hemolysis and a shortened red cell surviv-
al. In fact, any condition that shortens red cell survival or
necessitates blood transfusions will falsely lower HbA1c
levels, as for example, hemolytic anemias, blood loss, or
treatment with multiple transfusions.
But not all anemias will lower HbA1c levels. Both
iron deficiency anemia and pernicious anemias, for exam-
ple, are associated with a longer red blood cell survival,
which is associated with an increase in HbA1c levels. In
addition, in the case of iron deficiency, malondialdehyde,
which is increased in iron deficiency anemia, enhances the
glycation of hemoglobin, and the combination of these two
mechanisms regularly results in a false increase in HbA1c
levels in patients with iron deficient anemia. Chronic renal
failure (CRF) is also associated with a shortened red cell
survival and falsely low HbA1c levels, but in CRF, other
mechanisms are also in play that may instead raise the
HbA1c. These include decreased levels of erythropoietin,
increased glycation, higher levels of carbamylated hemo-
globin, and variable exposure to higher levels of glucose
during dialysis. Overall, however, HbA1c tends to be false-
ly lowered during CRF.
Other conditions to consider that diminish the util-
ity of HbA1c levels include chronic liver disease, which
is associated with anemia and shortened red cell survival.
When jaundice occurs, however, the bilirubin elevations
may artifactually increase HbA1c levels. Other diseases to
be considered that may cause shortened red cell survival
include splenomegaly due to any cause, rheumatoid arthri-
tis (6), or any of the many drugs or diseases that cause
hemolysis. The mechanisms may be diverse. High doses
of vitamins C and E are reported to inhibit glycation.
Hydroxyurea is associated with lower HbA1c levels but by
another completely different mechanism. It is reported that
hydroxyurea induces higher levels of hemoglobin F, and
when the hemoglobin is measured, some analytic methods
will give a lower HbA1c than would be expected by their
average glucose levels. Chronic alcoholism also may be
associated with falsely low HbA1c levels, although the
mechanism is unclear. There are also genetic variances in
the speed of glycation, one of the explanations given for
the observation that in the African American population,
the HbA1c may be higher than expected from the levels of
glycemia (7). One should not take an HbA1c at face value,
Copyright © 2016 AACE
since in some clinical settings, the assay is misleading and
cannot be used either for diagnosis or as a true measure
of glucose control. Also, the low sensitivity of HbA1c in
the diagnosis of early diabetes, which is approximately 0.5,
further limits its usefulness as a diagnostic tool. The high
specificity of the test (0.95) makes the HbA1c test unlikely
to be a false positive, but it may often provide a result that
is falsely negative.
Recently, however, a new problem has emerged.
While HbA1c levels are quite useful for the evaluation of
glucose control in both individuals and large populations,
when used in an iterative fashion, measuring progress of
glycemic control across periods of time and to follow the
progress of a patient, it must be done keeping in mind the
limitations of the HbA1c test.
But when HbA1c levels are used by payers uncriti-
cally to reward or punish health care providers, perverse
consequences may ensue. The problem is most acute
when HbA1c levels are misused by payers at the individ-
ual provider level, because the HbA1c level of the patient
may not reflect the average glycemic control of the patient
but instead any of the other nonglycemic related factors
previously described. As an example, Provider A has a
high proportion of patients with diabetes with CRF and
liver disease. Provider B has many patients with diabetes
who also have iron deficiency anemia and other nutrition-
al anemias. Even if the two providers have patients with
equal levels of glycemic control, the HbA1c levels would
tend to be higher in the second group than the first for
reasons that are unrelated to glycemic control. But in pay-
for-performance settings, the physician may be prodded to
overtreat the patients with falsely elevated HbA1c levels
and to undertreat those with falsely lower glucose levels,
thereby injuring each group of patients.
Not only physicians but policymakers as well need
to understand the limitations of HbA1c measurement and
why uncritical acceptance of the HbA1c values as an accu-
rate measure of glycemic control can lead to poor care and
poor clinical outcomes.
DISCLOSURE
The author has no multiplicity of interest to disclose.
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at: http://www.ngsp.org/factors.asp. Accessed August 25,
2016.
Copyright © 2016 AACE Commentary on Misleading HbA1c, AACE Clinical Case Rep. 2016;2(No. 4) e379
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