Glycated hemoglobin is a form of hemoglobin that is measured primarily to identify the
average plasma glucose concentration over prolonged periods of time. It is formed in
a non-enzymatic glycation pathway by hemoglobin's exposure to plasma glucose. Normal levels
of glucose produce a normal amount of glycated hemoglobin. As the average amount of plasma
glucose increases, the fraction of glycated hemoglobin increases in a predictable way.
This serves as a marker for average blood glucose levels over the previous months prior
to the measurement. In diabetes mellitus, higher amounts of glycated
hemoglobin, indicating poorer control of blood glucose levels, have been associated with
cardiovascular disease, nephropathy, and retinopathy. Monitoring HbA1c in type 1 diabetic patients
may improve outcomes.
History Hemoglobin A1c was first separated from other
forms of hemoglobin by Huisman and Meyering in 1958 using a chromatographic column. It
was first characterized as a glycoprotein by Bookchin and Gallop in 1968. Its increase
in diabetes was first described in 1969 by Samuel Rahbar et al. The reactions leading
to its formation were characterized by Bunn and his coworkers in 1975. The use of hemoglobin
A1c for monitoring the degree of control of glucose metabolism in diabetic patients was
proposed in 1976 by Anthony Cerami, Ronald Koenig and coworkers.
Principle Glycation of proteins is a frequent occurrence,
but in the case of hemoglobin, a nonenzymatic reaction occurs between glucose and the N-end
of the beta chain. This forms a Schiff base which is itself converted to 1-deoxyfructose.
This rearrangement is known as Amadori rearrangement. When blood glucose levels are high, glucose
molecules attach to the hemoglobin in red blood cells. The longer hyperglycemia occurs
in blood, the more glucose binds to hemoglobin in the red blood cells and the higher the
glycated hemoglobin. Once a hemoglobin molecule is glycated, it
remains that way. A buildup of glycated hemoglobin within the red cell, therefore, reflects the
average level of glucose to which the cell has been exposed during its life-cycle. Measuring
glycated hemoglobin assesses the effectiveness of therapy by monitoring long-term serum glucose
regulation. The HbA1c level is proportional to average blood glucose concentration over
the previous four weeks to three months. Some researchers state that the major proportion
of its value is weighted toward the most recent 2 to 4 weeks. This is also supported by the
data from actual practice showing that HbA1c level improved significantly already after
20 days since glucose-lowering treatment intensification. Measuring A1C
A number of techniques are used to measure A1C.
Laboratories use: High-performance liquid chromatography: The
HbA1c result is calculated as a ratio to total hemoglobin by using a chromatogram.
Immunoassay Enzymatic
Capillary electrophoresis Boronate affinity chromatography
Point of care devices use: Immunoassay
Boronate affinity chromatography In the United States, A1C testing laboratories
are certified by the National Glycohemoglobin Standardization Program to standardise them
against the results of the 1993 Diabetes Control and Complications Trial. An additional percentage
scale, Mono S is in use by Sweden and KO500 is in Japan.
Switch to IFCC units The American Diabetes Association, European
Association for the Study of Diabetes and International Diabetes Federation have agreed
that, in the future, HbA1c is to be reported in the International Federation of Clinical
Chemistry units. IFCC reporting was introduced in Europe except for the UK in 2003; the UK
carried out dual reporting from 1 June 2009 until 1 October 2011.
Conversion between DCCT and IFCC is by the following equation:
Interpretation of results Laboratory results may differ depending on
the analytical technique, the age of the subject, and biological variation among individuals.
Two individuals with the same average blood sugar can have A1C values that differ by as
much as 3 percentage points. Results can be unreliable in many circumstances, such as
after blood loss, for example, after surgery, blood transfusions, anemia, or high erythrocyte
turnover; in the presence of chronic renal or liver disease; after administration of
high-dose vitamin C; or erythropoetin treatment. In general, the reference range, is about
20–40 mmol/mol. Higher levels of HbA1c are found in people
with persistently elevated blood sugar, as in diabetes mellitus. While diabetic patient
treatment goals vary, many include a target range of HbA1c values. A diabetic person with
good glucose control has a HbA1c level that is close to or within the reference range.
The International Diabetes Federation and American College of Endocrinology recommend
HbA1c values below 48 mmol/mol, while American Diabetes Association recommends that the HbA1c
be below 53 mmol/mol for most patients. Recent results from large trials suggest that a target
below 53 mmol/mol may be excessive: Below 53 mmol/mol the health benefits of reduced
A1C become smaller, and the intensive glycemic control required to reach this level leads
to an increased rate of dangerous hypoglycemic episodes.
A retrospective study of 47,970 diabetes patients found that patients with an A1C more than
48 mmol/mol had an increased mortality rate, but a later international study contradicted
these findings. A review of the UKPDS ACCORD, ADVANCE and
VADT trials estimated that the risks of the main complications of diabetes decreased with
approximately 3% for every 1 mmol/mol decrease in HbA1c.
Practitioners must consider an individual patient's health, his/her risk of hypoglycemia,
and his/her specific health risks when setting a target A1C level. Because patients are responsible
for averting or responding to their own hypoglycemic episodes, the patient's input and the doctor's
assessment of the patient's self-care skills are also important.
Persistent elevations in blood sugar increase the risk of long-term vascular complications
of diabetes such as coronary disease, heart attack, stroke, heart failure, kidney failure,
blindness, erectile dysfunction, neuropathy, gangrene, and gastroparesis. Poor blood glucose
control also increases the risk of short-term complications of surgery such as poor wound
healing. Lower-than-expected levels of HbA1c can be
seen in people with shortened red blood cell lifespan, such as with glucose-6-phosphate
dehydrogenase deficiency, sickle-cell disease, or any other condition causing premature red
blood cell death. Blood donation will result in rapid replacement of lost RBCs with newly
formed red blood cells. Since these new RBCs will have only existed for a short period
of time, their presence will lead HbA1c to underestimate the actual average levels. There
may also be distortions resulting from blood donation which occurred as long as two months
before due to an abnormal synchronization of the age of the RBCs, resulting in an older
than normal average blood cell life. Conversely, higher-than-expected levels can be seen in
people with a longer red blood cell lifespan, such as with Vitamin B12 or folate deficiency.
The approximate mapping between HbA1c values given in DCCT percentage and eAG measurements
is given by the following equation: eAG(mg/dl) = 28.7 × A1C − 46.7
eAG(mmol/l) = 1.59 × A1C − 2.59 Data in parentheses are 95% confidence intervals
The 2010 American Diabetes Association Standards of Medical Care in Diabetes added the A1c
≥ 48 mmol/mol as another criterion for the diagnosis of diabetes.
Indications and use Glycated hemoglobin testing is recommended
for both checking the blood sugar control in people who might be pre-diabetic and monitoring
blood sugar control in patients with more elevated levels, termed diabetes mellitus.
There is a significant proportion of people who are unaware of their elevated HbA1c level
before they have blood lab work. For a single blood sample, it provides far more revealing
information on glycemic behavior than a fasting blood sugar value. However, fasting blood
sugar tests are crucial in making treatment decisions. The American Diabetes Association
guidelines are similar to others in advising that the glycated hemoglobin test be performed
at least two times a year in patients with diabetes that are meeting treatment goals
and quarterly in patients with diabetes whose therapy has changed or that are not meeting
glycemic goals. Glycated hemoglobin measurement is not appropriate
where there has been a change in diet or treatment within 6 weeks. Likewise, the test assumes
a normal red blood cell aging process and mix of hemoglobin subtypes. Hence, people
with recent blood loss, hemolytic anemia, or genetic differences in the hemoglobin molecule
such as sickle-cell disease and other conditions, as well as those that have donated blood recently,
are not suitable for this test. Due to glycated hemoglobin's variability,
additional measures should be checked in patients at or near recommended goals. People with
hemoglobin A1C values at 64 mmol/mol or less should be provided additional testing to determine
whether the HbA1c values are due to averaging out high blood glucose with low blood glucose
or the HbA1c is more reflective of an elevated blood glucose that does not vary much throughout
the day. Devices such as continuous blood glucose monitoring allow people with diabetes
to determine their blood glucose levels on a continuous basis, testing every few minutes.
Continuous use of blood glucose monitors is becoming more common, and the devices are
covered by many health insurance plans but not by Medicare in the United States. The
supplies tend to be expensive, since the sensors must be changed at least weekly. Another test
that is useful in determining if HbA1c values are due to wide variations of blood glucose
throughout the day is 1,5 Anhydroglucitol, also known as GlycoMark. GlycoMark reflects
only the times that the person experiences hyperglycemia above 180 mg/dL over a two-week
period. Concentrations of hemoglobin A1 are increased,
both in diabetic patients and in patients with renal failure, when measured by ion-exchange
chromatography. The thiobarbituric acid method shows that patients with renal failure have
values for glycated hemoglobin similar to those observed in normal subjects, suggesting
that the high values in these patients are a result of binding of something other than
glucose to hemoglobin. In autoimmune hemolytic anemia, concentrations
of hemoglobin A1 is undetectable. Administration of prednisolone will allow the HbA1 to be
detected. The alternative fructosamine test may be used in these circumstances and it
also reflects an average of blood glucose levels over the preceding 2 to 3 weeks.
All the major institutions like International Expert Committee Report, drawn from the International
Diabetes Federation, the European Association for the Study of diabetes, and the American
Diabetes Association, suggests the A1C level of 48 mmol/mol as a diagnostic level. The
Committee Report further states that, when A1C testing cannot be done, the fasting and
glucose tolerance tests be done. Diagnosis of diabetes during pregnancy continues
to require fasting and glucose tolerance measurements for gestational diabetes, and not the glycated
hemoglobin. Modification by exercise training
A meta-analysis of research done to identify the effect of two different kinds of training
programs on the glycated hemoglobin levels of individuals with T2DM found that the effect
of combining resistance exercise with aerobic exercise improved the glucose control more
than just the aerobics alone, but it should be noted that BMI of the resistance plus aerobic
exercise group decreased more than the aerobic only group. The average effect of the training
programs included reductions of glycated hemoglobin of 9 mmol/mol, which was a result similar
to that of long-term diet and drug or insulin therapy.
Standardization and traceability HbA1c is now standardized & traceable to IFCC
methods HPLC-CE & HPLC-MS. A new unit is used as part of this standardization.
See also Advanced glycation end product
Diabetes mellitus GlycoMark
Hemoglobin References
Le Fanu J. Doctor's diary. Daily Telegraph page 27 102013
External links National Diabetes Information Clearinghouse
American Diabetes Association Standards of Medical Care 2007
Hemoglobin A1c Test A1c at Lab Tests Online
MDRTC Hemoglobin A1C Fact Sheet Simple Online A1c Calculator
Metrika: A1C test for professionals and consumers. Developing Point of care HbA1c tests for Diabetes
monitoring. Aug 2008 Discusses different test methods
HbA1c to eAG calculator in mmol/l and mg/dl including resources. American Diabetes Association
What is HbA1c? HbA1c: analyte monograph - The Association
for Clinical Biochemistry and Laboratory Medicine. HbA1c DCCT to IFCC converter