The A1C Test

The American Diabetes Association (ADA) does not recommend use of the A1C test for diagnosis of diabetes. Instead, the fasting plasma glucose test should be used to diagnose diabetes in children and nonpregnant adults. The ADA recommends use of the A1C test as part of the initial assessment and in continuing care of people with diabetes. Physicians should perform the A1C test

• at least twice a year in patients who are meeting treatment goals and have stable glycemic control
• quarterly in patients not meeting treatment goals or when changes are made in therapy

In addition, point-of-care testing for A1C can help in making timely decisions about changes in therapy.

ADA Targets for the A1C Test

Group	Target Results
Patients in general	Less than 7 percent
Individual patients	As close to normal as possible-less than 6 percent-without significant hypoglycemia
Patients with a history of severe hypoglycemia, those with limited life expectancies, very young children, older adults, and patients with comorbid conditions	Less stringent goals

Effect of Hemoglobinopathies on A1C Test Results

With some assay methods, A1C tests in patients with hemoglobinopathies result in falsely high outcomes, overestimating actual average blood glucose levels for the previous 2 to 3 months. Physicians may then prescribe more aggressive treatments, resulting in increased episodes of hypoglycemia. Some assay methods used with some hemoglobinopathies may result in falsely low outcomes, leading to under-treatment of diabetes.

The A1C test is not recommended for diagnosis of diabetes in the general population because it is not sufficiently sensitive. Also important, in patients with hemoglobinopathies, results may be falsely elevated, so physicians may erroneously conclude a patient has diabetes. Confirmation with a fasting blood glucose is required for a diagnosis of diabetes to prevent inappropriate treatment decisions.

Hemoglobinopathies

Hemoglobin molecules in red blood cells transport and distribute oxygen to cells throughout the body. Hemoglobin is composed of heme-the portion of the molecule containing iron-and globin-a protein made up of amino acid chains.

Hemoglobin variants occur when mutations in the globin genes result in changes in the amino acids of the globin protein. Hundreds of variants have been identified; a small number of variants are common and have clinical significance. Hemoglobin variants are inherited in an autosomal recessive manner.

Common Types of Hemoglobinopathies

Table 1 summarizes the affected populations, prevalence, and outcomes of common hemoglobinopathies. These hemoglobinopathies may either falsely raise or lower A1C results, depending on the variant and the assay method.

People who are heterozygous for a variant are said to have a trait or to be carriers and are usually asymptomatic. Those who are homozygous generally have a disease condition. Hemoglobin SC (HbSC) is a compound heterozygous condition, meaning that the patient has inherited genes for two variants: HbS from one parent and HbC from the other.

Table 1. Common Hemoglobinopathies: Populations Affected, Prevalence, and Outcomes

Hemoglobin (Hb) Variant	Populations Affected	Prevalence (in the United States unless otherwise noted)	Outcome with One Abnormal Gene and One Normal Gene (Heterozygous State)	Outcome with Two Abnormal Genes (Homozygous State)
Hemoglobin S (HbS)	African Americans Hispanic Americans/Latinos Also found in East India, the Mediterranean, and the Middle East	About one in 12 African Americans has sickle cell trait 1 About one in 100 Hispanic Americans/Latinos has sickle cell trait 2 Sickle cell anemia occurs in one of every 500 African American births 1 Sickle cell anemia occurs in one of every 1,000 to 1,400 Hispanic American/Latino births 1	Sickle cell trait (also called HbAS): usually asymptomatic	Sickle cell anemia (also called HbSS disease): sickled red blood cells that interfere with circulation and decrease life span of red blood cells; can result in hemolytic, splenic sequestration, and aplastic crises and multiple complications
Hemoglobin C (HbC)	African Americans People of West African descent	About 2.3 percent of African Americans have HbC trait 3	HbC trait (also called HbAC): asymptomatic	HbC disease (also called HbCC disease): mild hemolytic anemia, mild to moderate enlargement of the spleen
Hemoglobin E (HbE)	Asian Americans, especially those of Southeast Asian descent Common in Cambodia, Indonesia, Laos, Malaysia, Thailand, and Vietnam. Also seen in southern China, India, the Philippines, and Turkey	Prevalence of HbE may be 30 percent in Southeast Asia 3	HbE trait (also called HbAE): asymptomatic	HbE disease (also called HbEE disease): mild hemolytic anemia, microcytosis, and mild enlargement of the spleen
Hemoglobin SC (HbSC)	African Americans and people of West African descent Also found in East India, the Mediterranean, and the Middle East		N/A	HbSC disease (also called sickle-hemoglobin C disease): mild hemolytic anemia and moderate enlargement of the spleen; may have blocking of blood vessels as in sickle cell anemia but milder symptoms
Hemoglobin F (HbF) elevated	Occurs in patients with hereditary persistence of fetal hemoglobin, sickle cell anemia, severe anemias, leukemia, and other conditions	About 1.5 percent have more than 2 percent HbF but some groups may have concentrations as high as 12 percent 3	N/A	Those with elevated HbF and sickle cell anemia may have a milder form of sickle cell anemia

¹ National Heart, Lung, and Blood Institute, NIH. Sickle cell anemia. Available at: www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_All.html. Posted May 2007. Accessed June 27, 2007.

² National Human Genome Research Institute, NIH. Learning about sickle cell disease. Available at: www.genome.gov/10001219. Posted February 2007. Accessed July 3, 2007.

³ Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clinical Chemistry. 2001;47(2):153-163.

Information about Assay Methods for Patients with Hemoglobinopathies

The NGSP provides a table on the NGSP website at http://www.ngsp.org/factors.asp describing the effects of frequently encountered Hb variants and derivatives on glycohemoglobin measurement for more than 25 assay methods. The NGSP website also includes a list of references for the information summarized in the table.

According to the NGSP, as of July 2007, 14 percent of laboratories are using assay methods with clinically significant HbAS interference; 13 percent use methods with clinically significant HbAC interference. However, after upcoming changes in reagents expected to be complete by the end of 2008, only about 5 percent of laboratories will be using methods resulting in significant HbAS or HbAC interference.

Alternative Tests

Physicians may wish to consider using other measures of average blood glucose levels, such as the fructosamine test, also called glycated serum protein or glycated albumin, with patients who have hemoglobinopathies where an accurate A1C result cannot be obtained. Serum proteins show average glucose levels over a much shorter period of time than the A1C test, usually about 2 to 3 weeks. Moreover, the fructosamine test is not standardized and the relationship of results of this test to glucose levels or risk for complications has not been established.

Recent Changes in A1C Reporting

A1C results will now be provided in the following ways:

• with the current name and units-as a percentage
• as estimated average glucose, also called eAG, in mg/dL or mmol/L
• with the current name and as mmol hemoglobin A1C/mole hemoglobin

Other Conditions that Can Affect A1C Test Results

A number of other conditions, such as those that reduce the life span of red blood cells, can affect A1C results. Recent acute blood loss or hemolytic anemia can falsely lower A1C results. Intake of large amounts of vitamin C or vitamin E can falsely lower or elevate results. Iron deficiency anemia can falsely elevate results.

Points to Remember

• Hemoglobinopathies are inherited hemoglobin variants caused by globin gene mutations.

• People of African, Mediterranean, or Southeast Asian descent are particularly at risk for having hemoglobin variants.

• Hemoglobin variants may confound results of the A1C test, which indicates average blood glucose levels over the preceding 2 to 3 months.

• False A1C test results can lead to false diagnosis or over-treatment or under-treatment of diabetes in people with hemoglobinopathies.

• Information to assist in selecting the best assay methods is available from the National Glycohemoglobin Standardization Program (NGSP).

• The most common hemoglobin variants include hemoglobin S, C, and E.

• People who are homozygous for a hemoglobin variant may have a disease condition-for example, those who are homozygous for the hemoglobin S variant have sickle cell anemia. Those who are heterozygous for a variant are said to have a trait or to be carriers and are usually asymptomatic.

• A booklet for people with diabetes about hemoglobin variants and the A1C test, For People of African, Mediterranean, or Southeast Asian Heritage: Important Information about Diabetes Blood Tests, is available from the National Diabetes Information Clearinghouse at 1-800-860-8747 or online at www.diabetes.niddk.nih.gov/dm/pubs/traitA1C.

Hope through Research

Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research. For information about current studies, visit www.ClinicalTrials.gov.

For More Information

National Glycohemoglobin Standardization Program
Internet: www.ngsp.org

American Diabetes Association
1701 North Beauregard Street
Alexandria, VA 22311
Phone: 1-800-DIABETES (342-2383)
Fax: 703-549-6995
Email: AskADA@diabetes.org
Internet: www.diabetes.org

National Heart, Lung, and Blood Institute Health Information Center
P.O. Box 30105
Bethesda, MD 20824-0105
Phone: 301-592-8573
Fax: 240-629-3246
Email: nhlbiinfo@nhlbi.nih.gov
Internet: www.nhlbi.nih.gov

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National Diabetes Information Clearinghouse

1 Information Way
Bethesda, MD 20892–3560
Phone: 1–800–860–8747
TTY: 1–866–569–1162
Fax: 703–738–4929
Email: ndic@info.niddk.nih.gov
Internet: www.diabetes.niddk.nih.gov

The National Diabetes Information Clearinghouse (NDIC) is a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the National Institutes of Health of the U.S. Department of Health and Human Services. Established in 1978, the Clearinghouse provides information about diabetes to people with diabetes and to their families, health care professionals, and the public. The NDIC answers inquiries, develops and distributes publications, and works closely with professional and patient organizations and Government agencies to coordinate resources about diabetes.

Publications produced by the Clearinghouse are carefully reviewed by both NIDDK scientists and outside experts. This publication was originally reviewed by Charles M. Peterson, M.D., M.B.A., Director, Division of Blood Diseases and Resources at the National Heart, Lung, and Blood Institute, National Institutes of Health, and Randie R. Little, Ph.D., National Glycohemoglobin Standardization Program, University of Missouri School of Medicine.

This publication is not copyrighted. The Clearinghouse encourages users of this publication to duplicate and distribute as many copies as desired.

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NIH Publication No. 09-6287
November 2008