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                    Sickle Cell Trait & Other Hemoglobinopathies & Diabetes

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                Sickle Cell Trait & Other Hemoglobinopathies & DiabetesSickle Cell Trait & Other Hemoglobinopathies & Diabetes
**On this page:**
Overview
    When to suspect that a patient with diabetes has a hemoglobinopathy
    What is a hemoglobinopathy?
    Who is more likely to have a hemoglobinopathy?
    Detecting hemoglobinopathies
    The A1C test
    Effect of hemoglobinopathies on A1C test results
    Information about assay methods for patients with hemoglobinopathies
    Other conditions that can affect A1C test resultsOverview
The A1C test is a useful clinical tool for health professionals to diagnose or monitor diabetes and prediabetes in most people, but may be less accurate when testing patients with inherited hemoglobin variants, also called hemoglobinopathies.1 For example, people of sub-Saharan African, Mediterranean, South or Southeast Asian descent are more likely to have hemoglobin variants S and E,2 and these variants may interfere with some laboratory and point-of-care A1C tests. If a patient’s A1C test results are at odds with their blood glucose testing results, interference should be considered.
Reliable A1C tests are available for people with most hemoglobin variants. The NGSP provides information about appropriate assay methods to use in patients with hemoglobin variants.3
The following information will help health care professionals understand which patients with diabetes are more likely to have a hemoglobinopathy, how to detect it, and the effects of hemoglobinopathies on A1C test results.
When to suspect that a patient with diabetes has a hemoglobinopathy
Most people who are heterozygous for a hemoglobin variant have one variant hemoglobin gene and one standard hemoglobin gene. These people generally have no symptoms and may not know that they carry this type of hemoglobin.4 Health care professionals should suspect the presence of a hemoglobinopathy when5
an A1C result is unexpected or at odds with other diabetes test results
    an A1C result is below 4 percent or above 15 percent
    the results of self-monitoring of blood glucose differ from A1C results
    a patient’s A1C result is significantly different from a previous A1C result, following a change in laboratory A1C methodsWhat is a hemoglobinopathy?
Hemoglobin is composed of heme—the portion of the molecule containing iron—and globin—a protein made up of amino acid chains.4 Hemoglobin variants occur when mutations in the globin genes change the amino acids of the globin.
These variants are inherited in an autosomal recessive manner and affect people who are4
homozygous, with a condition such as hemoglobin SS (HbSS). These patients have a copy of the variant gene from each parent and have sickle cell disease.
    heterozygous, with a condition such as hemoglobin AS (HbAS). These patients inherited a copy of the variant gene from one parent and may be referred to as “carriers” or as having the sickle cell “trait.” These patients are usually asymptomatic.
    compound heterozygous, with a condition such as hemoglobin SC (HbSC). These patients have inherited genes for two hemoglobin variant genes—HbS from one parent and HbC from the other—and may have less severe sickle cell symptoms.Who is more likely to have a hemoglobinopathy?
African Americans
African Americans have an increased risk of inheriting sickle cell trait, the condition in which people have both hemoglobin A (HbA), the usual form of hemoglobin, and hemoglobin S (HbS), a variant gene.4 African Americans are also at risk for having hemoglobin C (HbC), another variant gene.6 About 8 percent of African American babies are born with sickle cell trait.4 About 12.7 percent of African Americans ages 18 years or older have diabetes.7
Asian Americans
People of Southeast Asian descent are at risk for having hemoglobin E (HbE), another hemoglobin variant gene.2 Prevalence of diabetes in Asian Americans varies among subpopulations of this region. About 8 percent of Asian Americans ages 18 years or older have diabetes.7
Detecting hemoglobinopathies
If a health care professional suspects that a patient may have a hemoglobinopathy, the patient’s carrier status can be detected using hemoglobin electrophoresis, high-performance liquid chromatography (HPLC), or isoelectric focusing.8
The A1C test
The A1C test measures the amount of glycated hemoglobin in the blood, which reflects average blood glucose levels over the preceding 3 months.9 Also called the hemoglobin A1C, HbA1c, or glycohemoglobin test, the A1C test is based on the attachment of glucose to hemoglobin over the typical 120-day life span of a red blood cell.
The amount of glycated proteins is directly related to the amount of glucose in the blood. However, the A1C test is a weighted average, with the glucose level of the preceding 30 days contributing more to the test result than glucose levels 90 to 120 days earlier. Thus, clinically significant changes in glucose can be seen in the A1C without waiting 120 days for red blood cell turnover.9
When the A1C test is used for diagnosis, the blood sample must be sent to a laboratory that uses an NGSP-certified method for analysis to ensure the results are standardized.3
Effect of hemoglobinopathies on A1C test results
Laboratories use many different assay methods to measure A1C, but some of these methods can give inaccurate results when the patient has a hemoglobin variant such as sickle cell trait or an elevated level of fetal hemoglobin (HbF).3 Health care professionals or patients interested in the accuracy of a particular A1C method for patients with hemoglobin variants should first find out which method their laboratory is using.3
With some assay methods, A1C tests in patients with hemoglobinopathies result in falsely high outcomes, overestimating actual average blood glucose levels for the previous 3 months. Health care professionals might falsely diagnose patients or prescribe more aggressive treatments, resulting in increased episodes of hypoglycemia. Some assay methods used with certain hemoglobinopathies may result in falsely low outcomes, leading to undertreatment of diabetes.
Health care professionals should not use the A1C test for patients with HbSS, HbCC, or HbSC.3 These patients may suffer from anemia, increased red blood cell turnover, hemolysis, and transfusion requirements, which can adversely affect A1C as a marker of long-term glycemic control.3
Health care professionals should consider alternative forms of testing for these patients, such as glycated serum protein or glycated albumin. See additional information about other conditions that may give false test results.
Common types of hemoglobinopathies
The following table lists 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.
**Table 1. Common hemoglobinopathies: Populations affected, prevalence, and outcomes**
Hemoglobin Variant
            Populations Affected
            Prevalence (in the United States Unless Otherwise Noted)
            Outcome with One Hemoglobin Variant Gene and One Standard Gene (Heterozygous State)
            Outcome with Two Variant Genes (Homozygous State)Hemoglobin S (HbS)
            African Americans10
                Hispanic Americans/Latinos10
                Most common in Africa (especially Nigeria and the Republic of Congo) and India; also found in South and Central America, the Caribbean islands, and Mediterranean countries (such as Turkey, Greece, and Italy) 11
            About 1 in 13 African Americans has sickle cell trait4
                About 1 in 100 Hispanic Americans/Latinos has sickle cell trait12
                Sickle cell disease occurs in 1 of every 365 African American births10
                Sickle cell anemia occurs in 1 of every 16,300 Hispanic/Latino births10
            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 complicationsHemoglobin C (HbC)
            African Americans and people of West African descent2
                Also found in South and Central America, the Caribbean Islands, and Europe11
            About 2.3 percent of African Americans have HbC trait13
            HbC trait (also called HbAC): asymptomatic
            HbC disease (also called HbCC disease)
            Mild hemolytic anemia
                Mild to moderate enlargement of the spleenHemoglobin E (HbE)
            Asian Americans, especially those of Southeast Asian descent14
                Common in Cambodia, Laos, and Thailand; also seen in southern China, India, Sri Lanka, and Malaysia14
            Prevalence of HbE may be 30 percent in Southeast Asia13
            HbE trait (also called HbAE): asymptomatic
            HbE disease (also called HbEE disease)
            Mild hemolytic anemia
                Microcytosis
                Mild enlargement of the spleenHemoglobin SC (HbSC)
            African Americans and people of West or North African descent2
                Also found in parts of sub-Saharan Africa, the Middle East, and India2
            Not applicable
            Not applicable
            HbSC disease (also called sickle-hemoglobin C disease)
            Mild hemolytic anemia
                Moderate enlargement of the spleen
                May have blocking of blood vessels as in sickle cell anemia but milder symptomsHemoglobin 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 of 12 percent13 or higher in other parts of the world11
            Not applicable
            People with elevated HbF and sickle cell anemia may have sickle cell anemia15Information about assay methods for patients with hemoglobinopathies
The NGSP provides a table describing the effects of frequently encountered hemoglobinopathy variants and derivatives for more than 20 assay methods. Manufacturers of A1C methods have reduced analytic interference from hemoglobin variants. Therefore, A1C can be measured accurately in the presence of most hemoglobin variants, provided a suitable assay is used.16
Alternative tests
Health care professionals may consider using other measures of average blood glucose levels, such as the glycated albumin assay or the fructosamine assay (also called glycated serum protein), with patients who have hemoglobinopathies and an accurate A1C result cannot be obtained. However, the fructosamine and glycated albumin tests reflect average glucose levels over a much shorter period of time than the A1C test, usually about 2 to 3 weeks.17 Health care professionals should note that glycated albumin assays may vary between methods and that it is unclear if the assay results can predict if diabetes complications will develop.16
Other conditions that can affect A1C test results
Some physiological factors may change A1C concentration in ways unrelated to changes in glucose.16 Conditions or factors that can result in false A1C results include
chronic kidney disease
    iron-deficiency anemia
    altered red blood cell lifespan (a factor for people with anemia or heavy bleeding)More information is available for patients with diabetes about hemoglobin variants and the A1C test in the NIDDK health topic, The A1C Test and Race/Ethnicity.
References
[1] Little RR, Rohlfing C, Sacks DB. The National Glycohemoglobin Standardization Program: over 20 years of improving hemoglobin A1c measurement. *Clinical Chemistry*. 2019;65(7):839–848. doi:10.1373/clinchem.2018.296962
[2] Williams TN, Weatherall DJ. World distribution, population genetics, and health burden of the hemoglobinopathies. *Cold Spring Harbor Perspectives in Medicine*. 2012;2(9):a011692. doi:10.1101/cshperspect.a011692
[3] Factors that interfere with HbA1c test results. National Glycohemoglobin Standardization Program. Updated April 19, 2019. Accessed December 31, 2019. http://ngsp.org/factors.asp
[4] Sickle cell disease. National Heart, Lung, and Blood Institute. Updated August 2019. Accessed December 31, 2019. www.nhlbi.nih.gov/health-topics/sickle-cell-disease
[5] American Diabetes Association. Standards of medical care in diabetes—2019. *Diabetes Care*. 2019;42(Supp 1):S13–S28. doi: 10.2337/dc19-S002
[6] The A1C Test and Race/Ethnicity. National Institute of Diabetes and Digestive and Kidney Diseases. Updated March 2020. Accessed November 2, 2020. www.niddk.nih.gov/health-information/diagnostic-tests/a1c-test-race-ethnicity
[7] National Diabetes Statistics Report, 2017. Centers for Disease Control and Prevention. www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf (PDF, 768 KB)
[8] Sabath DE. Molecular diagnosis of thalassemias and hemoglobinopathies: an ACLPS critical review. *American Journal of Clinical Pathology*. 2017;148(1) 6–15. doi: 10.1093/ajcp/aqx047
[9] The A1C Test & Diabetes. National Institute of Diabetes and Digestive and Kidney Diseases. Updated April 2018. Accessed December 31, 2019. www.niddk.nih.gov/health-information/diabetes/overview/tests-diagnosis/a1c-test
[10] Data & statistics on sickle cell disease. Centers for Disease Control and Prevention. Updated August 9, 2017. Accessed December 31, 2019. www.cdc.gov/ncbddd/sicklecell/data.html
[11] Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. *New England Journal of Medicine*. 2017;376(16):1561–1573. doi:10.1056/NEJMra1510865
[12] Ojodu J, Hulihan MM, Pope SN, Grant AM; Centers for Disease Control and Prevention (CDC). Incidence of sickle cell trait—United States, 2010. *MMWR Morbidity and Mortality Weekly Report*. 2014;63(49):1155–1158.
[13] Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants on chemically modified derivatives on assays for glycohemoglobin [published correction appears in *Clinical Chemistry* 2001;47(6):1141]. *Clinical Chemistry*. 2001;47(2):153–163.
[14] Vichinsky E. Hemoglobin E syndromes. *Hematology*. *American Society of Hematology. Education Program*. 2007:79–83. doi:10.1182/asheducation-2007.1.79
[15] Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? *Blood* 2014;123:481–485. doi: 10.1182/blood-2013-09-528067
[16] Welsh KJ, Kirkman MS, Sacks DB. Role of glycated proteins in the diagnosis and management of diabetes: research gaps and future directions. *Diabetes Care*. 2016;39(8):1299–1306. doi:10.2337/dc15-2727
[17] Danese E, Montagnana M, Nouvenne A, Lippi G. Advantages and pitfalls of fructosamine and glycated albumin in the diagnosis and treatment of diabetes. *Journal of Diabetes Science and Technology*. 2015;9(2):169–176. doi:10.1177/1932296814567227        Last Reviewed October 2020
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