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% 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% 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% have more than 2% HbF but some groups may have concentrations as high as 12% 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.