Hemoglobin C Disease

At a glance

Genetically inherited hemolytic anemia, usually mild and often inapparent until adulthood. This disease is mainly encountered in populations of African descent, but also in populations of Sicilian and Hispanic descent. Hemoglobin C (Hb C) is one of the most common structural hemoglobin variants in the human population. Persons with hemoglobin C trait (Hb AC) are phenotypically normal, with no clinically evident limitations or symptoms, while those with Hemoglobin C Disease (Hb C) may have a mild degree of hemolytic anemia, splenomegaly, and borderline anemia.

Synonyms

CC Disease; Hemoglobinopathy C.

Nature

Hemolytic anemia with moderate reduction in red cell lifespan. In the oxyhemoglobin state, Hb C is less soluble than normal hemoglobin, thus forming intraerythrocytic crystals (tactoids); deoxygenation further reduces solubility and increases blood viscosity. Patients with Hb C disease have a survival advantage in areas of endemic Plasmodium Falciparum malaria.

Incidence

Given the proposed survival advantage conferred by Hb C against malaria, it is not surprising that Hb C appears to have originated on the west coast of Africa. It is found in diverse populations in Africa, southern Europe, and South and Central America, although its exact allelic distribution across these varied populations remains unclear. Hb C was found to reach its highest predicted frequency in the western part of Burkina Faso, with an allele frequency of 24%. In the United States, 2 to 3% of African Americans are heterozygotes for Hb C, and approximately 1 in 5000 are homozygotes.

Genetic inheritance

Autosomal codominant (biparental inheritance). The beta gene cluster is on chromosome 11.

Pathophysiology

The double helix of Hb C is composed of two normal alpha-chains and two variant beta-chains, in which glutamic acid is replaced by lysine at position 6. Hb C is unstable and tends to precipitate in erythrocytes where it crystallizes. This changes the physical properties of the erythrocytic membrane (decreased deformability and increased viscosity of blood). These crystal-containing red blood cells are removed by the spleen, which becomes enlarged with time (splenomegaly).

Diagnosis

Examination of the erythrocytes (blood smear) reveals several morphologic disorders (caused by crystallization of hemoglobin): target cells mainly, but also appearance of an off-center target, occasional pyknotic spherocytes, and polychromasia. Diagnosis is established by hemoglobin electrophoresis (100% Hb C in homozygotes; up to 35% Hb C in heterozygotes). Reticulocyte count and lactic acid dehydrogenase levels determine the extent of hemolysis.

Clinical aspects

Except for mild-to-moderate hemolytic anemia, most patients remain asymptomatic until adulthood. Symptoms usually consist of joint and musculoskeletal pain, visual disorders (retinopathy as a result of iron deposition in the Bruch membrane causing angioid streaks), cholelithiasis, and radiographic anomalies of the ...