Overview
Hemoglobin C disease is an autosomal recessive disorder that results from the biparental inheritance of the gene that encodes for hemoglobin C. It causes mild hemolytic anemia. Considered one of the benign hemoglobinopathies, hemoglobin C disease may not be diagnosed until adulthood. Patients with hemoglobin C disease require multispecialty care.
Pathophysiology
Hemoglobin C comprises 2 normal alpha chains and 2 variant beta chains in which lysine has replaced glutamic acid at position 6. This unstable hemoglobin precipitates in red blood cells (RBCs) to form crystals (see the image below). These intracellular crystals lead to a decrease in RBC deformability and an increase in the viscosity of the blood. The spleen effectively removes these crystal-containing cells.
Hemoglobin C disease. Much like the mechanism in sickle cell hemoglobin, the amino acid change in the hemoglobin C molecule impairs malaria growth and development. It reduces parasitemia and confers protection against mild malaria attack.[1, 2] Therefore, persons who are heterozygous for hemoglobin C have a survival advantage in areas where malaria is endemic. The risk of malaria is lower still in persons who are homozygous for hemoglobin C.
Epidemiology
In the United States, hemoglobin C disease has a prevalence of 0.017% in African Americans. In northern Africa, the prevalence of hemoglobin C disease is approximately 0.03%.[3] Hemoglobin C disease is present at birth,[4] though some cases may not be diagnosed until adulthood. The 2 sexes are affected equally. Although this condition primarily occurs in persons of African ancestry, it has also been reported in persons of Hispanic and Sicilian ancestry.
Prognosis
Overall, hemoglobin C disease is one of the more benign hemoglobinopathies. Patients have a normal life expectancy. Mild hemolytic anemia may result, accompanied by a mild-to-moderate reduction in RBC lifespan. Persons with hemoglobin C disease have sporadic episodes of musculoskeletal (joint) pain. Continued hemolysis may produce pigmented gallstones, an unusual type of gallstone composed of the dark-colored contents of red blood cells. The cause of pigmented gallstones is uncertain.
Clinical Presentation
Patient history and physical examination
Patients may have mild hemolytic anemia and an abnormal number of target cells. Aside from the anemia, most patients are asymptomatic. Symptoms that may occur include musculoskeletal pain, retinopathy, cholelithiasis, and dental infarction.
Retinopathy[5, 6, 7] may manifest as angioid streaks, a clinical manifestation of breaks in a brittle Bruch membrane.[8] These streaks appear as jagged, reddish-brown, subretinal lines that taper from the optic nerve. Chronic hemolysis causes iron deposition in the Bruch membrane. When this membrane breaks or cracks, choriocapillaries are disrupted, and photoreceptor cells are lost. These streaks can decrease visual activity.
Pigmented (bilirubin) gallstones result from excessive destruction of red blood cells (RBCs).
Dental radiographs show changes to the maxilla and mandible typically associated with persistent overgrowth of RBC-forming marrow, which is the basic process common to most hemolytic diseases and most hemoglobinopathies.
Aside from associated angioid streaks and splenomegaly, examination findings are unremarkable.
Complications
As indicated (see above), complications of hemoglobin C disease include cholelithiasis, splenomegaly, and angioid streaks may occur.
In addition, as in all chronic hemolytic anemias, a so-called aplastic crisis may occur, in which erythropoiesis becomes greatly impaired and more severe anemia ensues as a result of the inability of the marrow to produce erythroid cells at the rate required to compensate for the continuing hemolysis. These episodes are most frequently caused by parvovirus infection and usually resolve spontaneously within several days to a few weeks.
Parvovirus antibody studies are of limited value, because a large proportion of the population has had parvovirus infection. However, molecular diagnostic tests are available to confirm the presence of parvovirus. In addition, typical inclusions may be detected in early erythroid precursors in the bone marrow. Sometimes, intravenous immunoglobulin (IVIg) treatment is necessary to attempt to resolve the parvovirus infection.
Hemoglobin C disease can coexist with sickle cell hemoglobin (hemoglobin SC disease), which can lead to hemolytic anemia and pain crises. Some patients may have vaso-occlusive crises and aseptic necrosis of the femoral head.[11, 12]
Pregnancy complications are rare.[13]
Differential diagnosis
The differential diagnosis of hemoglobin C disease includes the following conditions:
Laboratory Studies
Newborn screening for sickle hemoglobinopathies is currently mandatory in 43 states; therefore, many patients who present already have a diagnosis.
Hemoglobin electrophoresis identifies and quantitates the type of hemoglobin present, as follows:
- Results for persons who are homozygous for hemoglobin C show 100% hemoglobin C
- Results for persons heterozygous for hemoglobin C may show as much as 35% hemoglobin C
- Results for persons who have hemoglobin C and beta-plus thalassemia show some hemoglobin A
- Results for individuals who have hemoglobin C and beta-zero thalassemia show no hemoglobin A; to distinguish these patients from homozygous C patients, the best method is to test both parents if possible[9]
Performing a complete blood count (CBC) is recommended. Iron studies determine if iron stores are adequate. A reticulocyte count and lactic dehydrogenase (LDH) levels determine the extent of hemolysis.
Examination of the red blood cells (RBCs) in the peripheral blood smear reveals target cells. Other abnormal morphologic forms that result in membrane-associated crystallized hemoglobin are an appearance of an off-center target, occasional pyknotic spherocytes (often with a cracked appearance), and polychromasia.
In an analysis of the membrane structure of homozygous C (CC) RBCs, Tokumasu et al noted that these blood cells differ from homozygous A (AA) RBCs with respect to their membrane lipid composition.[10] They reported that increased levels of externalized phosphatidylserine are expressed in a subset of CC erythrocytes. In addition, using detergent membrane analyses for rafter marker proteins, they found evidence that the membrane raft organization of CC erythrocytes differs from that of AA erythrocytes.
Moreover, CC erythrocytes had a lower average zeta potential than AA erythrocytes did, indicating that there are differences in surface electrochemical potential between the 2 types of RBCs. The authors also found that by treating AA erythrocytes with NaNO2 in order to oxidize the hemoglobin A molecules and raise membrane-associated hemichrome levels, the low zeta potential could be recapitulated in AA erythrocytes.
On the basis of these data, Tokumasu et al suggested that “increased hemichrome deposition and altered lipid composition induce molecular rearrangements in CC erythrocyte membranes, resulting in a unique membrane structure.”
Other Studies
Imaging studies
Dental radiographs may show infarction. If the patient has right upper quadrant pain, abdominal ultrasonography may show gallstones. Fluorescein angiography detects neovascularization present at the equatorial region of the eye, which may be missed with funduscopic examinations.
Histologic findings
In an oxygenized state, the hemoglobin C cell forms circulating intraerythrocytic crystals (tactoids) and has reduced solubility. In a deoxygenated state, virtually all hemoglobin C cells have crystalloid inclusions. Deoxygenation further reduces cell solubility and increases blood viscosity. Add 3% salt solution to a drop of blood and smear; the crystals then appear.
Treatment & Management
Patients can usually be evaluated in an outpatient setting. Monitor patients for anemia. Perform regular eye screening along with fluorescein angiography to assess for neovascularization. Patients with hemoglobin C disease require treatment only for acute problems. As with any chronic hemolytic anemia, folic acid at a dosage of 1 mg/day orally is indicated. Initiate short-term iron supplementation only if iron stores are low. Long-term antibiotic prophylaxis is not indicated.
Splenectomy may be indicated, and the presence of gallstones may warrant cholecystectomy. Admit patients if they require either of these procedures. Neovascularization present at the equatorial region of the eye can be treated with a laser to prevent bleeding.
Consultations that may be useful include the following:
- Dentist
- Geneticist
- Hematologist
- Ophthalmologist
No special diet is required. Physical activities are not restricted.Patients may benefit from genetic counseling.
Modiano D, Luoni G, Sirima BS, et al. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature. Nov 15 2001;414(6861):305-8. [Medline].
Rihet P, Flori L, Tall F. Hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack. Hum Mol Genet. Jan 1 2004;13(1):1-6.
Alkindi S, Al Zadjali S, Al Madhani A, Daar S, Al Haddabi H, Al Abri Q, et al. Forecasting hemoglobinopathy burden through neonatal screening in Omani neonates. Hemoglobin. Jan 2010;34(2):135-44. [Medline].
Olson JF, Ware RE, Schultz WH, Kinney TR. Hemoglobin C disease in infancy and childhood. J Pediatr. Nov 1994;125(5 Pt 1):745-7. [Medline].
Hingorani M, Bentley CR, Jackson H, et al. Retinopathy in haemoglobin C trait. Eye. 1996;10 ( Pt 3):338-42. [Medline].
Mantovani A, Figini I. Sickle cell-hemoglobin C retinopathy: transient obstruction of retinal and choroidal circulations and transient drying out of retinal neovessels. Int Ophthalmol. Apr 2008;28(2):135-7. [Medline].
Leveziel N, Bastuji-Garin S, Lalloum F, Querques G, Benlian P, Binaghi M, et al. Clinical and laboratory factors associated with the severity of proliferative sickle cell retinopathy in patients with sickle cell hemoglobin C (SC) and homozygous sickle cell (SS) disease. Medicine (Baltimore). Nov 2011;90(6):372-8. [Medline].
McBrayer GM, Semes L, Stephens GG. Angioid streaks and AC hemoglobinopathy--a newly discovered association. J Am Optom Assoc. Apr 1993;64(4):250-3. [Medline].
Nagababu E, Fabry ME, Nagel RL, Rifkind JM. Heme degradation and oxidative stress in murine models for hemoglobinopathies: thalassemia, sickle cell disease and hemoglobin C disease. Blood Cells Mol Dis. Jul-Aug 2008;41(1):60-6. [Medline].
Tokumasu F, Nardone GA, Ostera GR, et al. Altered membrane structure and surface potential in homozygous hemoglobin C erythrocytes. PLoS One. 2009;4(6):e5828. [Medline]. [Full Text].
Tripette J, Alexy T, Hardy-Dessources MD, et al. Red blood cell aggregation, aggregate strength and oxygen transport potential of blood are abnormal in both homozygous sickle cell anemia and sickle-hemoglobin C disease. Haematologica. Aug 2009;94(8):1060-5. [Medline]. [Full Text].
Gabrovsky A, Aderinto A, Spevak M, et al. Low dose, oral epsilon aminocaproic acid for renal papillary necrosis and massive hemorrhage in hemoglobin SC disease. Pediatr Blood Cancer. Jan 2010;54(1):148-50. [Medline].
Dare FO, Makinde OO, Faasuba OB. The obstetric performance of sickle cell disease patients and homozygous hemoglobin C disease patients in Ile-Ife, Nigeria. Int J Gynaecol Obstet. Mar 1992;37(3):163-8. [Medline].
Print
