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Hematology > Red Blood Cells and Disorders
Hemoglobin C Disease
Article Last Updated: Feb 7, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine
Suzanne M Carter is a member of the following medical societies: American Bar Association
Coauthor(s):
Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine
Editors: Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Ronald A Sacher, MB, BCh, MD, FRCPC, Director of the Hoxworth Blood Center, Professor, Departments of Internal Medicine and Pathology, University of Cincinnati Medical Center; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Author and Editor Disclosure
Synonyms and related keywords:
HbC disease, mild hemolytic anemia, benign hemoglobinopathies, musculoskeletal pain, joint pain, iron deficiency, iron supplementation, angioid streaks, hemoglobin C, gallstones, pigmented gallstones, malaria, Bruch membrane, retinopathy, cholelithiasis, dental infarction, hemolysis, HbC, splenomegaly
Background
Hemoglobin C disease is an autosomal recessive disorder that 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 to form crystals. These intracellular crystals lead to a decrease in red blood cell deformability and an increase in the viscosity of the blood. The spleen effectively removes these crystal-containing cells. 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 endemic areas. The risk of malaria is lower still in persons who are homozygous for hemoglobin C.
Frequency
United States
Hemoglobin C disease has a prevalence of 0.017% in African Americans.
International
In northern Africa, the prevalence of hemoglobin C disease is approximately 0.03%.
Mortality/Morbidity
Hemoglobin C disease is one of the more benign hemoglobinopathies. Some cases may not be diagnosed until adulthood.
- Mild hemolytic anemia (see Hemolytic Anemia) may result, accompanied by a mild-to-moderate reduction in the red blood cell 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.
Race
This condition primarily occurs in persons of African ancestry, but it has also been reported in persons of Hispanic and Sicilian ancestry.
Sex
Both sexes are affected equally.
Age
Hemoglobin C disease is present at birth.3
History
Other than mild hemolytic anemia, most patients are asymptomatic. Symptoms can include musculoskeletal pain, retinopathy,4 cholelithiasis, and dental infarction.
- Patients may have mild hemolytic anemia and an abnormal number of target cells.
- Some patients may present with joint pain.
- Retinopathy may manifest as angioid streaks, a clinical manifestation of breaks in a brittle Bruch membrane.5
- The 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 cells.
- Dental radiographs show changes to the maxilla and mandible typically associated with persistent overgrowth of erythrocyte-forming marrow, which is the basic process common to most hemolytic diseases and most hemoglobinopathies.
Physical
Except for associated angioid streaks and splenomegaly, examination findings are unremarkable.
Causes
Hemoglobin C disease is an autosomal recessive disorder that results from the biparental inheritance of the gene that encodes for hemoglobin C.
Hemolytic Anemia
Sickle Cell Anemia
Thalassemia, Beta
Lab 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. 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 from homozygous C patients, the best method is to test both parents if available.
- Performing a CBC count is recommended.
- Iron studies determine if iron stores are adequate.
- Reticulocyte count and lactic dehydrogenase (LDH) levels determine the extent of hemolysis.
- Examination of the erythrocytes 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.
Imaging Studies
- Dental radiographs may show infarction.
- If the patient has right upper quadrant pain, an abdominal ultrasound 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.
Medical Care
- Patients can usually be evaluated in an outpatient setting.
- Perform regular eye screening along with fluorescein angiography to assess for neovascularization.
Surgical Care
- Splenectomy may be indicated, and gallstones may require cholecystectomy.
- Neovascularization present at the equatorial region of the eye can be treated with a laser to prevent bleeding.
Consultations
- Dentist
- Geneticist
- Hematologist
- Ophthalmologist
Diet
No special diet is required.
Activity
Physical activities are not restricted.
Patients with hemoglobin C disease require treatment only for acute problems. Long-term antibiotic prophylaxis is not indicated.
Drug Category: Mineral supplementations
Iron supplementation is used to correct iron deficiency.
| Drug Name | Ferrous sulfate (Feosol, Fer-Iron, Ferospace, Slow FE) |
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| Description | A nutritionally essential inorganic substance that allows transportation of oxygen via hemoglobin. Used for simple iron deficiency and iron-deficiency anemia. |
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| Adult Dose | 325 mg/d PO |
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| Pediatric Dose | <12 years: Not established
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Absorption enhanced by ascorbic acid; interferes with tetracycline absorption; food and antacids impair absorption |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
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| Precautions | GI upset; iron toxicity is observed with ingestion of large amounts and can be fatal, especially in children; parenteral (IV) administration may cause several reactions, including headaches, malaise, fever, generalized lymphadenopathy, arthralgia, and urticaria; can cause severe anaphylaxis; possible phlebitis at infusion site |
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Further Inpatient Care
Admit patients if they require a cholecystectomy or splenectomy.
Further Outpatient Care
Monitor patients for anemia.
In/Out Patient Meds
- As with any chronic hemolytic anemia, folic acid at a dose of 1 mg/d PO is indicated.
- Initiate short-term iron supplementation only if iron stores are low.
Complications
- Cholelithiasis may occur.
- Splenomegaly may occur.
- Angioid streaks may occur.
- 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 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 vasoocclusive crises and aseptic necrosis of the femoral head.
Prognosis
Patients have a normal life expectancy.
Patient Education
- Patients may benefit from genetic counseling.
- Inform patients that the disease has a benign course during pregnancy.
Medical/Legal Pitfalls
- Failure to offer genetic counseling
- Failure to recommend ophthalmologic consult
Special Concerns
Pregnancy complications are rare.6
- 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.
- 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].
- 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].
- 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].
- Fabry ME, Kaul DK, Raventos C, et al. Some aspects of the pathophysiology of homozygous Hb CC erythrocytes. J Clin Invest. May 1981;67(5):1284-91. [Medline].
- Fairhurst RM, Casella JF. Images in clinical medicine. Homozygous hemoglobin C disease. N Engl J Med. Jun 24 2004;350(26):e24. [Medline].
- Fairhurst RM, Fujioka H, Hayton K, et al. Aberrant development of Plasmodium falciparum in hemoglobin CC red cells: implications for the malaria protective effect of the homozygous state. Blood. Apr 15 2003;101(8):3309-15. [Medline].
- Fort JA, Graham-Pole JR, Chopik J. Vasoocclusion with homozygous hemoglobin-C disease. Am J Pediatr Hematol Oncol. 1988;10(4):323-5. [Medline].
- Wickramasinghe SN, Akinyanju OO, Hughes M. Dyserythropoiesis in homozygous haemoglobin C disease. Clin Lab Haematol. 1982;4(4):373-81. [Medline].
Hemoglobin C Disease excerpt Article Last Updated: Feb 7, 2008
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