Hemoglobin C Disease

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Overview

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 CC) may have a mild degree of hemolytic anemia, splenomegaly, and borderline anemia. Although the clinical complications of hemoglobin C disease are not severe, inheritance with other hemoglobinopathies such as hemoglobin S may have significant consequences, and genetic counseling and anticipatory guidance play an important role in providing care for these individuals.

Pathophysiology

Hemoglobin C (Hb C) is a structural variant of normal hemoglobin A (Hb A) caused by an amino acid substitution of lysine for glutamic acid at position six of the beta hemoglobin chain. Hb C is less soluble than Hb A in red cells, likely from electrostatic interactions between positively charged β6-lysyl groups and negatively charged groups on adjacent molecules. Crystal formation may result, leading to increased blood viscosity and cellular rigidity, and shortened red cell survival.

Unlike sickle cell disease, Hb C does not cause linear intracellular polymerization upon encountering intravascular areas of low oxygen tension[1] . Thus, while there is evidence for reduced red cell deformability associated with the Hb C variant (see below), vaso-occlusion does not occur. Both the heterozygous and homozygous states may induce red cell dehydration (xerocytosis), and an elevated mean corpuscular hemoglobin concentration (MCHC) may be noted on a complete blood count.

A number of studies suggest that Hb C protects against malaria, providing a selective evolutionary advantage to people who express this hemoglobin variant in regions where this disease is endemic. A large case-control study in Burkina Faso found a strong association between resistance to clinical malaria and presence of the Hb C variant in both the heterozygous and the homozygous state.[2]

A study carried out in 4 rural villages of Burkina Faso found no evidence of protection for Hb C in the heterozygous state (odds ratio [OR] for Hb AC vs Hb AA, 1.49, P = 0.31), but did find protection was higher than even that observed with Hb S in the homozygous and double heterozygous states (OR for Hb CC and Hb SC vs Hb AA, 0.04; P = 0.002).[3]  

Smaller case-control and cross-sectional studies have reported no association between Hb C and reduced incidence of malaria parasitemia; however, one longitudinal study using family-based association analysis found a strong relationship between Hb C and protection against mild malaria, as well as a negative association between Hb C and parasitemia[2, 4, 5] .

In vitro studies have shown lower parasite multiplication rates in Hb CC than in Hb AA red blood cells, and it has been proposed that the inhibitory effect of Hb C on parasitemia may partially explain the protective effect against malaria[5] . Thus, it has been proposed that the Hb C variant has been evolutionarily selected for in regions across the globe where malaria is endemic, as is the case for the Hb S variant.

Epidemiology

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. Hb C is found in diverse populations in Africa, southern Europe, and South and Central America, though its exact allelic distribution across these varied populations remains unclear.

In a global database of population surveys, Hb C was found to reach its highest predicted frequency in the western part of Burkina Faso, with an allele frequency of 24%.[6, 7] In the United States, 2-3% of African Americans are heterozygotes for Hb C, and approximately 1 in 5000 are homozygotes.[8] Hb C has also been identified in individuals with no known African ancestry.[9]

Clinical Presentation

Hemoglobin C trait (Hb AC) is clinically silent. Hemoglobin C disease (Hb CC) is a mild disorder that generally does not cause any symptoms and is associated with a normal life expectancy.[10] Affected individuals exhibit normal growth and development and will tolerate surgery and pregnancy without issues.[11, 12]

Some patients may experience a mild hemolytic anemia, though under stress conditions the hemolysis may become more brisk and come to clinical attention. Affected patients may have splenic enlargement (splenomegaly). Case reports exist of spontaneous splenic rupture, but overall splenic function is unaffected.[13] As with other diseases causing chronic hemolytic anemia, cholelithiasis from pigmented gallstones occurs with increased frequency (see gallstones).

Co-inheritance

Hemoglobin C is mainly of clinical significance when inherited in combination with Hb S (Hb SC disease), or when co-inherited with β-thalassemia (hemoglobin C–β thalassemia). Little data exist regarding individuals who have very rare genotypes (eg, hemoglobin C–hemoglobin E compound heterozygotes), though these individuals would be expected to have few clinically evident limitations or symptoms.

Hemoglobin SC Disease

The clinical manifestations of Hb SC disease (hemoglobin SC disease), are generally similar to but less severe than those of Hb SS disease. Growth and development are normal or slightly decreased, vaso-occlusive episodes do occur but less frequently, and the median lifespan in the United States for male and female Hb SC patients is 60 and 68 years, respectively.[14, 15, 16, 17, 18, 19, 20] Importantly, two specific complications may occur more frequently in Hb SC than in Hb SS: vascular retinopathy see (Retinopathy) and avascular necrosis of the femoral head.

The Hb SC genotype is a well-known risk factor for proliferative sickle cell retinopathy (PSCR).[21, 22] . Stages of PSCR have been described by peripheral retinal ischemia, peripheral neovascularization, intravitreal hemorrhage, and tractional or mixed retinal detachment that can lead to vision loss. A longitudinal analysis showed that Hb SC patients were significantly more likely to develop severe (stage III-IV) PSCR than Hb SS patients.[23]

Avascular necrosis of the femoral head has also been reported with increased frequency in Hb SC than Hb SS. This phenomenon usually occurs during the final months of pregnancy in women with Hb SC and is attributed to fat emboli after bone marrow infarction.[24] A longitudinal study in patients with Hb SC reported advanced retinopathy in 22.9% and osteonecrosis in 14.8%,.re-emphasizing the prominence of these complicaitons in this population.[10]

Hemoglobin C–β thalassemia

Individuals may be compound heterozygotes for beta thalassemia and hemoglobin C, which could result in mild to moderate chronic hemolytic anemia. These patients are more likely to be symptomatically anemic due to alpha chain/beta chain expression imbalance, though generally their clinical phenotype closely resembles those with beta-thalassemia trait.

Differential Diagnosis

The differential diagnosis of hemoglobin C disease includes the following conditions:

Laboratory Studies

Patients can usually be evaluated in an outpatient setting. Routine screening laboratory studies are not necessary for asymptomatic patients; those with a moderate to severe clinical course should be evaluated for other hemoglobinopathies or chronic conditions.

The most commonly used method for the detection of hemoglobinopathies is hemoglobin electrophoresis or high-performance liquid chromatography (HPLC). Cellulose acetate screening will distinguish between the normal hemoglobins HbA, HbF, and HbA2, as well as the common variants, Hb S and Hb C, by charge. In the United States, newborn screening is the most common method of detecting individuals with Hb C disease. For those not diagnosed at birth, hemoglobin variant analysis by HPLC can provide the diagnosis.

Hemoglobin analysis results are as follows:

Hemoglobin variants that have the same mobility as Hb C include Hb E and Hb O-Arab. If co-migration is suspected, usually a second electrophoretic procedure is performed on citrate agar (acid electrophoresis), which is capable of distinguishing the respective variants.

In pregnancy, if prenatal screening suggests an increased risk of hemoglobinopathy, hemoglobin analysis is indicated for the mother. If maternal hemoglobin analysis shows that the mother is either homozygous or a heterozygous carrier for Hb C, paternal evaluation may be indicated to assess fetal risk of Hb SC disease. DNA-based testing for hemoglobin C can be performed during the first trimester of pregnancy from chorionic villus sampling at 10-12 weeks gestation, or by amniocentesis after 15 weeks' gestation.

Hemoglobin C Trait

Patients’ hemoglobin concentrations are usually within normal range, but the red cell mass and red cell survival may both be decreased[1] . Despite decreased survival, the reticulocyte count will not typically be increased; this is thought to be secondary to the lower oxygen affinity of Hb C, which facilitates sufficient oxygen delivery to tissues despite a lower red cell mass. Peripheral blood may show moderate amounts of target cells and intracellular crystals (5-30%)[24, 25] .

Hemoglobin C Disease

As stated before, hemolytic anemia may be mild to moderate in severity. Markers of hemolysis include increased LDH, reticulocyte count, and direct bilirubin[1] . Despite the anemia, reticulocyte counts are only slightly elevated in homozygous individuals, again due to the reduced oxygen affinity of this hemoglobin variant. Erythrocyte morphology is markedly abnormal, with prevalent microcytosis, target cells (>90%), spherocytes, and crystallized hemoglobin[26, 25, 27] .

As mentioned above, the reticulocyte count in these patients may be normal despite the presence of a chronic hemolytic anemia; this is proposed to be due to a reduced affinity of Hb C for oxygen. The lower affinity facilitates sufficient delivery of oxygen to tissues in the face of mild anemia.

The electrostatic interactions between the positively charged β-6 amino groups and the negatively charged groups on adjacent molecules lead to decreased solubility of deoxy-Hb C. This decreased solubility likely leads to shortened red cell survival. In settings of hypertonicity or deoxygenation, Hb CC cells form intracellular crystals of hemoglobin. These crystals reduce the red cells’ internal viscosity, leading to reduced deformability and a predisposition for fragmentation, spherocyte formation and splenic sequestration[27] .

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. Addition of 3% salt solution to a drop of blood will result in the appearance of the crystals, which are visible on a smear.

Treatment & Management

As with any chronic hemolytic anemia, body stores of folic acid may be depleted rapidly from high red cell turnover, and therefore folic acid at a dosage of 1 mg/day orally is indicated. Long-term antibiotic prophylaxis is not indicated, as these patients have normal splenic function. No special diet is required, and physical activities are not restricted.

Consultations that may be useful include the following:

Patients may benefit from genetic counseling, as it is important to discuss the possibility of potential co-inheritance with other hemoglobinopathies.

Author

Bryan A Mitton, MD, PhD, Clinical Instructor, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Stanford University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Tabitha M Cooney, MD, Pediatric Hematology/Oncology Fellow, Lucile Packard Children’s Hospital, Stanford University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MBBCh, FRCPC, DTM&H, Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Acknowledgements

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, MS is a member of the following medical societies: American Bar Association

Disclosure: Nothing to disclose. 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

Susan J Gross, MD, FRCS(C), FACOG, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, American Society of Human Genetics, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References

  1. Charache S, Conley CL, Waugh DF, Ugoretz RJ, Spurrell JR. Pathogenesis of hemolytic anemia in homozygous hemoglobin C disease. J Clin Invest. 1967 Nov. 46(11):1795-811. [View Abstract]
  2. Modiano D, Luoni G, Sirima BS, Simporé J, Verra F, Konaté A, et al. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature. 2001 Nov 15. 414(6861):305-8. [View Abstract]
  3. Mangano VD, Kabore Y, Bougouma EC, Verra F, Sepulveda N, Bisseye C, et al. Novel Insights Into the Protective Role of Hemoglobin S and C Against Plasmodium falciparum Parasitemia. J Infect Dis. 2015 Aug 15. 212 (4):626-34. [View Abstract]
  4. Rihet P, Flori L, Tall F, Traore AS, Fumoux F. Hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack. Hum Mol Genet. 2004 Jan 1. 13(1):1-6. [View Abstract]
  5. Agarwal A, Guindo A, Cissoko Y, Taylor JG, Coulibaly D, Koné A. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood. 2000 Oct 1. 96(7):2358-63. [View Abstract]
  6. Piel FB, Howes RE, Patil AP, Nyangiri OA, Gething PW, Bhatt S, et al. The distribution of haemoglobin C and its prevalence in newborns in Africa. Sci Rep. 2013. 3:1671. [View Abstract]
  7. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 2008 Jun. 86(6):480-7. [View Abstract]
  8. Schneider RG, Hightower B, Hosty TS, Ryder H, Tomlin G, Atkins R. Abnormal hemoglobins in a quarter million people. Blood. 1976 Nov. 48(5):629-37. [View Abstract]
  9. GALBRAITH PA, GREEN PT. Hemoglobin C disease in an Anglo-Saxon family. Am J Med. 1960 Jun. 28:969-72. [View Abstract]
  10. Powars DR, Hiti A, Ramicone E, Johnson C, Chan L. Outcome in hemoglobin SC disease: a four-decade observational study of clinical, hematologic, and genetic factors. Am J Hematol. 2002 Jul. 70(3):206-15. [View Abstract]
  11. Olson JF, Ware RE, Schultz WH, Kinney TR. Hemoglobin C disease in infancy and childhood. J Pediatr. 1994 Nov. 125(5 Pt 1):745-7. [View Abstract]
  12. 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. 1992 Mar. 37(3):163-8. [View Abstract]
  13. Lipshutz M, McQueen DA, Rosner F. Spontaneous rupture of the spleen in homozygous hemoglobin C disease. JAMA. 1977 Feb 21. 237(8):792-3. [View Abstract]
  14. Tripette J, Alexy T, Hardy-Dessources MD, Mougenel D, Beltan E, Chalabi T. 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. 2009 Aug. 94(8):1060-5. [View Abstract]
  15. Gabrovsky A, Aderinto A, Aderinto A, Spevak M, Vichinsky E, Resar LM. Low dose, oral epsilon aminocaproic acid for renal papillary necrosis and massive hemorrhage in hemoglobin SC disease. Pediatr Blood Cancer. 2010 Jan. 54(1):148-50. [View Abstract]
  16. Waltz X, Romana M, Lalanne-Mistrih ML, Machado RF, Lamarre Y, Tarer V, et al. Hematologic and hemorheological determinants of resting and exercise-induced hemoglobin oxygen desaturation in children with sickle cell disease. Haematologica. 2013 Jul. 98(7):1039-44. [View Abstract]
  17. Lemaire C, Lamarre Y, Lemonne N, Waltz X, Chahed S, Cabot F. Severe proliferative retinopathy is associated with blood hyperviscosity in sickle cell hemoglobin-C disease but not in sickle cell anemia. Clin Hemorheol Microcirc. 2013 Jan 1. 55(2):205-12. [View Abstract]
  18. Lemonne N, Lamarre Y, Romana M, Hardy-Dessources MD, Lionnet F, Waltz X, et al. Impaired blood rheology plays a role in the chronic disorders associated with sickle cell-hemoglobin C disease. Haematologica. 2014 May. 99(5):74-5. [View Abstract]
  19. Lamarre Y, Hardy-Dessources MD, Romana M, Lalanne-Mistrih ML, Waltz X, Petras M, et al. Relationships between systemic vascular resistance, blood rheology and nitric oxide in children with sickle cell anemia or sickle cell-hemoglobin C disease. Clin Hemorheol Microcirc. 2013 Jan 8. [View Abstract]
  20. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9. 330(23):1639-44. [View Abstract]
  21. 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. 2008 Apr. 28(2):135-7. [View Abstract]
  22. Chmel H, Bertles JF. Hemoglobin S/C disease in a pregnant woman with crisis and fat embolization syndrome. Am J Med. 1975 Apr. 58(4):563-6. [View Abstract]
  23. 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). 2011 Nov. 90(6):372-8. [View Abstract]
  24. Prindle KH Jr, McCurdy PR. Red cell lifespan in hemoglobin C disorders (with special reference to hemoglobin C trait). Blood. 1970 Jul. 36(1):14-9. [View Abstract]
  25. DIGGS LW, BELL A. INTRAERYTHROCYTIC HEMOGLOBIN CRYSTALS IN SICKLE CELL-HEMOGLOBIN C DISEASE. Blood. 1965 Feb. 25:218-23. [View Abstract]
  26. 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. 2008 Jul-Aug. 41(1):60-6. [View Abstract]
  27. Tokumasu F, Nardone GA, Ostera GR, Fairhurst RM, Beaudry SD, Hayakawa E. Altered membrane structure and surface potential in homozygous hemoglobin C erythrocytes. PLoS One. 2009. 4(6):e5828. [View Abstract]