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Hemoglobin C Disease

Hemoglobin C disease is a hemoglobinopathy causing mild hemolytic anemia


Presentation

Although individuals with Hemoglobin C disease have the disorder all their lives the symptoms are usually not be life threatening. Life expectancy is normal.

Chronic mild hemolytic anemia may cause fatigue and decreased activity tolerance. Also individuals may experience exacerbations of muscle and joint pain similar to those of sickle cells anemia [6].

Aplastic crises may occur with acute physiologic assault: injury with significant blood loss, severe infection, and pregnancy [5] [7].

Presentation

Patients with Hemoglobin C disease generally present with mild hemolytic anemia. Symptoms of anemia may also be present: fatigue, exercise intolerance, and chronic muscle and joint pain [5] [6]. They are otherwise asymptomatic.  

Complications of Hemoglobin C disease include:

Aplastic crisis happens when there is the need for red blood cells increases dramatically due to parvovirus infection, injury with blood loss, surgery, or excessive physical activity [7]. When red blood cell production cannot keep pace with need, severe anemia results. The episodes usually resolve spontaneously in several days or weeks. However in rare instances blood transfusions are required.

The retinopathy associated with Hemoglobin C disease if due to hypervacuolization of the retina resulting from the aggregation of the abnormal red blood cells and chronic anemia. Recent studies have shown the occurrence of retinopathy in individuals with Hemoglobin C trait as well [5].  

Differential diagnosis

The following diagnoses should be ruled out before Hemoglobin C disease is confirmed:

Aspiration
  • Hospital workup revealed a solitary intrathoracic mass in the posterior mediastinum, which was suspected to be a lymphoma based on fine-needle aspiration. The mass was excised and proved to be an extramedullary hematopoietic tumor.[ncbi.nlm.nih.gov]
Anemia
  • Chronic mild hemolytic anemia may cause fatigue and decreased activity tolerance. Also individuals may experience exacerbations of muscle and joint pain similar to those of sickle cells anemia.[symptoma.com]
  • Acute splenic sequestration crisis ( ASSC ), a common complication in homozygous sickle cell anemia, has been described infrequently in sickle-hemoglobin C (SC) disease in the absence of high altitude exposure.[ncbi.nlm.nih.gov]
  • Anemia usually is not severe enough to require blood transfusion.[merckmanuals.com]
  • Patients typically had a mild hemolytic anemia characterized by microcytosis and target cells.[ncbi.nlm.nih.gov]
  • The potential for multiorgan involvement secondary to vaso-occlusive crisis complicated the diagnosis and overlapped with the patient's clinical presentation of chronic bone pain and hemolytic anemia.[ncbi.nlm.nih.gov]
Family History of Anemia
  • At a Glance A family history of anemia in the absence of iron deficiency should prompt consideration of a hemoglobinopathy, and a number of these appear in the differential diagnosis. Hemoglobin C is an inherited mutation in the ß-globin gene.[clinicaladvisor.com]
Movement Disorder
  • Less common clinical presentations are epilepsy and movement disorders . Medical treatment consists of antiplatelet therapy to prevent thrombus formation.[omicsonline.org]
Neglect
  • Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med. 2011;41(6 Suppl 4):S398–405. View Article PubMed PubMed Central Google Scholar Steinberg MH.[bmchematol.biomedcentral.com]

Workup

Newborn screening for sickle hemoglobinopathies will identify various abnormalities in hemoglobin at birth. The purpose of newborn screening is to identify children with these genetic disorders early so treatment and monitoring can begin before morbidity or complications occur [2] [10].

Newborn screening for sickle cell disease and hemoglobinopathies began in the United States in 1990. Today all 50 states screen for these anomalies [2] [3].

Laboratory studies

The following laboratory studies should be done when Hemoglobin C disease is suspected:

  • Hemoglobin electrophoresis: To further evaluate the abnormality, hemoglobin electrophoresis is used. Individuals who are homozygous for hemoglobin C will have 100% hemoglobin C. Those who are heterozygous (have the trait) for hemoglobin C may have approximately 35% hemoglobin C [11].
  • Complete blood count (CBC)
  • Iron studies
  • Reticulocyte count and lactic dehydrogenase (LDH) levels
  • Peripheral blood smear

Imaging studies

Dental x-rays may show infarction or abnormal dental marrow. Abdominal ultrasonography may be used to diagnose gallstones and splenomegaly [4]. Examination of the retina of the eye using fluorescein angiography should be used to detect retinal abnormalities associated with vascular changes [4].

Periodic Patterns
  • Hemoglobin molecules measuring 70 A in diameter were readily identified within the period patterns of intracellular crystals. These findings suggest that the hemoglobin C molecules within C-C erythrocytes exist in an aggregated state.[ncbi.nlm.nih.gov]

Treatment

Hemoglobin C disease is a chronic disorder that affects those with the disease throughout their lives. Treatment is supportive and aimed at prevention and early detection of the complications of the disease. The primary interventions should include [6] [7]:

  • Routine monitoring for anemia.
  • Regular eye examination with fluorescein angiography for early detection of neovascularization.
  • Early detection and treatment of acute problems such as aplastic crisis
  • Folic acid (1 mg/day orally).
  • Iron supplementation only when iron stores are low.
  • Splenectomy with extreme splenomegaly.
  • Cholecystectomy if gallstones are presence.
  • Genetic counseling is recommended. 
  • No special diet is required.
  • No restriction in physical activities.

Prognosis

Although individuals with Hemoglobin C disease have the disorder all their lives the symptoms are usually not be life threatening. Life expectancy is normal.

Chronic mild hemolytic anemia may cause fatigue and decreased activity tolerance. Also individuals may experience exacerbations of muscle and joint pain similar to those of sickle cells anemia [6].

Aplastic crises may occur with acute physiologic assault: injury with significant blood loss, severe infection, and pregnancy [5] [7].

Etiology

Hemoglobin C is a structural variant of normal hemoglobin resulting from a substitution in amino acids at position 6 of the β-globin chain [1] [4]. It is a single gene autosomal recessive disorder associated with chronic mild anemia.

Like in sickle cell anemia, the abnormal hemoglobin C molecule gives protection against malaria [8] [9]. Hemoglobin C is linked to a 29% reduction in clinical malaria in individuals with the trait for the disease and a 93% reduction in those with the disease [8]. Since Hemoglobin C has a more limited pathology compared to the severity of Sickle cell anemia, it suggests that the incidence of Hemoglobin C disease will surpass sickle cell disease over time [8].

Epidemiology

Hemoglobin C disease occurs primarily in those of African descent. It is also seen occasionally in individuals of Hispanic and Sicilian ethnicity. Generally it occurs most often in areas with endemic malaria.

Hemoglobin C disease has an incidence of approximately 0.17% in African Americans. The incidence in North Africa may be as high as 13% [1] [10].

Although Hemoglobin C disease is present at birth [5], many patients world-wide are not diagnosed until adulthood [1].

Males and females are affected equally [1].

Sex distribution
Age distribution

Pathophysiology

Hemoglobin C is a variation in the structure of normal hemoglobin resulting from a substitution of lysine for glutamic acid at position 6 of the β-globin chain [1] [5] [4] in red blood cells. The abnormal hemoglobin C forms crystals [5]. The crystals affect the red blood cells by decreasing their ability to change shape in order to freely move through capillaries and blood vessels. This abnormality increases the viscosity of the blood [5].

Red blood cells with abnormal hemoglobin C have an accumulation of iron and lipids in their membranes which make these cells more friable and shorten their life span. The mechanisms for this are not known [4] [9].

The spleen removes the abnormal red blood cells and crystals from the circulatory system. As a result individuals with Hemoglobin C disease may experience splenomegaly [5] [6]. In individuals with normal hemoglobin about 3% of the total hemoglobin is removed from the circulatory system every day [4][8]. Hemoglobin C molecules are destroyed at a much higher rate resulting in mild anemia. With physiological stress from illness, injury, or exercise the rate of cell destruction increases even further[4] [9]. Physiological stress with exercise along with the increased blood viscosity result in exercise-induced hemoglobin desaturation [7].

Aplastic crisis may result. This, possibly life-threatening complication of Hemoglobin C disease is the sudden occurrence of severe anemia when the body cannot produce sufficient hemoglobin and red blood cells for the demand.

Prevention

The incidence of Hemoglobin C disease can only be prevented with extensive genetic counseling. Individuals with Hemoglobin C disease or Hemoglobin C trait should be counseled that [6]:

  • If both parents have the trait each child has a 25% chance of having the disease and a 50% chance of having the trait.
  • If one parent has the disease and the other parent has the trait all their children will at least have the trait and a 50% chance of having the disease.
  • If one parent has the disease and the other is free of the trait, each child will have the trait.

Prevention with regard to the management of Hemoglobin C disease should be aimed at the prevention of the complications of the disease.

The anemia of Hemoglobin C disease increases significantly with fever, infections (especially parvovirus B19), and pregnancy. The resulting aplastic anemia may necessitate blood transfusions [2]. Prevention and/or early intervention with these conditions is paramount in the care of individuals with Hemoglobin C disease.

Summary

Hemoglobin C disease is an autosomal recessive disorder causing mild hemolytic anemia [1]. It is a benign blood disorder involving the production of hemoglobin.

Today in the United States most individuals with Hemoglobin C disease are diagnosed in the newborn period through newborn screening programs [2] [3]. For those not screened, Hemoglobin C disease may not be diagnosed until adulthood.

Hemoglobin C is a common variant in the structure of human hemoglobin [1] [4]. The changes in the hemoglobin molecule cause the production of crystals within the red blood cells making them less flexible and decreasing their life span. Mild hemolytic anemia and increased blood viscosity result.

Symptoms of the disease include those associated with mild to moderate anemia: fatigue, exercise intolerance, susceptibility to infection, and retinal damage [5] [6] [7].

Although Hemoglobin C disease causes only mild clinical symptoms and complications, early diagnosis and genetic counseling are important [1].

Patient Information

What is Hemoglobin C disease?

Hemoglobin C disease is an inherited genetic blood disease which causes mild hemolytic (abnormal destruction of red blood cells) anemia.  It is an autosomal recessive disorder meaning the defective gene must come from both parents. Individuals with only one abnormal gene are asymptomatic and are said to have the trait for the disease.

What are the symptoms ofHemoglobin C disease?

The primary symptom of Hemoglobin C disease is a chronic mild anemia. Musculoskeletal pain may often occur especially when oxygen need increases. Retinal abnormalities, gallstones and enlarged spleen may also occur.

What causes Hemoglobin C disease?

Hemoglobin C disease is an inherited genetic disease. It is caused by a defect in the gene that controls the production of hemoglobin, the oxygen carrying portion of the blood.  Instead of normal hemoglobin, an abnormal Hemoglobin C is produced. Hemoglobin C forms crystals which cause them to be inflexible and short lied. 

Who gets Hemoglobin C disease?

Hemoglobin c disease occurs most frequently in those of African or African American descent.  It may also occur in individuals of Hispanic or Sicilian ethnicity.

Since Hemoglobin C disease is an autosomal recessive disorder it has the following inheritance pattern:

  • If both parents have the trait each child has a 25% chance of having the disease and a 50% chance of having the trait.
  • If one parent has the disease and the other parent has the trait all their children will at least have the trait and a 50% chance of having the disease.
  • If one parent has the disease and the other is free of the trait, each child will have the trait.

How is Hemoglobin C disease diagnosed?

Hemoglobin C disease in the United States will most often be identified through newborn screening done for sickle cell anemia and other hemoglobin abnormalities.

Further testing for the presence of Hemoglobin C is required to confirm the diagnosis.

How is Hemoglobin C disease treated?

Hemoglobin C disease is treated primarily by monitoring for the anemia and for the occurrence of complications.  Your health care provider may prescribe folic acid and iron supplements.

More involved interventions may be needed if someone with the disorder requires additional red blood cells or oxygen supply. These stressors may include:

  • Surgery
  • Injury involving blood loss
  • Chronic illness
  • Excessive physical activity

What are the complications of Hemoglobin C disease?

The possible complications of Hemoglobin C disease include:

  • Musculoskeletal pain
  • Damage to retina due to increase in blood vessels
  • Enlarged spleen
  • Gall bladder disease with gallstones
  • Dental problems due to damage to tooth marrow

What can we do to prevent the complications of Hemoglobin C disease?

To prevent the complications of Hemoglobin C disease individuals with the disorder should:

  • See their health care provider regularly to monitor their anemia.
  • Have regular eye examinations including fundoscopic exams.
  • Take supplements as prescribed.

References

Article

  1. 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.
  2. Michlitsch J, Azimi M, Hoppe C, Walters MC, Lubin B, Lorey F, Vichinsky E. Newborn Screening for Hemoglobinopathies in California. Pediatr Blood Cancer 2009 52,486–490.
  3. Roe AM, Shur N.  From New Screens to Discovered Genes:The Successful Past and Promising Present of Single Gene Disorders. American Journal of Medical Genetics 2007 145(C), 77–86.
  4. 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 41(1):60-6.
  5. Hingorani M, Bentley CR, Jackson H, Betancourt F, Arya R, Aclimandos, WA, Bird AC. Retinopathy in haemoglobin C trait. Eye 1996 10 (3), 338-42.
  6. Tripette J, Alexy T, Hardy-Dessources MD, Daniele M, Beltan E, Chalabi T, 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 2009 94(8):1060-5.
  7. Waltz X, Romana M, Lalanne-Mistrih ML, Machado RF, Lamarre Y, Tarer V, et at. Hematologic and hemorheological determinants of resting and exercise-inducd hemoglobin oxygen desaturation in children with sickle cell disease. Haematologica 2013 98(7):1039-44.
  8. Modiano D, Luoni G, Sirima BS, Simporé J, Verra F, Konaté A, Coluzzi M. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 2001 414(6861),305-8.
  9. 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 2004 13(1),1-6.
  10. Olson JF, Ware RE, Schultz WH, Kinney R. Hemoglobin C disease in infancy and childhood. J Pediatr 1994 125(5 Pt 1),745-7.
  11. Lemaire C, Lamarre Y, Lemonne N, Waltz X, Chahed S, Cabot. Severe proliferative retinopathy is associated with blood hyperviscosity in sickle cell hemoglobin-C disease but not in sickle cell anemia. Clin Hemorheol Microcirc 2013 55(2),205-12.
  12. Tokumasu F, Nardone GA, Ostera GR, Fairhurst RM, Beaudry SD,  Hayakawa E, Dvorak DA. Altered membrane structure and surface potential in homozygous hemoglobin C erythrocytes. Public Library of Science One 2009 4(6), e5828.

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Last updated: 2018-06-22 03:28