Mini-Symposium: Controversies in the Evaluation and Treatment of Sickle Cell Disease
Differences in the clinical and genotypic presentation of sickle cell disease around the world,☆☆,

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Summary

Sickle cell disease (SCD), caused by a mutation in the β-globin gene HBB, is widely distributed in malaria endemic regions. Cardiopulmonary complications are major causes of morbidity and mortality. Hemoglobin SS (Hb SS) represents a large proportion of SCD in the Americas, United Kingdom, and certain regions of Africa while higher proportions of hemoglobin SC are observed in Burkina Faso and hemoglobin Sβ-thalassemia in Greece and India. Coinheritance of α-thalassemia and persistence of hemoglobin F production are observed in highest frequency in certain regions of India and the Middle East. As confirmed in the PUSH and Walk-PHaSST studies, Hb SS, absence of co-inheriting alpha-thalassemia, and low hemoglobin F levels tend to be associated with more hemolysis, lower hemoglobin oxygen saturations, greater proportions of elevated tricuspid regurgitant jet velocity and brain natriuretic peptide, and increased left ventricular mass index. Identification of additional genetic modifiers will improve prediction of cardiopulmonary complications in SCD.

Introduction

Sickle cell disease (SCD) is the consequence of homozygosity for a single amino acid change in the β-globin chain that results in structurally abnormal hemoglobin S, or by compound heterozygosity for hemoglobin S and another β-globin chain abnormality, typically hemoglobin C or β-thalassemia. In addition, α-thalassemia is a modifier of the clinical manifestations of SCD. The sickle-cell gene, β-thalassemia and α-thalassemia are distributed widely throughout sub-Saharan Africa the Middle East and parts of the Indian subcontinent, all areas of high prevalence of malaria historically. This striking overlap in the historical distribution of malaria and hemoglobin S, β-thalassemia and α-thalassemia provides evidence that protection from malaria mortality is what provided a heterozygote advantage for these mutations to become prevalent in certain populations. Carrier rates for hemoglobin S range from 5% to 40% or more of the population in these areas [1].

Sickle cell disease is among the most common monogenetic diseases worldwide [2]. It is estimated that 312,000 people with hemoglobin SS (Hb SS) are born each year throughout the world, with the majority of these births (236,000) in sub-Saharan Africa [3]. Based on the World Health Organization published global prevalence map of SCD and other data (http://www.who.int/genomics/public/Maphaemoglobin.pdf), about 20–25 million individuals world-wide have homozygous SCD; 12–15 million in sub-Saharan Africa, 5–10 million in India and about 3 million distributed in other parts of the world. Migration patterns have led to the distribution of the sickle cell genes into regions that are not endemic for malaria. About 8% of African Americans carry the sickle gene [4], [5] and the expected incidence of SCD at birth is 1 in 625 [6], [7]. Approximately 100,000 people with SCD live in the United States [8].

Hemoglobin S polymerizes upon deoxygenation and this causes erythrocyte rigidity, sickling and early destruction. Vaso-occlusion and hemolysis related to these rigid and/or sickled cells lead to disease manifestations, including hemolytic anemia, severe pain episodes from bone marrow ischemia, central nervous system strokes, the acute chest syndrome, pulmonary hypertension, left-sided heart disease, bacteremia, leg ulcers, growth failure, priapism and damage to the spleen, kidneys, liver and bones [9]. The disease severity varies considerably among patients with SCD and even among those with Hb SS. While some patients have severe complications and die before the third decade, others may remain largely asymptomatic. For example, in an investigation of pain involving 3578 patients as a part of the Cooperative Study of Sickle Cell Disease (CSSCD), 5.2% had 3-10 painful episodes requiring medical care per year while 39% had none [10].

Prominent recognized factors that influence the severity of SCD include the genotype, for example Hb SS versus hemoglobin SC (Hb SC) versus hemoglobin Sβ-thalassemia (Hb Sβ-thalassemia), the coexistent presence of α-thalassemia, and the level of hemoglobin F (Hb F). We will consider the geographic distribution of these factors and how they influence the pulmonary and cardiac complications of SCD. This paper does not represent a formal meta-analysis or a comprehensive review of the literature. Rather it provides selected examples of geographic variation and prevalences.

Section snippets

Distribution of sickle cell disease genotypes in patients of predominantly African origin in the Americas and the UK

The predominant genotypes that give rise to SCD include Hb SS, Hb SC, Hb Sβ+-thalassemia and Hb Sβ0-thalassemia. Other rare forms include hemoglobin SD and hemoglobin SE. Three recent large multicenter cohorts provide the distribution of these genotypes among SCD patients of predominantly African origin in the Americas and the UK (Table 1). In a cross-sectional study conducted at three centers in Brazil, 773 children and adolescents 2–16 years of age were screened with transcranial Doppler

Geographic variability of distribution of sickle cell disease genotypes outside the Americas and UK

Given the fairly uniform distribution of sickle genotypes in the Americas and the UK, it is striking how different the distributions are in specific geographic areas where malaria is endemic (Table 2). Among three university hospital-based cohorts from Nigeria and Senegal, the proportion of Hb SS genotype ranged from 88–96%, of Hb SC from 4–12%, and Hb Sβ-thalassemia <1% [14], [15], [16]. In contrast, among 153 SCD individuals identified through screening programs in villages or schools in the

Geographic variability of α-thalassemia in sickle cell disease

The α-thalassemias are frequently encountered in malaria endemic regions of Southeast Asia, Africa, India, and the Middle East. The α-globin genes are duplicated on each copy of chromosome 16 for a total of four α-globin genes (αα/αα). Deletions (e.g. −α3.7 and −α4.2) or gene mutations (e.g. αConstant Spring and αTSaudi) result in decreased production of α-globin chains. In Southeast Asia, the pattern of cis-deletions (−/αα) are more common in α-thalassemia with a prevalence of 4 – 14% and some

Geographic variability of hemoglobin F in sickle cell disease

Fetal hemoglobin (HbF), which is composed of two α-hemoglobin subunits and two γ-hemoglobin subunits (α2γ2), is the major hemoglobin produced during fetal development. The expression of Hb F starts early in development, peaks in mid-gestation, and by six months of age very little is expressed in most people. Fetal hemoglobin has a higher affinity for oxygen than hemoglobin A (Hb α2β2) due to a decrease in its interaction with 2, 3-bisphosphoglycerate. It is thought that this increase in oxygen

Sickle cell disease genotype and cardiopulmonary complications of sickle cell disease

Clinical phenotypes and laboratory values vary among the Hb SS, SC, and Sβ+-thalassemia sickle cell genotypes. Patients with Hb SS have higher markers of hemolysis and lower hemoglobin values compared to those with Hb SC or Sβ+-thalassemia. Correspondingly, the prevalence of leg ulcers and priapisms, which are sickle phenotypes related to higher hemolytic rates, are more prevalent in individuals with Hb SS disease [62], [63]. Other complications of SCD including stroke, vaso-occlusive pain

α-Thalassemia and cardiopulmonary complications of sickle cell disease

α-Thalassemia (αα/α- or α-/α-) is present in approximately 1/3 of SCD patients and seems to lessen the clinical severity of disease by decreasing the mean corpuscular hemoglobin concentration, percentage of dense cells, degree of hemolysis and number of irreversibly sickled cells, and by increasing total hemoglobin levels and hemoglobin A2 levels [95], [96]. There seems to be a decreased incidence of involvement of vital organs in SCD patients with alpha-thalassemia [97], and alpha-thalassemia

Hemoglobin F and cardiopulmonary complications of sickle cell disease

Fetal hemoglobin levels vary over a 20-fold range in adults with SCD, and clinical observations suggest that higher levels of Hb F have beneficial effects [99], [109], including higher hemoglobin concentrations and less hemolysis [110], [111], [112]. In one study, end organ damage seemed to be decreased in patients with Hb F levels >10% and painful crises and pulmonary complications were decreased with levels >20% [109]. In the CSSCD, Hb F levels correlated inversely with the risk of painful

Conclusion

Sickle cell disease has a high prevalence across regions of sub-Saharan Africa, the Middle East, and India and modifying factors such as SCD genotype, coinheritance of α-thalassemia, and Hb F production vary by geographic region. The impact of SCD genotype on cardiopulmonary complications appears the most consistent of these factors. Patients with Hb SS or Sβ0-thalassemia have higher rates of hemolysis reflected by higher serum LDH levels and lower hemoglobin concentrations. This has correlated

Educational Aims

  • 1.

    To better understand the geographic distribution of sickle cell disease and its clinical modifiers: genotype, hemoglobin F concentration, and coinheritance of alpha-thalassemia.

  • 2.

    To better understand the influence of genetic modifiers on the cardiopulmonary complications of sickle cell disease.

  • 3.

    To better understand how genetic modifiers impact degree of hemolysis.

Future Research Directions

  • 1.

    To identify additional modifiers that may affect risk for non-cardiopulmonary complications.

  • 2.

    To identify additional modifiers that may affect risk for cardiopulmonary complications.

  • 3.

    To identify specific treatments aimed at targeting modifiers of sickle cell disease to improve its complications.

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    The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR000048. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

    ☆☆

    The Walk-PHaSST project was supported by federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contract HHSN268200617182C.

    The PUSH project was supported by grant numbers 2 R25 HL003679-08 and 1 R01 HL079912-02 from NHLBI, by Howard University GCRC grant number 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, and by the intramural research program of the National Institutes of Health.

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