Elsevier

The Lancet

Volume 376, Issue 9757, 11–17 December 2010, Pages 2018-2031
The Lancet

Seminar
Sickle-cell disease

https://doi.org/10.1016/S0140-6736(10)61029-XGet rights and content

Summary

Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa, where little is known about this disease; however, we do know that the disorder follows a more severe clinical course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased severity of sickle-cell disease. More work is needed to develop effective treatments that specifically target pathophysiological changes and clinical complications of sickle-cell disease.

Introduction

Sickle-cell disease is a multisystem disease, associated with episodes of acute illness and progressive organ damage, and is one of the most common severe monogenic disorders worldwide.1 Herrick2 first described the characteristic sickle-shaped erythrocytes in 1910 (figure 1), and understanding has gradually increased since then (table 1). Pauling and colleagues5 identified electrophoretic abnormalities in sickle haemoglobin (HbS) and coined the term “molecular disease” in 1949. The haemoglobin biophysics and genetics underlying the disease have been extensively studied and have helped the understanding of other molecular diseases. However, clinical management of sickle-cell disease is still basic and, although some evidence lends support to the use of blood transfusion and hydroxycarbamide in some circumstances, no drugs have been developed that specifically target the pathophysiology of this disease.

Section snippets

Classification

The term sickle-cell disease is used to refer to all the different genotypes that cause the characteristic clinical syndrome, whereas sickle-cell anaemia, the most common form of sickle-cell disease, refers specifically to homozygosity for the βS allele. In this Seminar, we mostly discuss sickle-cell anaemia, because there is little evidence for the management of other types of sickle-cell disease. In populations of African ethnic origin, sickle-cell anaemia typically accounts for 70% of cases

Pathophysiology

HbS is caused by a mutation in the β-globin gene in which the 17th nucleotide is changed from thymine to adenine and the sixth aminoacid in the β-globin chain becomes valine instead of glutamic acid.21 This mutation produces a hydrophobic motif in the deoxygenated HbS tetramer that results in binding between β1 and β2 chains of two haemoglobin molecules. This crystallisation produces a polymer nucleus, which grows and fills the erythrocyte, disrupting its architecture and flexibility and

Epidemiology

The global distribution of HbS is indicative of two factors: selection for carriers through their survival advantage in malaria-endemic regions and subsequent migration. Four region-specific African haplotypes (the Senegal, Benin, Bantu, and Cameroon haplotypes) and one Asian haplotype (the Arab-India haplotype) have been defined, providing support for the hypothesis that the mutation causing HbS has occurred, and been locally amplified, on at least two, and possibly several, separate occasions.

Phenotypic heterogeneity

The presentation and clinical course of sickle-cell disease shows substantial variation. For example, in the Cooperative Study of Sickle Cell Disease in the USA,68 39% of 3578 patients with sickle-cell anaemia had no episodes of pain but 1% had more than six per year. Such variability is characteristic of the disease and many of its complications, including cerebrovascular disease, acute chest syndrome, and premature death.

The two best established genetic modifiers are determinants of fetal

Diagnosis and screening

Diagnosis of sickle-cell disease is based on analysis of haemoglobin. Typically, this analysis involves protein electrophoresis or chromatography, which are cheap techniques and widely available worldwide, although haemoglobin mass spectrometry and DNA analysis are being increasingly used because these techniques enable high-throughput testing.89 Antenatal screening is available to women in some countries to help to identify couples who are at risk of having a baby with sickle-cell disease, and

Acute pain

Acute pain is the most common reason for admission to hospital for both adults and children, although it is more common in teenagers and young adults than in young children. Although acute vaso-occlusive pain is typically self-limiting and does not result in permanent organ damage, it is the most important complication from the patient's perspective, and increased frequency of pain is associated with early death in patients with sickle-cell anaemia who are older than 20 years.68 Frequent

Future developments

Stem-cell transplantation and gene therapy seem likely to become more widely applicable as new techniques develop, with the use of induced pluripotent stem cells offering the most promise.112 Data from genetic association studies should help to identify more unlinked and epigenetic factors to explain phenotypic diversity and to enable better prognosis, which might lead to the treatment of specific complications. Many drugs have given in-vitro or early benefit in sickle-cell disease without

Search strategy and selection criteria

We searched Medline and EmBase from 1960 to May, 2010, with the search term “sickle” in combination with the search terms “stroke”, “pain”, “infection”, “malaria”, “chest”, “kidney”, “vaso-occlusion”, “haemolysis”, “nitric oxide”, “epidemiology”, “screening”, “diagnosis”, “hydroxyurea”, “hydroxycarbamide”, “blood transfusion”, “iron chelation”, “gene therapy”, “transplantation”, “neurology”, “vasculopathy”, “pulmonary hypertension”, “cardiac”, and “treatment”. We mostly selected publications

References (150)

  • D Weatherall et al.

    A case for developing North-South partnerships for research in sickle cell disease

    Blood

    (2005)
  • JB Herrick

    Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia

    Arch Intern Med

    (1910)
  • VP Sydenstricker

    Further observations on sickle cell anemia

    J Am Med Ass

    (1924)
  • GS Graham

    Case of sickle cell anaemia with necropsy

    Arch Intern Med

    (1924)
  • L Pauling et al.

    Sickle cell anemia, a molecular disease

    Science

    (1949)
  • J Watson et al.

    The significance of the paucity of sickle cells in newborn negro infants

    Am J Med Sci

    (1948)
  • MF Perutz et al.

    X-ray and solubility studies of the haemoglobin of sickle-cell anaemia patients

    Nature

    (1951)
  • AB John et al.

    Prevention of pneumococcal infection in children with homozygous sickle cell disease

    BMJ

    (1984)
  • MH Gaston et al.

    Prophylaxis with oral penicillin in children with sickle cell anemia

    N Engl J Med

    (1986)
  • FL Johnson et al.

    Bone-marrow transplantation in a patient with sickle-cell anemia

    N Engl J Med

    (1984)
  • S Charache et al.

    Effect of hydroxyurea on frequency of painful crises in sickle cell anemia

    N Engl J Med

    (1995)
  • RJ Adams et al.

    Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography

    N Engl J Med

    (1998)
  • RL Nagel et al.

    The paradox of hemoglobin SC disease

    Blood Rev

    (2003)
  • GR Serjeant et al.

    Sickle cell disease

    (2001)
  • W Moo-Penn et al.

    The presence of hemoglobin S and C Harlem in an individual in the United States

    Blood

    (1975)
  • N Monplaisir et al.

    Hemoglobin S Antilles: a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes

    Proc Natl Acad Sci USA

    (1986)
  • HE Witkowska et al.

    Sickle cell disease in a patient with sickle cell trait and compound heterozygosity for hemoglobin S and hemoglobin Quebec-Chori

    N Engl J Med

    (1991)
  • RL Nagel et al.

    HbS-Oman heterozygote: a new dominant sickle syndrome

    Blood

    (1998)
  • D Masiello et al.

    Hemoglobin SE disease—a concise review

    Am J Haematol

    (2007)
  • A Geva et al.

    Hemoglobin Jamaica Plain—a sickling hemoglobin with reduced oxygen affinity

    N Engl J Med

    (2004)
  • HF Bunn

    Pathogenesis and treatment of sickle cell disease

    N Engl J Med

    (1997)
  • GM Brittenham et al.

    Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes

    Blood

    (1985)
  • CT Noguchi et al.

    Levels of fetal hemoglobin necessary for treatment of sickle cell disease

    N Engl J Med

    (1988)
  • PS Frenette

    Sickle cell vaso-occlusion: multistep and multicellular paradigm

    Curr Opin Hematol

    (2002)
  • A Turhan et al.

    Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm

    Proc Natl Acad Sci USA

    (2002)
  • JD Belcher et al.

    Transgenic sickle mice have vascular inflammation

    Blood

    (2003)
  • UR Osarogiagbon et al.

    Reperfusion injury pathophysiology in sickle transgenic mice

    Blood

    (2000)
  • KC Wood et al.

    Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice

    Faseb J

    (2005)
  • JD Belcher et al.

    Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice

    Am J Physiol Heart Circ Physiol

    (2005)
  • OS Platt et al.

    Mortality in sickle cell disease. Life expectancy and risk factors for early death

    N Engl J Med

    (1994)
  • CH Pegelow et al.

    Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia

    Am J Med

    (1997)
  • K Ohene-Frempong et al.

    Cerebrovascular accidents in sickle cell disease: rates and risk factors

    Blood

    (1998)
  • MT Gladwin et al.

    Pulmonary hypertension as a risk factor for death in patients with sickle cell disease

    N Engl J Med

    (2004)
  • GJ Kato et al.

    Cerebrovascular disease associated with sickle cell pulmonary hypertension

    Am J Hematol

    (2006)
  • GJ Kato et al.

    Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes

    Blood Rev

    (2007)
  • LM De Castro et al.

    Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes

    Am J Hematol

    (2008)
  • KI Ataga et al.

    Pulmonary hypertension in patients with sickle cell disease: a longitudinal study

    Br J Haematol

    (2006)
  • N Dham et al.

    Prospective echocardiography assessment of pulmonary hypertension and its potential etiologies in children with sickle cell disease

    Am J Cardiol

    (2009)
  • CP Minniti et al.

    Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

    Haematologica

    (2009)
  • RP Rother et al.

    The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease

    JAMA

    (2005)
  • T Repka et al.

    Hydroxyl radical formation by sickle erythrocyte membranes: role of pathologic iron deposits and cytoplasmic reducing agents

    Blood

    (1991)
  • CD Reiter et al.

    Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease

    Nat Med

    (2002)
  • RM Palmer et al.

    Vascular endothelial cells synthesize nitric oxide from L-arginine

    Nature

    (1988)
  • R De Caterina et al.

    Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines

    J Clin Invest

    (1995)
  • MT Gladwin

    Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome

    J Clin Invest

    (2006)
  • CR Morris et al.

    Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease

    JAMA

    (2005)
  • KI Ataga et al.

    Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension

    Haematologica

    (2008)
  • M Westerman et al.

    Microvesicles in haemoglobinopathies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy

    Br J Haematol

    (2008)
  • J Flint et al.

    The population genetics of the haemoglobinopathies

    Baillieres Clin Haematol

    (1998)
  • AC Allison

    Protection afforded by sickle cell trait against subtertian malarial infection

    BMJ

    (1954)

    • Cited by (0)

    View full text
    Copyright © 2010 Elsevier Ltd. All rights reserved.