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

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