
DEFINITION
Sickle Cell is an inherited blood disorder, characterized by sickle shaped red blood cells (1). There are different types of sickle cell disease. They include Hb SS, Hb SC, Hb S beta-thalassemia, and many others. HbSS is the most common and most severe type (12). It is common in people of African origin (1).
In sickle cell hemoglobin, αchains are normal and βchains are abnormal. The molecules of hemoglobin S polymerize into long chains and precipitate inside the cells. Because of this, the RBCs attain sickle (crescent) shape and become more fragile leading to hemolysis. Sickle cell disease occurs when a person inherits two abnormal genes (one from each parent) (1).
PREVALENCE
The highest prevalence in newborns with Sickle Cell Disease (SCD) is seen in middle and low socioeconomic countries. Africa is home to the majority of people living with SCD. About 236,000 babies are born with SCD in sub-Saharan Africa each year (more than 80 times as many as in the United States), and up to 90% will die during childhood, typically before their fifth birthday (13). The prevalence of sickle cell trait and the homozygous state in Nigeria, a country with the highest burden, are 25% and up to 2% respectively (14). Prevalence in the Indian subcontinent is second only to Africa.
The prevalence of the disease is high throughout large areas in sub-Saharan Africa, the Mediterranean basin, the Middle East, and India because of the remarkable level of protection that the sickle cell trait (i.e., heterozygosity for the sickle cell mutation in HBB) provides against severe malaria (2). Early diagnosis and initiation of treatment is crucial, without which about 90% of children die in the first few years of life. Infectious complications are a common cause of increased mortality in SCD patients, and this fact underlies the importance of improving nutrition, hygiene, and proper infrastructure especially in developing countries (3).
DISTRIBUTION
Statistics on the geographic distribution of sickle cell incidence and its consequences show that the odds are stacked against Africa, particularly Nigeria. While five percent of the world’s population carries the haemoglobinopathies, one out of every four Nigerian bears the mutant gene. Each year, of the approximately 300,000 infants born around the world with the sickle cell disease. The vast majority of these births occur in three countries: Nigeria, the Democratic Republic of the Congo, and India with more than 200,000 and 150,000 originating from Africa and Nigeria respectively. Mortality rate before the age of ten is 95% in Nigeria. Undoubtedly, Nigeria bears a disproportionate weight of the burden of this public health crisis (15).
Due to slave trading and contemporary population movements, the distribution of sickle cell disease has spread far beyond its origins. The number of patients with sickle cell disease is expected to increase, both in high-income and lower-income countries (2). A study by Piel et al, (2017) (4) has estimated that with improved survival and population movements, the overall global burden of SCD is increasing, with the annual number of SCD newborns being expected to increase from 300,000 to more than 400,000 between 2010 and 2050 (3).
SIGNS AND SYMPTOMS
Signs and symptoms of sickle cell anemia usually appear around 6 months of age. They vary from person to person and may change over time. Signs and symptoms can include:
Anemia: Sickle cells break apart easily and die. Red blood cells usually live for about 120 days before they need to be replaced. But sickle cells typically die in 10 to 20 days, leaving a shortage of red blood cells (anemia). Without enough red blood cells, the body can't get enough oxygen, and this causes symptoms like (depending on the severity) fatigue, weakness, headaches, etc. (5).
Pain crisis, or sickle crisis: This occurs when the flow of blood is blocked to an area because the sickled cells have become stuck in the blood vessel, thereby occluding the vessel. The pain can occur anywhere, but most often occurs in the chest, arms, and legs (6). The pain varies in intensity and can last for a few hours to a few days. Some people have only a few episodes of pain crises a year, others have a dozen or more a year. A severe episode of pain crisis requires hospital stay. Some adolescents and adults with sickle cell anemia also have chronic pain, which can result from bone and joint damage, ulcers, and other causes (5).
Swelling of hands and feet: The swelling is caused by sickle-shaped red blood cells blocking blood circulation in the hands and feet.
Frequent infections : Sickle cells can damage the spleen, increasing vulnerability to infections. Infants and children with sickle cell anemia commonly receive vaccinations and antibiotics to prevent potentially life-threatening infections, such as pneumonia.
Delayed growth or puberty: Red blood cells provide the body with the oxygen and nutrients needed for growth. A shortage of healthy red blood cells can slow growth in infants and children and delay puberty in teenagers.
Vision problem: Tiny blood vessels that supply the eyes can become plugged with sickle cells. This can damage the retina — the portion of the eye that processes visual images — and lead to vision problems (5).
Jaundice, or yellowing of the skin, eyes, and mouth: Jaundice is a common sign and symptom of sickle disease. Sickle cells do not live as long as normal red blood cells and they die faster than the liver can filter them out. Bilirubin (which causes the yellow color) from these broken-down cells builds up in the system causing jaundice (6).
PROGNOSIS
Sickle cell disease (SCD) is a pediatric disease that is fatal in countries that do not have access to comprehensive care for patients with this disease and do not practice newborn screening (NBS). In developed countries, children with SCD that are recognized early by NBS are likely to live into adulthood, although their overall life expectancy is decreased by 20 to 30 years without curative hematopoietic stem cell transplant (8).
Some people with the disease can remain without symptoms for years, while others do not survive beyond infancy or early childhood. New treatments for SCD are improving life expectancy and quality of life (7). Other factors that affect prognosis include genotype, hemoglobin level, number of crises per year, and the presence of neurologic or renal disease.
Genotype & hemoglobin level: One study of patients with SCD across 3 tertiary care facilities in the United States reported that the hemoglobin SS and Sβ0 genotypes confer a worse prognosis than the SC and Sβ+ genotypes. Older studies reported the expected survival of patients with hemoglobin SS to be 42 to 48 years and the survival of those with hemoglobin SC to be 60 to 68 years 10. Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease (9). Fetal hemoglobin (HbF) levels are associated with positive outcomes and prolonged survival in patients with SCD. One study of patients with SCD across 3 tertiary care facilities in the United States reported that the hemoglobin SS and Sβ0 genotypes confer a worse prognosis than the SC and Sβ+ genotypes. Older studies reported the expected survival of patients with hemoglobin SS to be 42 to 48 years and the survival of those with hemoglobin SC to be 60 to 68 years 10. Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease (9). Fetal hemoglobin (HbF) levels are associated with positive outcomes and prolonged survival in patients with SCD. One study of patients with SCD across 3 tertiary care facilities in the United States reported that the hemoglobin SS and Sβ0 genotypes confer a worse prognosis than the SC and Sβ+ genotypes. Older studies reported the expected survival of patients with hemoglobin SS to be 42 to 48 years and the survival of those with hemoglobin SC to be 60 to 68 years 10. Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease (9). Fetal hemoglobin (HbF) levels are associated with positive outcomes and prolonged survival in patients with SCD.
Stroke: A history of any cerebrovascular event is associated with decreased survival
Renal disease: the presence of proteinuria and a decreased glomerular filtration rate (GFR) are also associated with decreased longevity.
Crises/year: An inverse relationship exists between the number of pain crises per year and mortality. The median survival for patients who have 0 to 4 pain crises per year is 61 years, whereas it is 53 years for those with more than 4 pain crises per year.
Infections: remains a leading cause of death in children with SCD, including infection with malaria in countries where it is endemic (10).
PREVENTION AND TREATMENT
Genotype testing: Genotype screening before marriage has a lot of benefits for both partners and the children they plan to have. It saves couples and their offspring the stress that comes with the management of sickle cell disease. Preventive programs consisting of public education, population screening, genetic counseling, and prenatal diagnosis have been very effective in reducing rates of β-Thalassemia major (16). Genotype screening before marriage has a lot of benefits for both partners and the children they plan to have. It saves couples and their offspring the stress that comes with the management of sickle cell disease. Preventive programs consisting of public education, population screening, genetic counseling, and prenatal diagnosis have been very effective in reducing rates of β-Thalassemia major (16).
Managing Pain Crises: Prevention is the best approach to pain management in SCD. Patients with SCD may implement a few simple actions focused on prevention; these include drinking plenty of water, exercising, and avoiding exposure to extreme temperature changes and high altitudes. Painful crises can be managed with pain medication, such as nonsteroidal anti-inflammatory drugs. However, a few patients will require opioid treatment or hospitalization to treat severe episodes.
Transfusion therapy: Blood transfusions make it possible to manage acute conditions—immediately improving blood flow, increasing the oxygen-carrying capacity of the blood, and preventing possible complications of SCD. Several risks are associated with transfusion therapy.
Hydroxyurea: was the first treatment approved by the US Food and Drug Administration (FDA) for patients with SCD. Hydroxyurea increases the level of fetal hemoglobin (HbF) and decreases hemoglobin S (HbS) polymerization. The administration of hydroxyurea is well tolerated, with few short-term side effects observed.
Stem cell transplant: is the only curative therapeutic approach in SCD. This treatment can be undertaken when a donor is available and when the benefits of the procedure outweigh the risks involved in a hematopoietic transplant, such as rejection and intracranial hemorrhage 11.
CURRENT RESEARCH EFFORT
1. Modifying the Patient’s Genotype:
● Gene addition using lentiviral vector-based strategies
● Gene editing: Gene-editing corrects a specific defective DNA in its native location
2. Targeting Hemoglobin S Polymerization
3. Targeting Vaso Occlusion
4. Targeting Inflammation (17).
REFERENCES
1. K Sembulingam PhD and Prema Sembulingam PhD. Essentials of medical physiology. Madha Medical College & Research Institute Kundrathur Main Road, Kovur, Thandalam (Near Porur)Chennai, Tamil Nadu, India.
2. Dan L. Longo, M.D., The new england journal of medicine. n engl j med 376;16 nejm.org April 20, 2017. DOI: 10.1056/NEJMra1510865
3. Dibya L. Praharaj, Anil C. Anand Sickle Hepatopathy, 2020 journal of clinical and experimental hepatology. https://doi.org/10.1016/j.jceh.2020.08.003
4. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376:1561–1573.
5. Mayo clinic. Sickle cell anemia, https://www.mayoclinic.org/diseases-conditions/sickle-cell-anemia/symptoms-causes/syc-20355876 2022. Accessed 16 Mar 2023.
6. Johns Hopkins Medicine, Sickle cell disease, https://www.hopkinsmedicine.org/health/conditions-and-diseases/sickle-cell-disease 2023. Accessed 17 Mar 2023.
7. Cleveland clinic, Sickle cell disease, https://my.clevelandclinic.org/health/diseases/12100-sickle-celldisease#:~:text=Outlook%20%2F%20Prognosis&text=People%20who%20have%20sickle%20cell,expectancy%20and%20quality%20of%20life. 2022. Accessed 17 Mar 2023.
8. Sedrak A, Kondamudi NP. Sickle cell disease. StatPearls [Internet]. Updated September 6, 2021. Accessed 17 Mar 2023.
9. Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, Chui DH, Steinberg MH. Fetal hemoglobin in sickle cell anemia. Blood. 2011 Jul 7;118(1):19-27. doi: 10.1182/blood-2011-03-325258. Epub 2011 Apr 13. PMID: 21490337; PMCID: PMC3139383.
10. Kyle Habet MD, Rare disease advisor. https://www.rarediseaseadvisor.com/disease-info-pages/sickle-cell-disease-prognosis/ 2021. Accessed 17 Mar 2023.
11. Diana Diez Gaspar, PharmD, PhD, Rare disease advisor. https://www.rarediseaseadvisor.com/disease-info-pages/sickle-cell-disease-prognosis/ 2021. Accessed 17 Mar 2023.
12. Ashorobi D, Ramsey A, Yarrarapu SNS, et al. Sickle Cell Trait. [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537130/
13. Albert E. Zhou, M.D., Ph.D., and Mark A. Travassos, M.D. Bringing Sickle-Cell Treatments to Children in Sub-Saharan Africa. nejm.org August 11, 2022. DOI: 10.1056/NEJMp2205013.
14. Hezekiah Isa, Samuel Adegoke, Anazoeze Madu, Abdul-Aziz Hassan, Chinatu Ohiaeri, Reuben Chianumba, Biobele Brown, Emmanuel Okocha, Ngozi Ugwu, Ijeoma Diaku-Akinwumi, Titilope Adeyemo, Aisha Kuliya-Gwarzo, Livingstone Dogara,Haliru Lawal, Yohanna Tanko, Adama Ladu, Umar Kangiwa, Lilian Ekwem, Seyi Oniyangi,Tambi Wakama, Domic Umoru, Olaniyi Olanrewaju. Sickle cell disease clinical phenotypes in Nigeria: A preliminary analysis of the Sickle Pan Africa Research Consortium Nigeria database.2020. https://doi.org/10.1016/j.bcmd.2020.102438
15. Kolade Ajilore, Emmanuel Onyeisi Morka, Kevin Onyenankeyab. Rethinking the sickle cell awareness campaign in West Africa: Evidence from Nigeria. March 2019.DOI: https://doi.org/10.31920/2516-5305/2019/v16n1a9
16. SS Sabitha Rani, IS Vamshidhar, S Bangaru, NA John1, J John. A Study of Spectrum of Sickle Cell Anemia and Thalassemia in a Teaching Institute of South India. 2022. DOI: 10.4103/njcp.njcp_1742_21
17. Gabriel Salinas Cisneros and Swee L. Thein Recent Advances in the Treatment of Sickle Cell Disease. 2020 https://doi.org/10.3389/fphys.2020.00435
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