Sickle cell Disease, a Global Health Priority
Rita Bellevue MD
“Sickle cell disease / Thalassemia” represents the most prevalent genetic disorder worldwide and the first known molecular disease affecting millions of individuals. It is an inherited disorder of the hemoglobin, a protein molecule in the red blood cells which brings oxygen to the tissue.
There are 3 normal hemoglobin’s in an adult: Hemoglobin A constitutes 96% of the normal hemoglobin, hemoglobin A2 less than 4%, hemoglobin fetal(F), less than 1%. Normal hemoglobin’s contain 2 pairs of globin polypeptides chains and to each is linked to a heme group (2 alpha and 2 Beta for hemoglobin A, 2 alpha and 2 gammas for hemoglobin F, 2 alpha 2 delta for hemoglobin A2).
Sickle cell hemoglobin results from a point mutation (GAG to GTG) in the sixth codon of the gene for Beta Globin where the sixth amino acid of the polypeptide chain is valine instead of glutamic acid. This leads to the polymerization of the hemoglobin S molecules when deoxygenated with formation of the characteristic sickle cell shape.
The disease is characterized by painful vaso-occlusive crisis, life-long hemolytic anemia, and progressive organ damage. The pathophysiology of vaso-occlusion is a complex process which involved acute and chronic inflammatory conditions and a cascade of interactions among several cell types including endothelial cells, white blood cells, platelets, cellular adhesions molecules and sickle red blood cells. With vaso- occlusion, the area of the body involved is deprived of blood, oxygen and nutrients with development of ischemia and infarction.
The term sickle cell anemia is reserved for a person who is homozygous for the sickle or S gene (SS). Those who have inherited one S gene and a gene for a different hemoglobin variant or for a Beta- thalassemia mutation are double heterozygotes. An individual who has one sickle gene and a normal gene has sickle cell trait (AS, carrier state) and does not have sickle cell anemia. The most common sickle cell disease encountered are SS, SC, S Beta Thalassemia, SD Punjab, SE, SO Arab. Sickle cell anemia is the most severe form of the disease. Individuals with SO Arab and SD Punjab have the same symptoms as SS. SB0Thalassemia are variable.SB+ thalassemia and SC appear more moderate.
However, all sickle cell disease variants share the same clinical symptomatology, the severity is unpredictable and progressive. Organ damage may be detected for the first time during the fourth even the fifth decade because of different complications such as (Hip avascular necrosis or sickle cell retinopathy in SC and S Beta+ Thalassemia), following a routine eye examination or a hemoglobin electrophoresis. It is important to keep in mind that individuals with SC and SBeta- Thalassemia may have a normal hematocrit and hemoglobin level and often are diagnosed as having sickle cell trait and treated as opiates seeking individuals in the Emergency Department.
Here are some of the common complications of Sickle Cell Disease:
Vaso-occlusive crisis or pain crisis /dactylitis
chronic pain and various co-morbidities
Hematologic complications( Aplastic crisis, splenic sequestration, increased hemolysis)
Major organ complications( CVA, Acute Chest Syndrome, Pulmonary Hypertension, Cardiomyopathy, Cholelithiasis , Renal Disease, Ophthalmologic complications, Priapism, Leg Ulcerations, Avascular Necrosis, Sickle Cell Liver Disease, Arthropathy , Neuropathy).Infections and Sepsis.
Geographic Distribution of the Sickle Cell Gene:The Sickle Cell gene is widely distributed throughout the world and is associated with haplotypes representing independent mutations. These mutations happened in areas where malaria was common. Some studies shown the relative infrequency of malaria in person with the sickle cell trait (AS). In endemic areas of malaria there was a natural resistance against the development of malaria in patient with trait. There are 5 known globin Haplotypes, named after the places where they were first described:
These are the Benin haplotype, the Bantu haplotype (Central West Africa) the Senegal haplotype (Central African Republic), the Cameron haplotype, the Asian-Arab haplotype( India and Middle Eastern Arab Countries).
The Asian haplotype is found in the Eastern province of Saudi Arabia but patients from the Western province have the Benin Type. The Benin haplotype spreads to North Africa, Sicily, Greece, Albania, Southern Turkey. The Benin haplotype is seen also in Algeria, Morocco, Tunisia. The Bantu haplotype is seen mostly in Angola, DR Congo, and Mozambique. The sickle cell gene is in lower frequency in Iran, Syria, Jordan, the Bedouins of Israel and Palestine. Slave trade accounts for the Distribution of the S gene from Equatorial Africa to North America, Central and South America and the Caribbean’s (which include Spanish speaking countries such as Puerto Rico, Cuba and Dominican Republic). The S gene is mostly the Benin haplotype and In South America mostly the Bantu haplotype
Sickle Cell Gene in UK came mostly from Caribbean’s, Ghana, Nigeria, and Central Africa. In France mostly from North and West Africa and in Germany from Turkish Immigrants.
The diagnostic of sickle cell disease cannot be made by the sickling and the solubility testing methods because of their inability to differentiate sickle cell disease from sickle cell trait. Solubility testing also has false positive and false negative results. The false negative is seen in severe anemia, patients on chronic transfusion, always during the neonatal period because of the high percentage of fetal hemoglobin (Hb F) and with deteriorated agent. The false positive is seen in hyperlipidemia, extreme leukocytosis, hyperglobulinemia, with too much reagent and deteriorated agent. Solubility testing does not detect individuals who have hemoglobin C, D, E, O Arab and Beta thalassemia trait.
It is appropriate only in an emergency to determine the presence of hemoglobin S in a patient seen in The Emergency Department as the results of the blood send for electrophoresis is not immediately available. Hemoglobin electrophoresis, isoelectric focusing and high-performance liquid chromatography are laboratory methods used for the diagnostic of sickle cell disease. Some accurate, rapid and inexpensive tests for SCD are being developed and tested
Intervention in sickle cell disease:
The introduction of universal newborn screening in United States with prophylaxis penicillin, pneumococcal vaccine and basic vaccinations, comprehensive health care, transcranial doppler and prophylaxis transfusion have decrease morbidity and mortality (90% of children live to adulthood). SCD affect approximately 100,000 individuals in United States. The transition from pediatric to adult care, treatment disparity remains a problem from lack of access to adult specialty providers. Although individuals with SCD are living longer long term complications and lifelong disability still remain a crucial problem for many. Beside chronic transfusion only 2 medications are approved to treat the Disease: Hydroxyurea for adults (underused by clinicians or very poor adherence by patients) and young children (2 years and older) and more recently in 2017 Endari (adult and children from 5 years old). New drugs are on clinical trials. The only cure is hematopoietic stem cell transplantation but not every individual affected has a HLA- matched sibling donor. Gene therapy is currently being tested in clinical trials and is promising. Gene editing techniques are in their infancy.
Newborn Screening with comprehensive care is now universal in United Kingdom.UK has the highest number of patients in Europe. Newborn screening has been increasing in European Countries.
Sickle Cell Disease: A Global Public Health Problem and Challenge
More than 300,000 infants are born with sickle cell disease every year globally where up to 1 to 2% occur in high resources setting and more of 90% of birth occur in developing countries mostly in Africa and India. Most of these children died undiagnosed from overwhelming pneumococcal sepsis, splenic sequestration, or malaria. The following table is an estimated Number of newborns with SCD in Africa and India for the year 2010 (Piel et al. 2013)
Country Sickle Cell Birth/Year
Democratic Republic of Congo 39,743
What about newborn Screening in these Countries?
The vast majority of infants and children are not routinely screened for SCD. Screening newborns, prophylactic penicillin, pneumococcal vaccine and vaccinations, daily hydroxyurea is lifesaving. However, neonatal screening is available only in few countries of the Sub-Sahara Africa. Implementation of newborn screening worldwide could save the life of almost ten millions of children.
In Tanzania, the need for intervention to reduce the mortality was recognized. As such Tanzania is developing a national policy under the leadership of the Minister of Health and Social Welfare.
Many countries such as Benin, Ghana, Cameron, DR Congo, Tanzania and Nigeria have established Sickle Disease Centers. Successful pilot newborn screening studies have been done in many African countries. An important feature is the interest of the Minister of Health or the Central and State Government support in the development of newborn Screening with establishment of Centers (20 in Uganda in 2017) often in area with high number of infants with Sickle Cell Disease( Ghana, Tanzania, Uganda as examples). In June 19, 2018, World Sickle Cell Day, the Minister of Health in Uganda announced that hydroxyurea should be added to the essential list of medications available to the public. The announcement followed the study done to evaluate the safety of hydroxyurea in a malaria-endemic area. Newborn Screening is so crucial because approximately 1000 infants are born daily in Africa with sickle cell disease. In Uganda babies exposed to HIV were tested for HIV and SCD. The implementation of a universal vaccination program is an opportunity to diagnosed SCD in babies not tested.
In India, newborn screening is now conducted. The Central and State Governments are establishing Centers for diagnostic and comprehensive care for individuals identified with the disease. The Asian haplotype has a more benign course because of a high fetal hemoglobin. But there are individuals who have severe sickle disease, developed sepsis, required transfusion and benefited from hydroxyurea.
What about middle-income countries. In Jamaica newborn screening and Health Care Maintenance are essential components of SCD in Jamaica and have been in existence for years. The Minister of Health is very involved in Jamaica in Education and the provision of comprehensive care to Jamaican patients. The Childhood Survival for SCD in Jamaica is 84%, compare to 94% in USA, 99% in UK and only 10% in Africa. In Brazil, after 10 years there is a steady decrease in mortality rate. An important fact is involvement of the government of Brazil in newborn screening, testing, education and the production of educational brochures.
The United Nations have designated Sickle Cell Disease as a Global Public Health Problem on a resolution in December 22, 2008, with June 19, becoming a National and International Day each year. The first World Day was celebrated on June 19, 2009.
Quoting DR Ohene –Frimpong MD of the Sickle Cell Foundation of Ghana and active member of the Global Sickle Cell Disease Network
« Unfortunately, despite the work done in Ghana and across Africa, much remains to be done to reduce infant mortality. 90% of children with SCD in resource-poor countries will not survive to adulthood. In Ghana, we have seen that simple public health measures, especially newborn screening, help children lead more normal life. In the first 10 years of newborn screening, we made dramatic improvement in reducing sickle cell related childhood mortality»
In 2016, ASH the American Society of Hematology formed the ASH Coalition. The Coalition is taking measures to raise awareness of SCD in Africa and low resource areas globally in an effort to improve health outcomes for people with the Disease from infant to adulthood.
This quote from DR Alexis Thompson President of the American Society of Hematology and active Leader of the ASH Coalition could be apply to low income countries where newborn screening is not established and where sickle cell anemia is not recognized as a global health issue.
«One of the greatest hurdles we face in the heartbreaking rate of mortality caused by SCD in SUB-Sahara Africa is lack of awareness of the condition and the simple relatively inexpensive intervention that can save lives. It starts with early recognition, ideally through newborn screening».
In conclusion, Sickle Cell Disease is a global health issue. We need to work together to find solutions to resolve the problem. The establishment of newborn screening is important for the prevention of death in newborns and children < than 5 years of age. It is time to invest in sickle cell as a priority.
Rita Bellevue MD
Member AMHE, New York Chapter