Sickle Cell Disease: Causes, Treatment, and Psychosocial Impact

Introduction

Sickle cell disease affects millions of people throughout the world. The disease is particularly prominent among sub-Saharan African populations, where incidence rates are very high. In the western and central African regions, for example, almost 25% of people carry the sickle cell trait, and 1 to 2% of babies are born with the disease. In Nigeria alone, approximately 45,000 to 90,000 newborn babies are identified with the condition every year. The disease is also common in South and Central American countries, Cuba, and in Mediterranean countries such as Greece, Turkey, and Italy. In Asia, India and Saudi Arabia have a high incidence of the disease.

In the United States, sickle cell disease presents a significant healthcare problem, with more than 70,000 cases and an average of 1,000 new babies born with the condition each year (CDC). More than two million people are thought to be genetically predisposed to the condition and carry the sickle cell trait. Of all ethnic groups in the United States, the African American population has the highest predisposition, with one in every 500 people identified with the disease and one in twelve carrying the sickle cell trait. The next ethnic group at risk is the Hispanic population, with an incidence rate of 1 in every 1,000 to 1,400 people (CDC). A brief overview of sickle cell disease, its treatment, and its psychosocial implications provides useful insight into this debilitating condition.

Sickle Cell Disease Etiology

Sickle cell disease refers to a group of genetic disorders that result in alteration of the hemoglobin structure and disruptions in the normal circulation mechanism. This produces symptoms ranging from intense and intermittent pain, anemia, and stroke, to a high risk for infections and severe organ damage due to disrupted blood supply. This is an inherited disorder; those identified with the most common form — sickle cell anemia (Hb SS) — have inherited one sickle cell gene from each parent. It is also possible for a person to inherit one sickle cell gene from one parent and a different type of abnormal gene from the other parent, resulting in a different form of the disease known as hemoglobin S thalassemia. People who inherit one sickle cell gene from one parent and a normal gene from the other have what is known as the sickle cell trait, but not sickle cell disease. Children born to such parents are at greater risk of developing the condition (Nemours Foundation).

Molecular studies show that the substitution of valine in place of glutamic acid at the 6th position of the beta chain changes the structure of the resulting hemoglobin in such a way that it elongates red blood cells into a sickle shape (Allan Platt). Thus the normally disc-shaped red blood cells are contorted into elongated, sickle-shaped cells. Due to their distorted shape, these red blood cells find it difficult to pass through blood vessels, resulting in blockages along narrow vessels. The result is severe pain caused by the blockage. Because the lack of blood supply also means a lack of oxygen, the cells of affected organs are at risk of hypoxia and subsequent organ damage. Furthermore, sickle cells have a significantly shorter lifespan compared to normal red blood cells. Normal red blood cells live up to 120 days, while sickle cells survive only 10 to 20 days, producing a condition known as anemia — a lower-than-normal red blood cell count (Nemours Foundation).

Sickle cell disease can be diagnosed through blood tests in both children and adults. Hemoglobin electrophoresis, isoelectric focusing, and liquid chromatographic techniques are commonly used. Solubility testing methods are also sometimes employed, though they are not appropriate for testing infants. In the United States, screening newborns for sickle cell disease has become routine, as the risk of mortality from opportunistic infections is very high among babies with sickle cell anemia. A study has demonstrated that a prophylactic course of oral penicillin reduces the risk of pneumococcal sepsis in infants by 84%, underscoring the importance of newborn screening (Doris L. Wethers, 2000).

Diagnosis and Pathophysiology

Sickle hemoglobin forms stiff polymers upon deoxygenation, which deform normal red blood corpuscles and cause vaso-occlusion — or blood vessel blockage — particularly in smaller vessels. Even in larger blood vessels, the accumulation of sickle cells in the vascular endothelium slows blood flow. Because of the relatively shorter lifespan of sickle red cells, patients with sickle cell anemia typically have a high white blood cell count, which results in the production of harmful levels of cytokines. High hemolysis also causes additional cardiac strain due to the extra effort required to pump blood, and cardiomegaly is a frequently observed coexistent condition among children with sickle cell disease. The overworked bone marrow also demands additional calories to support normal growth.

In some cases, the bone marrow is unable to sufficiently compensate for the rapid loss of red cells, resulting in severe anemia due to bone marrow aplasia. People with sickle cell disease not infrequently develop an enlarged spleen, caused by the trapping of abnormal red blood cells in the spleen — a condition known as splenic sequestration crisis. This is of particular significance for children, as the spleen is an important defensive organ that filters bacteria and other harmful organisms. Splenic dysfunction due to the accumulation of sickle cells is a major concern for sickle cell patients (Doris L. Wethers).

Pharmacological interventions focus on providing relief and managing symptoms and complications. Typical interventions include antibiotics to fight opportunistic infections, effective pain management therapy, and psychosocial support for the patient. In cases of severe anemia, blood transfusions may be necessary, and care must be taken to manage possible complications from frequent transfusions. Iron overload, for example, is a real concern because red blood corpuscles contain iron, and above-normal iron levels have toxic effects on vital organs such as the heart, liver, and kidneys. Managing iron overload is therefore an important consideration for sickle cell patients receiving blood transfusions (SCDAA).

Treatment Methods

Hydroxyurea is one of the principal drugs used in managing the symptoms of sickle cell disease. The drug works by inducing the production of fetal hemoglobin. Because fetal hemoglobin is known to prevent the formation of sickle cells, the drug increases the mean corpuscular volume of red cells and minimizes the number of sickle cells in the bloodstream. A 1995 NIH study of hydroxyurea in patients over 18 years of age showed promising results, including considerably reduced periods of painful crisis and a 50% reduction in episodes of acute chest syndrome. The FDA approved the drug in 1998 for the treatment of adult sickle cell disease patients in the United States. The NIH clinical study was based on homozygous patients only (sickle cell anemia), and future results are awaited for data on other variants of the disease.

Erythropoietin is another drug proven to be effective in symptomatic control. Its mechanism of action is similar to that of hydroxyurea — it works by increasing fetal hemoglobin levels in the patient's red blood cells. In the human body, the kidneys synthesize erythropoietin in response to hypoxemia. Nitric oxide is well known for its muscle-relaxing properties and is used in treating conditions of respiratory distress and pulmonary hypertension. Nitric oxide works by interfering with the polymerization of sickle hemoglobin.

Currently, bone marrow transplantation is the only option that offers the prospect of a total cure or a significant reduction in symptoms. It is advisable for patients who manifest intense and frequent symptoms. Some early studies have shown that patients with fetal hemoglobin levels below 8.6% experience severe and frequent symptoms and are ideal candidates for bone marrow transplantation. This criterion is generally applied in light of the potential complications of the procedure, which include a transplant mortality rate of 15% and a 15% risk for graft-versus-host disease. Younger patients recover significantly better than adults following transplantation, and current statistics project improved outcomes, with a reduced mortality rate of approximately 5%. This remains a relatively new procedure, with only around 200 people with sickle cell disease having undergone it to date (Debby Golonka).

With advances in genetic science, the search for a cure for sickle cell disease through gene therapy is ongoing. Researchers cloned the beta-globin gene many years ago, and current research is focused on the locus control region and the use of adeno-associated viruses (AAV) as vectors. Research is also directed at inserting AAV into pluripotent stem cells so as to trigger the natural synthesis of healthy beta-globin. However, many biomolecular mechanisms remain poorly understood, and a clearer knowledge of these is necessary before gene therapy can be offered as a practical solution for sickle cell disease. One important challenge, for example, is overcoming the immune response to the viral vector.

Conclusion

Sickle cell disease is a distressing and debilitating genetic disorder with associated psychosocial implications, as with any other chronic incurable disease. Beyond the risky procedure of bone marrow transplantation, there is no real hope for a complete cure through other current interventions. Pharmacological therapy is thus largely focused on symptomatic management and on reducing the discomfort and pain experienced by patients. Drugs such as hydroxyurea, erythropoietin, and nitric oxide have shown considerable success in palliating symptoms. Newborn screening and prophylactic antibiotic doses have proven promising in preventing opportunistic bacterial infections and reducing associated infant mortality.