Sickle cell disease

Sickle cell disease is an inherited blood dysfunction that affects hemoglobin or red blood cells which transports oxygen to the rest of the body. The disease got its name because affected hemoglobin exhibits a sickle instead of manifesting the usual disc or doughnut-like shape of a normal cell. When a normal blood cell discharges oxygen in the body, it still maintains its normal shape. In a diseased cell, however, the cell becomes sickle-shaped. normal blood cells are also pliable, easily moved in the vessels of the blood through the bloodstream (Bloom 1995).

This is not the case for cells afflicted with the disease. They are rigid and more often than not, get wedged and trapped in blood vessels, impeding blood flow. Normal blood cells in contrast to damaged ones subsist in the system for about 120 days, while the live for half the same time or even in some cases, less. The lowering of hemoglobin/red blood cell levels in the body eventually leads to anemia. It is also possible for an individual to develop other health problems like increased heart rate, blindness, exhaustion, respiratory diseases and skin breakouts (Bloom 1995).

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Types and terminology

People who have sickle cell gene could either have the sickle cell trait (trait was inherited from one of the parent) or sickle cell anemia, which is inherited if both parents have the sickle cell trait. For a person to be afflicted with the sickle cell disease (Hemoglobin SS), he must inherit both genes from his parents. If both genes are copied from the parents, the child is homozygous and will have the anemia. A single copy of the gene makes a child heterozygous to the disease and the child could either have the other two types of this disease (Hemoglobin SC disease and Hemoglobin sickle beta-thalassemia). Having only inherited a trait from one of the parents will not result in sickle cell anemia or Hemoglobin SS, however, it will increase his chances of passing the disease to his offspring, especially if his/her partner also have the same genetic factor. In some instances, he may exhibit mild symptoms of the disorder. (Steinberg 1999).

Sickle cell disease is a disorder that is now a world-wide problem. Initially though of as only affecting people with African ancestry, the disease is now prevalent in countries found in the Mediterranean region, North and South America, the West Indies and Eastern Europe.  In the United States alone, one out of 10 African Americans is heterozygous while one out of every 400 African Americans are homozygous. (Steinberg 1999).

Signs and symptoms

Symptoms of the disease vary at every age group. In children, especially infants, the signs do not manifest until the child reaches the third or up to its first year because of the high levels of HbF prevalent in the blood. Common symptoms include inflammation of limbs, nosebleeds, shortness of breath, respiratory infections, high fever and pain in the chest, belly, hands and feet and the joins/cartilages. In toddlers and children in general, there are several indications that suggest that the disease is active. Children normally complain of extreme pain, usually in the limbs and the back area, yellowish complexion, anemia, extreme fatigue and mood swings. It is also common for children to exhibit bedwetting (NIH 2002).

From puberty to adulthood, patients complain of increased severity of pain, particularly in the joints/bones. The individual may also experience gum problems, skin ulcers and delayed puberty in teens. At this point, the anemia continues to progress (NIH 2002).

At all age levels, the most common denominator is pain. The experience of pain varies from individual to individual. Some do not experience it but those who do describe the feeling as akin to a constant pounding pain, especially in the bone area. Sickle cell patients also have a higher risk or more prone to both minor and life-threatening ailments because of lowered anti-bodies. Individuals with sickle cell disease, especially children are more susceptible to meningitis. An infant can immediately die from it within a few hours. Roughly ten percent of sickle cell patients may suffer stroke at age 20. When the patient suffers a stroke, it diminishes his/her mobility, mental faculties and may even lead to retardation. Males also may suffer from erectile dysfunction (priapism) that may lead to impotence. There is also an increase risk of blindness due to retinal damage (Steinberg 1999).  .

Diagnosis

It is advisable for people who belong to ethnicities that have high percentages of risk factors to undergo screening/diagnostic examination in order to detect any abnormalities in their Hb types.  In cases where both parents are identified to having sickle cell traits, a prenatal prognosis is advised. If the results are positive, it is recommended for the parents to undergo counseling in order to establish if they would continue with the pregnancy or opt for a termination. In cases where the trait is not yet identified, it is recommended to undergo an Amniocentesis screening at antenatal clinics before planning to have a baby. (NIH 2002).

There are some cases of mild or manageable sickle cell disease in children whose parents both have sickle cell traits; unfortunately there is no foolproof way of determining this from the initial results of the screening. In the onset, the parents who plan to continue to have children despite the risk of passing the disease should take into consideration the odds – the status of available therapies, pain and disease management, the chances of their child suffering from debilitating pain, increased medical care/expenditures and the likelihood of a shorter natural life. Parents who chose to keep their offspring are advised to be attentive and in constant communiqué with their doctors/physicians because there is always the risk of the child acquiring a life-threatening illness (NIH 2002).

There is also modern technique being practiced called the preimplantation genetic diagnosis. This procedure is applicable for in-vitro pregnancies to check for the existence or lack of sickle-cell mutation in the fertilized eggs (NIH 2002).

In a majority of hospitals in the United States, infants are immediately screened upon birth through a simple blood test. In forty-four states and territories, this screening is now mandatory. If diagnosed early on, the child has greater chances of survival and led a more productive life (NIH 2002).

In teens and adults, a hemoglobin electrophoresis test is recommended. This simple blood test could easily be administered by a doctor or at sickle cell foundations throughout the US. It is also important to undergo other screenings to rule out conditions/ailments that mimics the symptoms of the disease. There is a degree of difficulty in establishing bone tissue disorders with symptoms associated with sickle cell disease. More often, the presiding physician would recommend magnetic resonance imaging (MRI) or bone scans. Other disorders that may be mistaken for sickle cell disease include the following:  diseases of the liver, hepatitis, kidney dysfunction, rheumatic fever and heart disease.  There are also other genetic anomalies that may lead to sickling of hemoglobin without resulting to any devastating damage (i.e. hemoglobin I, Bart’s hemoglobin and hemoglobin C). (Steinberg 2001).

Pathophysiology

Since hemoglobin is a vital component of red blood cells, the abnormality that is found in people with this disease is exemplified in the three kinds of hemoglobin: Hemoglobin A (HbA), Hemoglobin S (HbS) and Hemoglobin F (HbF). The normal red blood cells that are produced from childhood to adulthood have the HbA molecule. The abnormal variant of HbA or HbS has an abnormality on one of the proteins that makes up its beta globin amino acid profile. Even a fraction of an abnormality in this amino acid chain could have devastating results in the system. HbF is the hemoglobin molecule produced during the development of the fetus in the womb and during a short period after the birth has taken place. There are also some instances wherein people still have HbF in their system throughout their lifetime. In most cases, these molecules are replaced by a majority of HbA. HbF have properties which block the production of sickle-cells. Because of its existence during fetal development, children that are homozygous do not immediately contract sickle cell anemia. If the child continues to have the HbF molecule in their lifetime, the child has better protection against the devastating effects of the disease. This is the reason why HbF is being used as a foundation for modern therapies on sickle cell disease. (Steinberg 2001).

The disease is an outcome of the alteration that takes place in the HbS. The vicious effect of the sickle cell initiates when it loses the oxygen that is inherent in its consistency. As soon as the affected cells loses oxygen or deoxygenated, it transforms into polymers. Polymers are rigid and are characterized as having a crescent shape. This polymerization process is the key transformation that eventually leads to further cell damage and illness. In addition to being rigid, polymers have a glue-like consistency, unable to pass through blood vessels and capillary like normal cells do. They obstruct proper blood flow by sticking to the walls of the blood vessels.  Hypoxia or the lack of oxygen will cause severe pain, the onset of the sickle cell crisis. In the long run, organ damage will continue and the pain will progress from severe to chronic.  Because of lack of oxygen, the environment develops more acid and speeds up the process of the polymerization of the rest of the healthy blood cells (Steinberg 2001).

Polymerization also causes dehydration in the cell by limiting the distribution of both water and potassium. In order for normal cells to survive, a balance of retaining and flushing liquids must be met. Once the cell is afflicted and becomes dehydrated, it produces more calcium, increasing the production levels of HbS and increasing the pace of sickle cell anemia (Steinberg 2001).

The increase of HbS also contributes to the elimination of the clotting agent of the blood (nitric oxide). Nitric oxide is also the component of the blood that keeps the blood vessels pliable and supple. This deficiency will later result in extreme pain. In people who have inherited the disease, the degree of the damage in the body depends on several aspects. First is the severity of the deoxygenation. If there are high levels of oxygen loss, it will result to severe pain and organ destruction, particularly the respiratory system. Once the lungs are affected, it leads to sharp and excruciating chest pain. Second aspect is the degree of acidity found in the bloodstream. If the body’s acid levels are lower, it will result in less organ damage. Normally if the sickle cells are active, it affects parts of the body that are naturally acidic – i.e. spleen. Third factor is the number or concentration of HbS. If the number of HbS in the system is manageable, the more beneficial it is for the patient. Last is the existence of HbF in the body. As mentioned earlier, some individuals retain this molecule from childhood to adulthood. If the level of HbF, for instance, is high, then the easier it is to manage the disease and apply appropriate therapy (NIH 2002).

Genetics

Genetics play a vital role in understanding and managing the disease. The genetic structure of the sickle cell anemia was first studied and discovered by Nobel-prize winning chemist Linus Pauling in 1949. In his study, he mentioned that the disease was caused by the abnormal mutation in the protein structure of the hemoglobin. It was also the first disease that was distinguished using molecular studies (Steinberg 1999).

The chromosome that is affected by this abnormality is chromosome 11. Although the mutation is only a small part of the composition of the chromosome mentioned, the alteration in the chemical discrepancy is enough to produce devastating results on the properties of the iron and protein complex of the hemoglobin. (Steinberg 1999).

The protein composition of the hemoglobin has four pairs of two alpha globin and two beta globin. These pairs are being determined by the a and b globin genes. To ensure proper function, these four pairs must work with one another. In the case of sickle cell anemia, the b globin gene mutates and as a result of the alteration, produces a non-polar protein called valine, instead of glutamic acid, the electrically charged protein. The polymerization also produces the glue-like consistency at the surface of the b pairs due to the lack of oxygen. The polymers adhere with each other and because of this mutation, affect the shape of the red blood cell and its ability to carry oxygen to the rest of the body (Steinberg 2001).

There are several ways of inheriting this disease at varying levels of severity. If both parents have the same traits, the probability of a child being born normal is 1:4, for a child to be born with the disease the ratio is also set at 1:4. The chances of the child being born with the trait is 1:2.             To inherit the sickle beta thalassemia, the probability of the parents in siring a child that will have beta thalassemia is set at a ratio of 1:4.  In this instance, the severity of the condition is unpredictable but in most cases quite manageable. The significance of the condition is based on the very nature of the beta thalassemia, whether it is bo or b+.  For parents who have one sickle trait and one hemoglobin C trait, the chance of the child in having hemoglobin SC is pegged at 1:4. Fortunately, this type of sickle cell is milder that sickle cell anemia (Steinberg 2001).

Treatment

 

Sickle Cell Disease cannot be cured because it is a genetic disorder. In the past 25 years, research and constant studies on the alleviation of its symptoms have dramatically improved, making it possible for patients to enjoy a better quality of life and longer life expectancy. Twenty-five years ago, life expectancy for patients was set at an average of 14 years. The mortality rate, especially with women was also high in the past twenty five years. Because of these advances and also better healthcare, the average lifespan is set at approximately 50 years or more. Women are also living longer, as a matter of fact, this demographic live longer than their male counterparts (NIH 2002).

The identification of the biological and chemical behavior of the system, particularly the gene that encourages or inhibits the production of sickle cell is still subject for further and extensive research. Treatments are still at the experimental level and most are concerned with the fundamental development of the disease at its root level– the causality of polymerization in red blood cells.  There are three accepted approaches to treatment: fetal hemoglobin production, maintenance of hydration in cells and bone marrow transplants (NIH 2002).

Because of initial research conducted which noted that fetal hemoglobin (HbF) effectively block red blood cells from sickling, current studies on the subject revealed that the symptoms of sickle cell anemia could be reduced by utilizing Hydroxyurea, a chemical that encourages  the production of HbF. This drug destroys HbS residing at the bone marrow, prompting an increase in the production of HbF (NIH 2002).

This drug is the only widely accepted prescription for the prevention and reduction of chronic pain and crisis among patients, reducing to as much as 50% with continued use.  Initial studies have shown that the drug may have other benefits. Researchers are optimistic that the drug may also encourage the recovery of the spleen. The hydrating properties of the drug may in the long run, outweigh its effect in improving the production of HbF. A recent study in 2002 also indicated that prolonged use of the drugs greatly improve the health of the patients, resulting in lesser hospital admittance and transfusion (NIH 2002).

The drug however is not a universal remedy because not all patients respond to the drug. Further studies are also needed to determine its long-term effect to the rehabilitation of the spleen, bone marrow, retinal complications, strokes, etc. In some cases, it was said to have stimulated skin breakouts in some, while others experienced contraindications like gastroenteritis, nausea, migraine,  skin discoloration, delirium and even shock.  Some are also concerned that long-term use might pose a risk for certain cancers and malignancies in pregnant mothers (NIH 2002).

For patients who do not respond to Hydroxyurea, another alternative being targeted for use are Butyrates. Butyrates are by products of carbohydrates. It was reported in 2001 that   Butyrates therapy by intravenous administration improved in healing ulcers affected by sickle cell anemia. Researchers are optimistic that a combination of these two drugs will be available in the future (NIH 2002).

There is also an interest in studying the processes that leads to cellular damage, significantly caused by dehydration and abnormal potassium release… Studies have revealed the benefits of using accessible drugs like the antifungal component Clotrimazole, Magnesium and zinc in retaining the water within the red blood cell. Aside from retaining water, these drugs were said to have lowered incidents of crisis and prevented pain occurrence. Further research is still being conducted on the long-time implications of this form of treatment (Steinberg 2001).

Among the three, bone marrow or stem cell transplant is considered to be the only true cure for this disease. Under this procedure, stem cells are cultivated from healthy bone marrow tissue acquired from a genetically linked donor. The stem cells would later develop into the three components of the blood – red blood cells, white blood cells and platelets. Through this process, the damaged cells of the patient will be replaced by the healthy producers of hemoglobin (Steinberg 2001).

Currently this process is still being perfected and has yielded noteworthy results (up to 85% success rate) among the patients who have been selected for the procedure.   Possible candidates for this procedure are this with high risk of stroke, acute anemia and those suffering chronic pain. Unfortunately, only a small percentage of patients (about 7%) qualify for the for this procedure. It also has it share of complications. The mortality rate for patients who undergo this treatment is 1:10. There is also a possibility of rejection in which the antibodies of the patient may attack the healthy cells transplanted from the donor, even with anti-rejection drugs, the risk is still high. Other complications from this treatment are: upper respiratory infection, infertility and cancer (NIH 2002).

The has also been studies to used stems cells obtained from placenta and umbilical cord to be used on individuals who have no genetic match. Stem cells harvested this way also reproduce/regenerate faster.   It was also assumed that because of the immaturity of the stems cells from these sources, the risk of rejection will be reduced. (Steinberg 2001)

Gene therapy propositions which some researches are studying are based on a premise that the affected gene could be replaced directly by healthy genes to prevent the propagation of sickle cells in the system. So far, this procedure was only successfully applied to mice. Further studies and methods need to be developed to check its applicability to humans. Ambitious it may seem, the outcome is promising for this new school of treatment (Steinberg 2001).

There is no proven and universal treatment for patients with this disease yet. Patients are living longer, more meaningful lives today because of more information and awareness in managing the disease. Regular visits to the physician, periodic physical examinations, proper rest and relaxation, avoidance of areas that might increase risk in acquiring complications/ailments and leading a healthy life style ensures well being and   maintenance (NIH 2002).

Diet also plays a fundamental role in ensuring the body is strong enough to ward off complications and boost the production or healthy cells. Foods rich in pytochemicals, protein, omega 3, antioxidants, and beta carotene coupled with increase fluid intake will lessen the risks associated with the disorder. Doctors also advised increase in fluid intake and low impact exercises (NIH 2005).

Food supplements like multivitamins, particularly B complex vitamins and folic acid (especially during pregnancy) are highly recommended to lower the risk of heart disease and strokes. The inclusion of minerals like zinc and magnesium are also beneficial to any therapeutic regimen as these minerals are known to encourage hydration in red blood cells (Allen 2005).

The administration of analgesics during crisis also alleviates the pain to tolerable levels, reducing the need for hospitalization. Complimentary therapies like massages, aroma therapy and stress management helps lessen the recurrence of chronic pain (NIH 2002).

More importantly, any chronic and debilitating disease places a lot of pressure and stress on the patient (especially children) and his family. It is imperative to have a strong family, social, and psychological support system and a positive outlook to effectively manage the disease (Allen 2005).

The future in terms of treatment for this disease shows a lot of potential and progress, if the previous years are an indication of things to come. In  the past twenty five years, the life expectancy for sickle cell patients have more than doubled, the early screening of infants have been mandated by law in a many states and territories (NIH 2002).  More importantly, exploratory researches on the possible treatment for this disorder may be currently incomplete but fruitful. Hopefully, in the future, as more advancements in science, particularly genetic engineering takes place; mortality rates for this chronic disease will be a thing of the past.

 

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