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Sickle Cell Anemia: A Neglected Disease
Diagnosis and Treatment
Sickle cell anemia is an inherited blood disorder caused by a defect in the gene
that codes for beta hemoglobin. The defective hemoglobin may cluster together and form long, rod-shaped structures that cause red blood cells to assume a sickle shape. Such red blood cells deliver less oxygen to body tissues and organs, and may break into pieces that disrupt blood flow in blood vessels. This process produces chronic anemia, periodic episodes of severe pain and serious damage to tissues and organs. Life expectancy of people with sickle cell anemia is shortened to 42 years for males and 48 years for females.
Sickle cell anemia is inherited from two unaffected parents who have the sickle
cell trait (carriers). In the U.S., the disease afflicts more than 100,000 people; most of them are African-Americans. The best way to avoid having a child with the disease is for a woman who is a carrier not to conceive a child from a man who is also a carrier. About three million African-Americans are unaffected carriers who can pass the disease to their children. Genetic blood analysis and hemoglobin electrophoresis techniques are now available to test carriers and infants suspected to have the disease.
Sickle cell anemia is an inherited blood disorder in which red blood cells have
abnormal crescent or sickle shapes. In patients with sickle cell anemia, the hemoglobin is defective and may cluster together and form long, rod-shaped structures that cause red blood cells to become stiff and assume a crescent or sickle shape. Hemoglobin is a protein inside red blood cells that carries oxygen from the lungs to body tissues and organs and brings carbon dioxide back to the lungs. In patients with sickle cell anemia, however, hemoglobin distorts the shape of red blood cells. The fragile, sickle-shaped red blood cells deliver less oxygen to the body’s tissues, and can break into pieces that disrupt blood flow. Unlike normal red blood cells, sickle-shaped cells cannot squeeze through small blood vessels and stack up causing blockages that deprive tissues and organs of oxygen-carrying blood. This process produces chronic anemia and periodic episodes of pain and ultimately can damage tissues and vital organs and lead to other serious medical problems.
Bone marrow – the red, spongy material found in the cavities of many large bones
– regularly produces red blood cells. Bone marrow also produces white blood cells that
fight infection and platelets to help blood clots. The RBCs produced by the bone marrow
are not directly involved in sickle cell anemia. Once RBCs leave the bone marrow, they
normally live for about 120 days in the bloodstream before they die and need to be
replaced. However, sickle cells die after only 10 to 20 days. Because they cannot be
replaced fast enough, the blood is chronically short of red blood cells, a condition called
Sickle-shaped red blood cells were first reported by James Herrick in 1904. The
disease was named “sickle-cell anemia” by Vernon Mason in 1922. Reason that sickle-cell disease was associated with an alteration of hemoglobin was published in 1949 by Linus Pauling and coworkers. This was the first time a genetic disease was linked to a mutation of a specific protein, a milestone in the history of molecular biology.
The origin of the mutation that led to the sickle cell gene was initially thought to
be in the Arabian Peninsula, spreading to Asia and Africa. It is now known, from evaluation of chromosome structures, that there have been at least four independent mutational events, three in Africa and a fourth in either Saudi Arabia or central India. These independent events occurred between 70,000 and 150,000 years ago.
The first approved drug for the causative treatment of sickle cell anemia,
Hydroxyurea, was shown to decrease the number and severity of attacks in a study in 1995 and shown to possibly increase survival time in a study in 2003. This is achieved, in part, by reactivating fetal hemoglobin production in place of the defective hemoglobin that causes sickle cell anemia.
Sickle cell anemia is a genetic disorder caused by a defect in the gene that codes
for hemoglobin – the red, iron-rich protein that gives red blood cells their red color. Hemoglobin allows RBCs to carry oxygen from the lungs to all parts of the body, and to carry carbon dioxide from the body parts to the lungs so that it can be exhaled. Hemoglobin consists of four subunits: two subunits called beta hemoglobin and two subunits called alpha hemoglobin. The disorder occurs in the gene that codes for beta hemoglobin, the HBB (hemoglobin, beta) gene. The instructions for alpha hemoglobin are carried in another gene.
Under normal circumstances, the body makes healthy hemoglobin known as
hemoglobin A. Individuals with sickle cell anemia make hemoglobin S – S stands for sickle.
The sickle cell gene is passed from generation to generation in a pattern of
inheritance called autosomal recessive inheritance. This means that both parents must pass on a defective form of the gene to their child to be affected. Most often, the disorder is passed down the family tree by parents who have the sickle cell trait (carriers).
The presence of two defective alleles (SS) causes sickle cell anemia, and the
presence of one defective allele (AS) causes the sickle cell trait. People with the sickle trait are called carriers. If both parents are carriers (AS), the chance of having a child with sickle cell anemia (SS) is 25 percent, the chance of having a normal child (AA) is also 25 percent, and the chance of having a child with the trait or a carrier (AS) is 50 percent.
People with the sickle cell trait, called carriers, make both normal hemoglobin and
sickle cell hemoglobin. Their body may contain some sickle RBCs, but they usually don’t experience symptoms unless they’re in an area with low oxygen – such as at high altitudes on an airplane or on a mountain. However, they are carriers of the disorder, and they can pass it to their children. The few sickle RBCs carriers produce give them resistance against malaria. Because of this, heterozygotes (AS) have a higher fitness than either of the homozygotes (AA and SS) in malaria-infested areas. The illness is still prevalent due to the evolutionary advantage of the heterozygotes. Without endemic malaria, such as in West Africa, the condition is purely disadvantageous, and will tend to breed out of the affected population. In the U.S., where there is no endemic malaria, the incidence of sickle cell trait (carriers) among African Americans is lower (about 8%) than in West Africa and is falling.
The gene responsible for sickle cell anemia is located on the short arm of
chromosome 11. Sickle cell anemia is caused by a point mutation in the beta hemoglobin gene, replacing the amino acid glutamic acid with the less polar amino acid valine at the sixth position of the β chain.
1. Vaso-occlusive crisis (painful crisis). Caused by sickle-shaped red blood cells that
obstruct blood capillaries and restrict blood flow to organs, resulting in ischemia (restriction in blood supply), pain, and organ damage. Because of its narrow vessels and function in clearing defective RBCs, the spleen is frequently affected. It’s usually infracted before the end of childhood. This autosplenectomy increases the risk of infection from encapsulated organisms; preventive antibiotics and vaccinations are recommended for those with such asplenia (absence of normal spleen function). Bones, especially weight-bearing bones, are also a common target of vaso-occlusive damage. This is due to bone ischemia.
2. Hand-foot syndrome associated with pain, swelling and fever. 3. Fatigue, paleness, and shortness of breath. 4. Anemia. This is the most common symptom of the disease. RBCs become
deformed into the sickle shape, which causes them to lose their oxygen-carrying capacity. The cells become stiff and sticky and get stuck in the blood vessels, destroyed by the spleen, or simply die because of their abnormal shape. The decrease in RBCs causes anemia. Severe anemia can make a person pale and tired, and makes the person’s ability to carry oxygen to the tissues and organs more difficult. Healing and normal growth and development may be delayed because of chronic anemia.
5. Pain in organs and joints. This is caused by the blockage of blood flow. The pain
can occur anywhere, but most often in the chest, arms and legs. Painful swelling of the fingers and toes, called dactylitis, can occur in infants and children under 3 years of age. Priapism is a painful sickling that occurs in the penis. Any interruption in blood flow to the body can result in pain, swelling, and possible death of the surrounding tissue not receiving adequate blood and oxygen.
6. Eye problems. The retina can deteriorate due to lack of nourishment from
circulating blood. This can cause blindness.
7. Jaundice, yellowing of eyes and skin due to breakdown of red blood cells. 8. Leg ulcers 9. Delayed growth and puberty. Slow rate of growth due to shortage of RBCs. 10. Infections, primarily pneumonia. This is the result of spleen damage from sickled
RBCs, thus preventing the spleen from destroying bacteria in the blood. Pneumococcal infections used to be the principal cause of death in children until physicians began routinely giving penicillin on a preventive basis from birth or early infancy until the age of five years.
11. Stroke. Defective hemoglobin damages RBCs causing them to stick to blood
vessel walls. Blocked blood vessels in the brain causes stroke, primarily in children.
12. Acute chest syndrome. This is caused by infection or by trapped sickled cells in
the lungs. It’s characterized by chest pain, fever, hard breathing, and pulmonary infiltrate on chest X- ray.
13. Decreased immune reactions due to hyposlenism (malfunctioning of spleen). 14. Priapism and infarction of the penis. 15. Acute papillary necrosis in the kidneys.
16. During pregnancy, intrauterine growth retardation and spontaneous abortion. 17. Pulmonary hypertension 18. Congestive heart failure 19. Chronic renal failure. 20. Bloody urine (hematuria) and frequent urination
Diagnosis and Treatment
Blood test using hemoglobin electrophoresis is now performed at the same time
and from the same blood samples as other routine new-born screening tests. If the test shows the presence of sickle hemoglobin, a second blood test is performed to confirm the diagnosis. The test also shows whether or not the child carries the sickle cell trait. Treatment of sickle cell anemia includes:
1. Painkilling drugs and oral and intravenous fluids to reduce painful (vaso-
occlusive) crises and prevent complications. Painful crises are treated symptomatically with analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. Non-narcotic medications may be effective, but some patients will require narcotics. Diphenhydramine is also an effective agent to control any itching associated with the use of opioids.
2. Management of acute chest crises is similar to vaso-occlusive crises with the
addition of antibiotics, oxygen administration for hypoxia, and close observation.
3. Blood transfusion. This corrects anemia by increasing the number of normal
RBCs in circulation. Blood transfusion can also be used to treat spleen enlargement in children and to prevent stroke. Lack of matching donors is a common problem.
4. Oral antibiotics. Giving penicillin twice a day from age two months to age five
years to prevent pneumococcal infection and early death.
5. Hydroxyurea. This is the first approved drug for sickle cell anemia. It increases
survival time by reactivating fetal hemoglobin production in place of the hemoglobin S that causes sickle cell anemia. It may help reduce the frequency of pain crises and acute chest syndrome. Hydroxyurea had previously been used as a chemotherapy agent, and there are some concerns that long-term use may cause tumors or leukemia in certain people.
6. Zinc is given as it stabilizes the membrane. 7. Folic acid to help prevent severe anemia. 8. Nitric oxide. People with sickle cell anemia have low levels of nitric oxide, a gas
that helps keep blood vessels open and reduces the stickiness of RBCs.
9. Butyric acid is a food additive that may increase the amount of fetal hemoglobin
10. Nicosan (Hemoxin in the U.S.). This is a phytochemical that has antisickling
effect and prevents hemoglobin from forming rod-shaped structures. The drug was discovered and tested in Nigeria, West Africa. Claimed to reduce episodes of painful crises. An American pharmaceutical is seeking FDA approval.
11. Clotrimazole is an over-the-counter medication that is used to treat fungal
infections. It helps prevent a loss of water from RBCs, which may reduce the number of sickle cells that form.
12. Drinking plenty of water daily (8-10 glasses) or receiving fluid intravenously to
13. Supplemental oxygen through a breathing mask 14. Gene therapy is under investigation. 15. Bone marrow transplants can cure the disease, but it is only recommended in a
minority of patients. This is mostly due to the high risk of the procedure (the drugs needed to make the transplant possible are highly toxic) and the difficulty in finding suitable donors. Also, bone marrow transplants are much more expensive than other treatments.
16. Hemapheresis followed by erythropheresis. Separating blood into its component
parts (hemapheresis) and removing sickled RBCs (erythropheresis) and exchanging them with normal cells to keep the disease under control
a. Dialysis or kidney transplant for kidney disease b. Gallbladder removal (gallstone) c. Hip replacement for avascular necrosis of the hip (death of the joint) d. Irrigation or surgery for priapism e. Surgery for eye problem f. Surgery for stokes g. Wound care or surgery for leg ulcers
Women who carry the sickle cell trait may want to see a genetic counselor before
trying to conceive a child from a man who is also a carrier. A carrier impregnating a carrier is the main cause of having children with sickle cell anemia. A genetic counselor can explain the risk of having a child with sickle cell anemia. The counselor can also explain possible treatments, preventive measures, and reproductive options.
There is an in vitro fertilization procedure that improves the chances for parents
who both carry the sickle cell gene to have a child with normal hemoglobin. This
procedure is called preimplantation genetic diagnosis. First, eggs are taken from the
mother. Then, sperm is taken from the father. In a laboratory, the eggs are fertilized with
the sperm. The fertilized eggs (zygotes) are then tested for the presence of the sickle cell
gene. Fertilized eggs free of the sickle cell gene can be implanted into the mother for
normal development. However, the procedure is expensive.
Taking steps to stay healthy is central for anyone with sickle cell anemia. Eating
well, getting adequate rest and protecting yourself from infections are good ways to maintain your health and prevent crises.
Infants and children with sickle cell anemia need to receive regular childhood
vaccinations. Children and adults with sickle cell anemia also should have a yearly flu shot and be immunized against pneumonia. If you or your child has sickle cell anemia, follow these suggestions to stay healthy:
1. Take folic acid supplements daily, and eat a balanced diet. Bone marrow needs
folic acid and other vitamins to make new RBCs.
2. Drink plenty of water. Staying hydrated helps keep your blood diluted, which
reduces the chance that sickle cells will form.
3. Avoid temperature extremes. Exposure to extreme heat or cold can trigger the
4. Avoid stress. A sickle crisis can occur as a result of stress. 5. Exercise regularly, but don’t overdo it. Consult your doctor. 6. Fly on commercial airplanes with pressurized cabins. Unpressurized aircraft
cabins don’t provide enough oxygen. Low oxygen levels can trigger a sickle cell crisis.
7. Avoid high-altitude areas. Traveling to a high-altitude area may also trigger a
If you or someone in your family has sickle cell anemia, you need help to handle
the stresses of coping with this lifelong disease. Talk to your doctor. Sickle cell centers and clinics also can provide information and counseling. Many areas have sickle cell support groups for families affected by the disease.
It’s especially important to find ways to control and cope with pain. Different
techniques work for different people, but it might be worth trying heating pads, hot baths, massages or physical therapy. Prayer, family and friends also can be a source of support.
If you have a child with sickle cell anemia, the best way to help is to learn as
much as you can about the disease and to make sure your child gets the best health care possible. A child with sickle cell anemia has special needs and requires regular medical care to stay healthy. Your doctor can explain how often to bring your child for medical care and what you can do if he or she becomes ill.
You may also want to let teachers and caregivers know about your child’s illness.
Help them understand what kinds of exercises and situations can be harmful to your child, and teach them to recognize signs of infection.
Sickle cell anemia is a disease that has not gotten enough attention. Although it is
the first genetic disease described to man, it has just one FDA-approved medication. Hydroxyurea is the first and the only treatment approved by the FDA. Ten years after its approval, only 5 percent of those who qualify use it. Ignorance on the part of both physicians and patients is to blame for underuse of Hydroxyurea. The medication has been proven to dramatically reduce pain crises, hospitalizations and some organ damage. It may even prolong survival.
Doctors have long measured sickle cell anemia’s severity by how often patients
seek care for pain crises. This practice downplays the disease because patients usually tough out even severe, crisis-like pain at home, reserving doctor and hospital visits for just the most intense episodes.
Hospitals around the country just began a long-awaited study to see whether the
same ingredient that powers the impotence drug Viagra may prevent death from a leading sickle cell killer, lung damage known as pulmonary hypertension. Other researchers are testing if inhaling nitric oxide could stem pain attacks. And scientists are developing ways to improve sickle cell survival through bone-marrow transplants that have helped some children, but that typically is too risky for adults.
Still, that work is centered in a handful of specialty hospitals – far removed from
the day-to-day struggles of sickle cell sufferers, who often show up in emergency rooms desperate for pain relief only to be falsely stigmatized as narcotic-seekers.
In Canada, Health Canada doesn’t keep any statistics of the disease. No one
knows how many people in Canada are affected by the disease.
Various approaches are being sought for preventing painful episodes and
complications of the disease. The use of phytochemicals such as Nicosan (Hemoxin in
the U.S.) is being investigated to treat sickle cell disease. Nicosan has an antisickling
effect and prevents hemoglobin from clustering and forming rod-shaped structures.
Patients who participated in various trials experienced no episodes of painful crises. Gene
therapy is under investigation.
Aldrich, T. K., and R. L. Nagel. 1998. Pulmonary complications of sickle cell disease. In: Bone, R. C. et al., editors: Pulmonary and Critical Care Medicine
, 6th edition, St. Louis: Mosby, pp. 1-10. Allison, A. C. 2004. Two lessons from the interface of genetics and medicine. Genetics
166:1591-1599. Chestnut, D. 1994. Perceptions of ethnic and cultural factors in the delivery of services in the treatment of sickle cell anemia. Journal of Health and Social Policy, 5(3/4), 236. Desai, D. V., H. Dhanani. 2004. Sickle cell disease: History and Origin. The Internet Journal of Hematology 1 (2). ISSN 1540-2649. Kwiatkowski, D. P. 2005. How malaria affected the human genome and what human genetics can teach us about malaria. Am. J. Hum. Genet
. 77:171-92. Pauling, L., H. A. Itano, S. J. Singler, & I. C. Wells. 1949. Sickle-cell anemia: A molecular disease. Science
110:543-547. Pearson, H. 2005. Sickle cell anemia and severe infections due to encapsulated bacteria. J. Infect. Dis
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http://www.mercola.com/display/PrintPage.aspx?docid=30236&Print. [ Part I, Ref. I, Part II, Ref. II, Appendix ]By Gary Null PhD, Carolyn Dean MD ND, Martin Feldman MD, Debora Rasio MD,Dorothy Smith PhD ABSTRACT A definitive review and close reading of medical peer-review journals, and government health statisticsshows that American medicine frequently causes more harm than good. The numbe
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