Sickle-cell anemia is an inherited blood disorder that arises from a single amino acid substitution in one of the component proteins of hemoglobin. The component protein, or globin, that contains the substitution is defective. Hemoglobin molecules constructed with such proteins have a tendency to stick to one another, forming strands of hemoglobin within the red blood cells. The cells that contain these strands become stiff and elongated--that is, sickle shaped.
Sickle-shaped cells--also called sickle cells--die much more rapidly than normal red blood cells. Normal red blood cells survive for approximately 120 days in the bloodstream; sickle cells last only 10-12 days. The body cannot create replacements fast enough and anemia develops due to the chronic shortage of red blood cells. Further complications arise because sickle cells do not fit well through small blood vessels, and can become trapped. The trapped sickle cells form blockages that prevent oxygenated blood from reaching associatedtissues and organs. Considerable pain results in addition to damage to the tissues and organs. This damage can lead to serious complications, including stroke and an impaired immune system. Sickle cell anemia primarily affects people with African, Mediterranean, Middle Eastern, and Indian ancestry. In theUnited States, African Americans are particularly affected.
Normal hemoglobin is composed of a heme molecule and two pairs of proteins called globins. Humans have the genes to create six different types of globins--alpha, beta, gamma, delta, epsilon, and zeta--but do not use all of them atonce. Which genes are expressed depends on the stage of development: embryonic, fetal, or adult. Virtually all of the hemoglobin produced in humans from ages two to three months onward contains a pair of alpha-globin and beta-globin molecules.
A change, or mutation, in a gene can alter the formation or function of its product. In the case of sickle cell hemoglobin, the gene that carries the blueprint for beta-globin has a minute alteration that makes it different from the normal gene. This mutation affects a single nucleic acid along the entire DNA strand that makes up the beta-globin gene. (Nucleic acids are the chemicals that make up deoxyribonucleic acid, known more familiarly as DNA.) Specifically, the nucleic acid, adenine, is replaced by a different nucleic acid called thymine.
Because of this seemingly slight mutation, called a point mutation, the finished beta-globin molecule has an amino acid substitution: valine occupies thespot normally taken by glutamic acid. (Amino acids are the building blocks ofall proteins.) This substitution creates a beta-globin molecule--and eventually a hemoglobin molecule--that does not function normally.
Normal hemoglobin, referred to as hemoglobin A, transports oxygen from the lungs to tissues throughout the body. In the smallest blood vessels, the hemoglobin exchanges the oxygen for carbon dioxide, which it carries back to the lungs for removal from the body. The defective hemoglobin, designated hemoglobin S, can also transport oxygen. However, once the oxygen is released, hemoglobin S molecules have an abnormal tendency to clump together. These aggregatedhemoglobin molecules form strands within red blood cells, which then lose their usual shape and flexibility.
The rate at which hemoglobin S aggregation and cell sickling occur depends onmany factors, such as the blood flow rate and the concentration of hemoglobin in the blood cells. If the blood flows at a normal rate, hemoglobin S is re-oxygenated in the lungs before it has a chance to aggregate. The concentration of hemoglobin within red blood cells is influenced by an individual's hydration level--that is the amount water contained in the cells. If a person becomes dehydrated, hemoglobin becomes more concentrated in the red blood cells.In this situation, hemoglobin S has a greater tendency to clump together andinduce sickle cell formation.
Genes are inherited in pairs, one copy from each parent. Therefore, each person has two copies of the gene that makes beta-globin. As long as a person inherits one normal beta-globin gene, the body can produce sufficient quantitiesof normal beta-globin. A person who inherits a copy each of the normal and abnormal beta-globin genes is referred to as a carrier of the sickle cell trait. Generally, carriers do not have symptoms, but their red blood cells contain some hemoglobin S. A child who inherits the sickle cell trait from both parents--a 25% possibility if both parents are carriers--will develop sickle cell anemia.
Worldwide, millions of people carry the sickle cell trait. Individuals whoseancestors lived in sub-Saharan Africa, the Middle East, India, or the Mediterranean region are the most likely to have the trait. The areas of the world associated with the sickle cell trait are also strongly affected by malaria, adisease caused by blood-borne parasites transmitted through mosquito bites.According to a widely accepted theory, the genetic mutation associated with the sickle cell trait occurred thousands of years ago. Coincidentally, this mutation increased the likelihood that carriers would survive malaria outbreaks. Survivors then passed the mutation on to their offspring, and the trait became established throughout areas where malaria was common.
Although modern medicine offers drug therapies for malaria, the sickle cell trait endures. Approximately 2 million Americans are carriers of the sickle cell trait. Individuals who have African ancestry are particularly affected; one in 12 African Americans are carriers. An additional 72,000 Americans have sickle-cell anemia, meaning they have inherited the trait from both parents. Among African Americans, approximately one in every 500 babies is diagnosed with sickle-cell anemia. Hispanic Americans are also heavily affected; sickle-cell anemia occurs in one of every 1,000-1,400 births. Worldwide, it has beenestimated that 250,000 children are born each year with sickle-cell anemia.
The severity of the symptoms cannot be predicted based solely on the geneticinheritance. Some individuals develop health- or life-threatening problems ininfancy, but others may have only mild symptoms throughout their lives. Forexample, genetic factors, such as the continued production of fetal hemoglobin after birth, can modify the course of the disease. Fetal hemoglobin contains gamma-globin in place of beta-globin; if enough of it is produced, the potential interactions between hemoglobin S molecules are reduced.
Common symptoms of anemia include fatigue, paleness, and a shortness of breath. A particularly severe form of anemia--aplastic anemia--occurs following infection with parvovirus. Parvovirus causes extensive destruction of the bonemarrow, bringing production of new red blood cells to a halt. Bone marrow production resumes after 7-10 days; however, given the short lives of sickle cells, even a brief shut-down in red blood cell production can cause a precipitous decline in hemoglobin concentrations. This is called "aplastic crisis."
Painful crises, also known as vaso-occlusive crises, are a primary symptom ofsickle-cell anemia in children and adults. The pain may be caused by small blood vessel blockages that prevent oxygen from reaching tissues. An alternateexplanation, particularly with regard to bone pain, is that blood is shuntedaway from the bone marrow but through some other mechanism than blockage bysickle cells. These crises are unpredictable, and can affect any area of thebody, although the chest, abdomen, and bones are frequently affected sites. There is some evidence that cold temperatures or infection can trigger a painful crisis, but most crises occur for unknown reasons. The frequency and duration of the pain can vary tremendously. Crises may be separated by more than ayear or possibly only by weeks, and they can last from hours to weeks.
The hand-foot syndrome is a particular type of painful crisis, and is often the first sign of sickle-cell anemia in an infant. Common symptoms include pain and swelling in the hands and feet, possibly accompanied by a fever. Hand-foot syndrome typically occurs only during the first four years of life, withthe greatest incidence at one year.
Sickle cells can impede blood flow through the spleen and cause organ damage.In infants and young children, the spleen is usually enlarged. After repeated incidence of blood vessel blockage, the spleen usually atrophies by late childhood. Damage to the spleen can have a negative impact on the immune system, leaving individuals with sickle-cell anemia more vulnerable to infections.Infants and young children are particularly prone to life-threatening infections.
Anemia can also impair the immune system, because stem cells--the precursorsof all blood cells--are earmarked for red blood cell production rather than white blood cell production. White blood cells form the cornerstone of the immune system within the bloodstream.
The energy demands of the bone marrow for red blood cell production compete with the demands of a growing body. Children with sickle-cell anemia have delayed growth and reach puberty at a later age than normal. By early adulthood,they catch up on growth and attain normal height; however, weight typically remains below average.
Blockage of blood vessels in the brain can have particularly harsh consequences and can be fatal. When areas of the brain are deprived of oxygen, controlof the associated functions may be lost. Sometimes this loss is permanent. Common stroke symptoms include weakness or numbness that affects one side of the body, sudden loss of vision, confusion, loss of speech or the ability to understand spoken words, and dizziness. Children between the ages of 1-15 are at the highest risk of suffering a stroke. Approximately two-thirds of the children who have a stroke will have at least one more.
Acute chest syndrome can occur at any age, and is caused by sickle cells blocking the small blood vessels of the lungs. This blockage is complicated by accompanying problems such as infection and pooling of blood in the lungs. Affected persons experience fever, cough, chest pain, and shortness of breath. Recurrent attacks can lead to permanent lung damage.
Males with sickle-cell anemia may experience a condition called priapism. (Priapism is characterized by a persistent and painful erection of the penis.) Due to blood vessel blockage by sickle cells, blood is trapped in the tissue of the penis. Damage to this tissue can result in permanent impotence in adults.
Both genders may experience kidney damage. The environment in the kidney is particularly conducive for sickle cell formation; even otherwise asymptomaticcarriers may experience some level of kidney damage. Kidney damage is indicated by blood in the urine, incontinence, and enlarged kidneys.
Jaundice and an enlarged liver are also commonly associated with sickle-cellanemia. Jaundice, indicated by a yellow tone in the skin and eyes, may occurif bilirubin levels increase. Bilirubin is the final product of hemoglobin degradation, and is typically removed from the bloodstream by the liver. Bilirubin levels often increase with high levels of red blood cell destruction, butjaundice can also be a sign of a poorly functioning liver.
Some individuals with sickle-cell anemia may experience vision problems. Theblood vessels that feed into the retina--the tissue at the back of the eyeball--may be blocked by sickle cells. New blood vessel can form around the blockages, but these vessels are typically weak or otherwise defective. Bleeding,scarring, and retinal detachment may eventually lead to blindness.
Sickle-cell anemia is suspected based on an individual's ethnic or racial background, and on the symptoms of anemia. A blood count reveals the anemia, anda sickle cell test reveals the presence of the sickle cell trait. The sicklecell test involves mixing equal amounts of blood and a two percent solutionof sodium bisulfite. Under these circumstances, hemoglobin exists in its deoxygenated state. If hemoglobin S is present, the red blood cells are transformed into the characteristic sickle shape. This transformation is observed witha microscope, and quantified by expressing the number of sickle cells per 1,000 cells as a percentage. The sickle cell test confirms that an individual has the sickle cell trait, but it does not provide a definitive diagnosis forsickle-cell anemia.
To confirm a diagnosis of the sickle cell trait or sickle cell anemia, another laboratory test called gel electrophoresis is performed. This test uses anelectric field applied across a slab of gel-like material to separate proteinmolecules based on their size, shape, or electrical charge. Although hemoglobin S (sickle) and hemoglobin A (normal) differ by only one amino acid, theycan be clearly separated using gel electrophoresis. If both types of hemoglobin are identified, the individual is a carrier of the sickle cell trait; if only hemoglobin S is present, the person most likely has sickle-cell anemia. The gel electrophoresis test is also used as a screening method for identifying the sickle cell trait in newborns. More than 40 states screen newborns in order to identify carriers and individuals who have inherited the trait from both parents.
Early identification of sickle-cell anemia can prevent many problems. The highest death rates occur during the first year of life due to infection, aplastic anemia, and acute chest syndrome. If anticipated, steps can be taken to avert these crises. With regard to long-term treatment, prevention of complications remains a main goal. Sickle-cell anemia cannot be cured--other than through a risky bone marrow transplantation--but treatments are available for symptoms.
Pain is one of the primary symptoms of sickle-cell anemia, and controlling itis an important concern. The methods necessary for pain control are based onindividual factors. Some people can gain adequate pain control through over-the-counter oral painkillers (analgesics), local application of heat, and rest. Others need stronger methods, which can include administration of narcotics.
Blood transfusions are usually not given on a regular basis but are used to treat painful crises, severe anemia, and other emergencies. In some cases, such as treating spleen enlargement or preventing stroke from recurring, blood transfusions are given as a preventative measure. Regular blood transfusions have the potential to decrease formation of hemoglobin S, and reduce associated symptoms. However, regular blood transfusions introduce a set of complications, primarily iron loading, risk of infection, and sensitization to proteinsin the transfused blood.
Infants are typically started on a course of penicillin that extends from infancy to age six. This treatment is meant to ward off potentially fatal infections. Infections at any age are treated aggressively with antibiotics. Vaccines for common infections, such as pneumococcal pneumonia, are administered when possible.
Emphasis is being placed on developing drugs that treat sickle cell anemia directly. The most promising of these drugs in the late 1990s is hydroxyurea, adrug that was originally designed for anticancer treatment. Hydroxyurea hasbeen shown to reduce the frequency of painful crises and acute chest syndromein adults, and to lessen the need for blood transfusions. Hydroxyurea seemsto work by inducing a higher production of fetal hemoglobin. The major side effects of the drug include decreased production of platelets, red blood cells, and certain white blood cells. The effects of long-term hydroxyurea treatment are unknown.
Bone marrow transplantation has been shown to cure sickle cell anemia in severely affected children. Indications for a bone marrow transplant are stroke,recurrent acute chest syndrome, and chronic unrelieved pain. Bone marrow transplants tend to be the most successful in children; adults have a higher rateof transplant rejection and other complications.
The procedure requires a healthy donor whose marrow proteins match those of the recipient. Typically, siblings have the greatest likelihood of having matched marrow. Given this restriction, fewer than 20% of sickle-cell anemia individuals may be candidates. The percentage is reduced when factors such as general health and acceptable risk are considered. The procedure is risky for the recipient. There is approximately a 10% fatality rate associated with bonemarrow transplants done for sickle-cell anemia treatment. Survivors face potential long-term complications, such as chronic graft versus host disease (animmune-mediated attack by the donor marrow against the recipient's tissues),infertility, and development of some forms of cancer.
In general, treatment of sickle-cell anemia relies on conventional medicine.However, alternative therapies may be useful in pain control. Relaxation, application of local warmth, and adequate hydration may supplement the conventional therapy. Further, maintaining good health through adequate nutrition, avoiding stresses and infection, and getting proper rest help prevent some complications.
Several factors aside from genetic inheritance determine the prognosis for affected individuals. Therefore, predicting the course of the disorder based solely on genes is not possible. In general, given proper medical care, individuals with sickle cell anemia are in fairly good health most of the time. Thelife expectancy for these individuals has increased over the last 30 years, and many survive well into their 40s or beyond. In the United States, the average life expectancy for men with sickle cell anemia is 42 years; for women, it is 48 years.
Inheritance cannot be prevented, but it may be predicted. Screening is recommended for individuals in high-risk populations; screening at birth offers theopportunity for early intervention; pregnant women and couples planning to have children may also wish to be screened to determine their carrier status;and carriers may consider genetic counseling to assess any risks to their offspring. The sickle cell trait can also be identified through prenatal testing; specifically through use of amniotic fluid sampling or chorionic villus sampling.