Structural Biochemistry/Protein function/Heme group/Hemoglobin/Sickle disease

General information
Sickle cell anemia is a genetically inherited disease in which the people who suffer from this disease develop abnormally shaped red blood cells - an elongated shape like a sickle instead of the normal spherical shape of hemoglobin - which decrease its affinity to oxygen. Sickle cell anemia is a disease that are passed down from family members in which the red blood cells form an abnormal sickle shape instead of the round (doughnut) shape. A more in depth look at the red blood cells show that the hemoglobin in the affected cells form large fibrous aggregates, resulting from their sickle shape. This shape then clogs capillaries and prevent blood flow, causing poor circulation and leading to higher risks for stroke, organ damage, and bacterial infections. Anemia is caused by the fact that the sickle shaped cells are not retained in circulation for as long as normal blood cells do, and the bone marrow, where the cells are produced, cannot keep up to speed with making new cells. Sickle cell is usually a deadly heritable disease which primarily is associated with those of African descent. The main difference between those affected with sickle cell anemia is that when the hemoglobin is deoxygenated the hemoglobin bends to the "sickle" shape. The oxygenated hemoglobin actually is the same as those oxygenated hemoglobin in normal people. The hemoglobin mentioned has two parts: the heme and the globin. The heme is contains the iron which is used to transport the oxygen through the blood stream. The globin is a complex protein that keeps the hemoglobin in a liquid like state.



Symptoms and Effects
-The most well known symptom is anemia-- the delay of healing and growth as well as the affecting the oxygen flow to the rest of the body. This often results in paleness, weakness, and tiredness. -Other symptoms include jaundice, or yellowing, of the skin, mouth, and eyes caused by the deposits of bilirubin from the excess of dead sickle cells before the liver filters them out. -Enlargement, scarring, and damage to the spleen if the sickle cells pool there. -Acute chest syndrome, if the sickle cells occur in the chest, this can lead to lung damage. -Sickle crisis, caused by sickle cells clustering in blood vessels and constricting the flow of blood. This results in pain, swelling, and possibly death. The symptoms do not usually occur until after the age of four. Some others symptoms are shortness of breath, rapid heart rate, paleness, fatique, or yellowing of the eyes and skin. [Pubmed Health].

Complications of Sickle cell anemia:

Different parts of the body are effected by sickle cell anemia in different ways. For instance, “hand-foot syndrome” can either effect the hands or the feet or the two simultaneously. For infants, this is often the first sign of sickle cell disease. This occurs when the small vessels in the hands and/or feet are blocked by sickle cells. The result of this process can lead to fever, pain in the bones, and/or swelling on the surface of the hands and/or feet.

Another complication of sickle cell anemia is “Splenic Crisis.”  This occurs when the spleen becomes to large due to an overload of sickle cells flowing into it. In this case, the cells clog the spleen and disrupts it usual function, which is to fight infections by filtering out abnormal red blood cells. Without the spleen’s normal function, the overload soon leads to a shrinkage of the spleen. The only way to correct this abnormality is by undergoing blood transfusion. In addition, the spleen is the most vital organ in the body in fighting infections. Without its proper function, infections can occur that would have the ability to kill a person in a matter of days. For young children, pneumonia is the most common infection caused by sickle cell disease.

Acute chest syndrome is very similar to pneumonia and is a life threatening condition caused by sickle cell disease. This occurs when sickle cells flow into the lungs and cause symptoms such as fever and chest pains. When lung damage is extended over a long period of time, pulmonary arterial hypertension is the result. The symptoms include irregular breathing patterns and high blood pressure.

Sickle cell disease can have a major effect on the growth and puberty of children. Basically, children with this disease experience a shortage in red blood cells, which causes their growth rate to decrease relative to a child without the disease. When these children become adults, they are usually thinner and smaller in comparison to the average adult. Besides, people with sickle cell anemia may have some symptoms of infections as the following: bone infection, gallbladder infection, lung infection, urinary infection, delayed growth and puberty, or even painful joints caused by arthritis. [Pubmed Health].

Two forms of stroke can also occur as a result to sickle cell disease. One form of stroke happens when sickle cells flow into the brain and block blood vessels. The second form of stroke occurs as a result of the first case; bursting blood vessels. If death isn’t the result of this complication, then a person may experience learning disabilities or paralysis.

Vision can also be effected by sickle cell disease. In order to have clear vision, our small blood vessels have to have the ability to transport oxygen into our eyes. If the small blood vessels become blocked by sickle cells, the thin layers of the retina become damaged. Since the retinas are responsible for sending images of what we see to our brain, without this function, blindness is the result.

“Gallstones” is a complication that is the result of the release of hemoglobin from a dead red blood cell. In addition, stones may from in the gallbladder due to the overload of a compound called, bilirubin. When fattening meals are consumed, one may experience discomfort in the right side of the belly, right shoulder, or between the shoulder blades. Nausea, vomiting, sweating, and chills can also occur.

For people between the ages of ten and fifty, ulcers on the legs may form. They are treatable, but reoccurring.

One of the most serious, but rare complications of sickle cell disease is multiple organ failure, when three major organs fail. This will cause serious effects in a person’s mental state, like tiredness and general loss of interest in everyday activities. Fever is also common.

Treatment:

Due to the crisis known as vaso-occlusive, people with sickle cell disease experience painful episodes. There are, however, various types of treatment available. One type of treatment, used for children with sickle cell disease, is folic acid and penicillin. This treatment requires that the patient take 1mg of folic acid every single day for life. As a result of the undeveloped immune system the patient must then take penicillin daily by the age of five.

For children, bone marrow transplants help to suppress this severe disease.

Hydroxyurea is a drug that has the ability to reactivate fetal hemoglobin, which can extend the lifetime for a person living with sickle cell anemia. This drug has also been used in chemotherapy.

Currently, gene therapy is being researched as a possible treatment for these disease. Also, the use of phytochemicals, like nicosan.

Overall, people with sickle cell anemia need to have their treatment continuously and nonstop. In order to get a better treatment, they must seek help from their health care providers and also from clinics that are in charge of sickle cell anemia disease. At the hospital or clinics, patients can receive treatments for sickle cell anemia such as blood transfusion, pain medicines, lots of fluids, and antibiotics to prevent bacterial infections. However, some people might need to do dialysis or kidney transplant, surgery for the eye, or even the wound care for leg ulcers. [Pubmed Health].

Cause of disease
By investigating the amino acid sequence of the hemoglobin of affected cells, scientists have shown that there is a single substitution of valine for glutamate in position 6 of the β-chain of hemoglobin that results in this disorder. The mutated hemoglobin is called S-hemoglobin, for sickle cell anemia. When hemoglobin is in its T-state, the additional valine residues bind to a hydrophobic area on other S-hemoglobin molecules, forming a chain of hemoglobin that in turn pulls the red blood cell into its signature sickle shape. This dangerous effect only occurs on hemoglobin in its deoxygenated state because oxygenated hemoglobin has the R conformation, which covers the hydrophobic patch that the extra valine binds to. People who have this disease must have inherited this mutation from both parents as it is a recessive trait. A recessive trait means that the disease will only be expressed if both of the individual's alleles code for that trait. To summarize, sickle cell anemia results from the aggregation of mutated deoxyhemoglobin molecules, where aggregation is caused by interation between Val 6 on a beta chain of one Hb molecule and a hydrophobic patch (formed by Phe 85 and Val 88) on a beta chain of another deoxygenated hemoglobin molecule.

Diagnosis:

Hb levels are usually high for people effected by sickle cell anemia. Hyposplenism may appear on a blood film analysis.

Induction of sickle cells can be promoted by the addition of sodium metabisulfite on a blood film. A “sickle cell solubility test” can also be used to detect the presence of sickle hemoglobin.

Gel electrophoresis can be used to detect abnormalities in hemoglobin.

Sickle cell disease in Africa
1/100 of West Africans suffer from sickle cell anemia, and a much larger percentage of the population has the sickle cell trait in comparison to other regions in the world. The mosquito-borne protozoan Plasmodium falciparum, infect erythrocytes, which cause them to adhere to capillary walls and block blood flow to vital organs. The reason of the high probability of West Africans having sickle cell anemia is because of the common disease reign the region, malaria. Individuals who carry the sickle cell anemia gene are found to be more resistant to malaria due to the effect of Plasmodia has on infected erythrocytes. Plasmodia lowers the intracellular pH in erythrocytes by roughly 0.4, which causes hemoglobin to favor deoxyhemoglobin formation. Deoxyhemoglobin has a higher tendency for sickling, which creates a tendency for infected erythrocytes to be removed by the spleen. Furthermore, sickling also mechanistically disrupts erythrocyte adhesion to capillary walls.

As a result, individuals who carry this trait have resistance to malaria. Individuals who are even heterozygous have an adaptive advantage to homozygous individuals who do not carry sickle cell anemia and are unable to seek proper medical treatment. Therefore, the sickle cell trait is extremely common in West Africa, where malaria is also a big factor, contributing to the death toll.

Importance of Sickle Cell
With the sickle cell disorder, Linus Pauling was the first to propose and observe the direct connection between the variation of one single amino acid squence that can result in a sickle shaped red blood cell.Therefore, Sickle Cell studies are important in studying genetically linked diseases. Linus Pauling was able to propose this thought due to his background in studying atoms and his eventual journey through medicine. His diverse academic background gave him a unique viewpoint to which he advanced immunology. Much of his studies were based on normal and abnormal hemoglobin cells. Pauling later went on to write Sickle Cell Anemia, A Molecular Disease, in 1949. In his later years, Pauling used his research on hemoglobin to for social, political and scientific endeavors.

reference
Rees DC, William TN, Gladwin MT. Sickle-cell disease. Pubmed Health. Lancet 2010. < http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001554/>