Sickle-cell disease

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Overview
Sickle-cell disease is a group of genetic disorders caused by sickle hemoglobin (Hgb S or Hb S). In many forms of the disease, the red blood cells change shape upon deoxygenation because of polymerization of the abnormal sickle hemoglobin, the hemoglobin sticks to each other, causing the cell to get a rigid surface and sickle shape. This process damages the red blood cell membrane, and can cause the cells to become stuck in blood vessels. This deprives the downstream tissues of oxygen and causes ischemia and infarction, which may cause organ damage, such as stroke. The disease is chronic and lifelong. Individuals are most often well, but their lives are punctuated by periodic painful attacks. Life-expectancy is shortened, but contemporary survival data is lacking. Older studies indicated that sufferers could live to an average of 40 to 50 years, with the average age for males being 42 and the average age for females being 48. Sickle-cell disease occurs more commonly in people (or their descendants) from parts of the world such as sub-Saharan Africa, where malaria is or was common, but it also occurs in people of other ethnicities. As a result, those with sickle cell disease are resistant to malaria since the red blood cells are not conducive to the parasites. The mutated allele is recessive, meaning it must be inherited from each parent for the individual to have the disease.

History
This collection of clinical findings was unknown until the explanation of the sickle cells in 1910 by the Chicago cardiologist and professor of medicine James B. Herrick (1861-1954) whose intern Ernest Edward Irons (1877-1959) found "peculiar elongated and sickle shaped" cells in the blood of Walter Clement Noel, a 20 year old first year dental student from Grenada after Noel was admitted to the Presbyterian Hospital in December 1904 suffering from anemia. Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" while an undergraduate. Noel completed his studies and returned to capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada.

The disease was named "sickle-cell anemia" by Vernon Mason in 1922. In retrospect some elements of the disease had been recognised earlier: a paper in the Southern Journal of Medical Pharmacology in 1846 described the absence of a spleen in the autopsy of a runaway slave. The African medical literature reported this condition in the 1870s where it was known locally as ogbanjes ('children who come and go') because of the very high infant mortality in this condition. And a history of the condition tracked reports back to 1670 in one Ghanaian family. Also, the practice of using tar soap to cover blemishes caused by sickle cell sores was prevalent in the African American community.

Proof 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 3,000 and 6,000 generations ago, approximately 70,000-150,000 years.

Types and terminology
"Sickle-cell anemia" is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes Hgb S. Sickle cell anemia is also referred to as "SS disease," "Hemoglobin S," or permutations thereof. Other forms of sickle-cell disease include:
 * sickle-hemoglobin C disease
 * sickle beta-plus-thalassaemia
 * sickle beta-zero-thalassaemia

These other forms of sickle-cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes Hgb S and one copy of another abnormal hemoglobin allele. "Sickle-cell anemia" is a synonym for "sickle-cell disease".

The term "disease" is applied here since the inherited abnormality causes a pathological condition that can lead to death and severe complications. Not all inherited variants of hemoglobin are detrimental, a concept known as genetic polymorphisms. Hemoglobin is one of the best-characterized proteins in terms of inherited variants; some variants manifest as severe thalassaemia, such as beta-zero-thalassaemia, and other variants manifest as a milder thalassaemia, such as beta-plus-thalassaemia.

Signs and symptoms
Patients with sickle-cell anemia can have symptoms that vary in severity.

Vaso-occlusive crises
A vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in ischemia, pain, and organ damage.

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected. It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anemia. This autosplenectomy increases the risk of infection from encapsulated organisms;  preventive antibiotics and vaccinations are recommended for those with such asplenia.

Bones, especially weight-bearing bones, are also a common target of vaso-occlusive damage. This is due to bone ischemia.

A recognised type of sickle crisis is the acute chest crisis, a condition characterised by fever, chest pain, hard breathing, and pulmonary infiltrate on chest X-ray. Given that pneumonia and intrapulmonary sickling can both produce these symptoms, the patient is treated for both conditions.

Other sickle-cell crises

 * Aplastic crises are acute worsenings of the patient's baseline anemia producing pallor, tachycardia, and fatigue. This crisis is triggered by parvovirus B19, which directly affects erythropoiesis (production of red blood cells). Parvovirus infection nearly completely prevents red blood cell production for 2-3 days. In normal individuals this is of little consequence but the shortened red cell life of sickle-cell patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the illness and the rapid turnover of red cells leads to the drop in hemoglobin. Most patients can be managed supportively; some need blood transfusion.
 * Splenic sequestration crises are acute, painful enlargements of the spleen. The abdomen becomes bloated and very hard. Management is supportive, sometimes with blood transfusion.

Complications
Sickle-cell anemia can lead to various complications, including:
 * Vaso-occlusive crisis (otherwise known as painful crisis): Most patients with sickle-cell disease have periodic intensely painful episodes called vaso-occlusive crises. The frequency, severity, and duration of these crises vary tremendously. Painful crises are treated with hydration and analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is effective for the itching associated with the opioid use. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.
 * Acute chest syndrome is a life-threatening condition characterised by chest pain, shortness of breath, fever, hypoxaemia and pulmonary infiltrates on chest X-ray. It can be triggered by pain crisis, respiratory infection, bone-marrow embolization, or possibly by atelectasis, such as can be caused by opiate administration, or surgery.
 * Overwhelming post-(auto)splenectomy infection is due to functional asplenia, caused by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae. Daily penicillin prophylaxis is the most commonly used treatment during childhood with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for H. influenzae, S. pneumoniae and Neisseria meningitidis.
 * Stroke can result from a progressive vascular narrowing of blood vessels, preventing oxygen from reaching the brain. Cerebral infarction occurs in children, and cerebral hemorrhage in adults.
 * Cholelithiasis and cholecystitis (gallstones) may result from excessive bilirubin production and precipitation due to prolonged haemolysis.
 * Avascular necrosis (aseptic bone necrosis) of the hip may occur as a result of ischemia.
 * Decreased immune reactions due to hyposplenism (malfunctioning of the spleen)
 * Priapism and infarction of the penis.
 * Osteomyelitis (bacterial bone infection) - Salmonella is noted much more commonly than in the general population, although Staphylococcus is still the most common.
 * Opioid tolerance can occur as a normal, physiologic response to the therapeutic use of opiates. Addiction to opiates occurs no more commonly among individuals with sickle cell disease than among other individuals treated with opiates for other reasons.
 * Acute papillary necrosis in the kidneys.
 * Leg ulcers
 * In eyes, background retinopathy, proliferative retinopathy, vitreous hemorrhages and retinal detachments can occur. Regular annual eye checks are required.
 * During pregnancy, intrauterine growth retardation, spontaneous abortion and pre-eclampsia are the possibilities.

Diagnosis
Full blood count will reveal haemoglobin levels in the range of 6-8 g/dL with a high reticulocyte count. On a peripheral blood film, one can observe features of hyposplenism i.e., target cells and Howell-Jolie Bodies. Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulphite. Another test is Sickle Solubility test. A mixture of haemoglobin S (Hb S) in a reducing solution e.g., sodium dithionite gives a turbid appearance while normal Hb gives a clear solution. Abnormal hemoglobin forms can be detected on hemoglobin electrophoresis, a form of gel electrophoresis on which the various types of hemoglobin move at varying speed. Sickle-cell hemoglobin (HgbS) and hemoglobin C with sickling (HgbSC)&mdash;the two most common forms&mdash;can be identified from there. Genetic testing is rarely performed.

X-Ray
(Images shown below are courtesy of RadsWiki)

Pathophysiology
Sickle-cell anemia is caused by a point mutation in the β-globin chain of hemoglobin, replacing the amino acid glutamic acid with the less polar amino acid valine at the sixth position of the β chain. The association of two wild-type α-globin subunits with two mutant β-globin subunits forms hemoglobin S, which polymerises under low oxygen conditions causing distortion of red blood cells and a tendency for them to lose their elasticity.

New erythrocytes are quite elastic, which allows the cells to deform to pass through capillaries. Often a cycle occurs because as the cells sickle, they cause a region of low oxygen concentration which causes more red blood cells to sickle. Repeated episodes of sickling causes loss of this elasticity and the cells fail to return to normal shape when oxygen concentration increases. These rigid red blood cells are unable to flow through narrow capillaries, causing vessel occlusion and ischaemia.

Genetics
In people heterozygous for HgbS (carriers of sickling hemoglobin), the polymerisation problems are minor. In people homozygous for HgbS, the presence of long chain polymers of HbS distort the shape of the red blood cell, from a smooth donut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers only have symptoms if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated. Normally these painful crises occur 0.8 times per year per patient. The sickle cell disease occurs when the sixth amino acid, glutamic acid is replaced by valine to change is structure and function.

The gene defect is a known mutation of a single nucleotide (see single nucleotide polymorphism - SNP) (A to T) of the β-globin gene, which results in glutamic acid to be substituted by valine at position 6. hemoglobin S with this mutation are referred to as HbS, as opposed to the normal adult HbA. The genetic disorder is due to the mutation of a single nucleotide, from a GAG to GUG codon mutation. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structure of hemoglobin. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. The deoxy form of hemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic residues of the valine at position 6 of the beta chain in hemoglobin are able to bind to the hydrophobic patch, causing hemoglobin S molecules to aggregate and form fibrous precipitates.

The allele responsible for sickle-cell anemia is autosomal recessive and can be found on the 11th chromosome. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier. If two parents who are carriers have a child, there is a 1-in-4 chance of their child developing the illness and a 1-in-2 chance of their child just being a carrier. Since the gene is incompletely recessive, carriers have a few sickle red blood cells at all times, not enough to cause symptoms, but enough to give resistance to malaria. Because of this, heterozygotes have a higher fitness than either of the homozygotes. This is known as heterozygote advantage. Due to the evolutionary advantage of the heterozygote, the illness is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India and the Middle East.

The Price equation is a simplified mathematical model of the genetic evolution of sickle cell anemia.

The malaria parasite has a complex life cycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cell to rupture, making the plasmodium unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle cell trait (selection for the heterozygote).

In the USA, where there is no endemic malaria, the incidence of sickle cell anemia amongst African Americans is lower (about 8%) than in West Africa and is falling. Without endemic malaria from Africa, the condition is purely disadvantageous, and will tend to be breed out of the affected population.



Inheritance

 * Sickle-cell conditions are inherited from parents in much the same way as blood type, hair color and texture, eye color and other physical traits.
 * The types of hemoglobin a person makes in the red blood cells depend upon what hemoglobin genes the person inherits from his or her parents.

Examples

 * 1) If one parent has sickle-cell anemia ("rr" in the diagram above) and the other is Normal (RR), all of their children will have sickle cell trait (Rr).
 * 2) If one parent has sickle-cell anemia (rr) and the other has Sickle Cell Trait (Rr), there is a 50% chance (or 1 out of 2) of a child having sickle cell disease (rr) and a 50% chance of a child having sickle cell trait (Rr).
 * 3) When both parents have Sickle Cell Trait (Rr), they have a 25% chance (1 of 4) of a child having sickle cell disease (rr), as shown in the diagram above.
 * 4) Sickle-cell anemia is caused by a recessive allele. Two carrier parents have a one in four chance of having a child with the disease. The child will be homozygous recessive.

Febrile illness
Children with fever are screened for bacteremia i.e. complete blood count, reticulocyte count and blood culture taken. Younger children (varies from center to center) are admitted for intravenous antibiotics while older children with reassuring white cell counts are managed at home with oral antibiotics. Children with previous bacteremic episodes should be admitted.

Zn administration
Zinc is given as it stablises cell membrane.

Painful (vaso-occlusive) crises
Most people with sickle cell disease have intensely painful episodes called vaso-occlusive crises. The frequency, severity, and duration of these crises, however, vary tremendously. Painful crises are treated symptomatically with analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is effective for the itching associated with the opioid use.

Acute chest crises
Management is similar to vaso-occlusive crises with the addition of antibiotics (usually a quinolone or macrolide, since wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome), oxygen supplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the patients red cell mass for normal red cells, which decreases the percent hemoglobin S in the patient's blood.

Hydroxyurea
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 (Charache et al) and shown to possibly increase survival time in a study in 2003 (Steinberg et al) . This is achieved, in part, by reactivating fetal hemoglobin production in place of the hemoglobin S that causes sickle cell anemia. Hydroxyurea's clinical benefits can actually precede the induction of fetal hemoglobin, however. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but it is likely that the benefits outweigh the risks.

Future treatments
Various approaches are being sought for preventing sickling episodes as well as for the complications of sickle-cell disease. Other ways to modify Hb switching are being investigated, including the use of phytochemicals such as Nicosan.

Gene therapy is under investigation.

Situation of carriers
People who are known carriers of the disease often undergo genetic counseling before they have a child. A test to see if an unborn child has the disease takes either a blood sample from the unborn or a sample of amniotic fluid. Since taking a blood sample from a fetus has risks, the latter test is usually used.

After the mutation responsible for this disease was discovered in 1979, the U.S. Air Force required African American applicants to test for the mutation. It dismissed 143 applicants because they were carriers, even though none of them had the condition. It eventually withdrew the requirement, but only after a trainee filed a lawsuit.

Additional Readings

 * Chestnut, D. (1994). Perceptions of ethnic and cultural factors in the delivery of services in the treatment of sickle cell disease. Journal of Health and Social Policy, 5(3/4), 236.