Sickle-cell disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2], Shyam Patel [3]

Sickle-cell disease is a group of genetic disorders of the red blood cell caused by a mutation in the β-globin chain gene of hemoglobin at the 6th position replacing glutamic acid to valine. HbS polymerizes reversibly when deoxygenated to form a network of fibrous hemoglobin polymers that stiffens the RBC membrane, giving it a sickle shape. These sickled cells loose the pliability to cross thin capillaries and possess a sticky membrane, giving it a property to adhere to the endothelium of blood vessels, thereby causing vaso-occlusion. It causes significant morbidity and mortality, particularly in people in the Mediterranean and African region. The treatment includes measures to avoid vaso-occlusion, such as avoidance of dehydration, low oxygen conditions, or cold weather. Hydroxyurea has been used to increase fetal hemoglobin production.

Sickle-cell disease was first discovered by James Herrick, an American cardiologist and professor of medicine, in 1910 following presentation by his intern Ernest Irons.^[1] In 1922, the phrase, “sickle-cell anemia,” was first used by Verne Mason, M.D. at Johns Hopkins University to describe the shape of the red blood cells.

Sickle-cell disease may be classified according to the number and type of the two alleles of beta-globin. Sickle-cell disease may also be classified as an autosomal recessive genetic disorder. Sickle cell disease does not have a traditional classification method, as is true for other hemoglobinopathies.^[2] However, there are a few particular subtypes. Each subtype is based on the number and type of hemoglobin allele(s). The letter S denotes an allele with the sickle cell mutation. The subtypes (and the associated disease in parentheses below) are as follows:

• HbSS (sickle cell anemia)
• HbSC (milder form of sickle cell anemia)
• HbAS (sickle cell trait)
• HbSB+thal (beta-thalassemia anemia)
• HbSB0thal (beta-thalassemia anemia)

• Other variants of sickle cell disease include HbSD, HbSE, or HbSO (one sickle cell gene and one other gene).^[2]

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The pathophysiology of sickle cell disease is based on a mutation in the beta-globin chain of hemoglobin, which leads to red blood cell sickling and vaso-occlusive crises. The pathogenesis of sickle cell disease is characterized by an amino acid substitution on the beta-globin chain on chromosome 11, resulting in red blood cell sickling and vaso-occlusive episodes in various organs. A mutation in beta-globin, namely a a point mutation in exon 1 that substitutes valine for glutamic acid, has been associated with the development of sickle cell disease, involving the hemoglobin synthesis pathway.^[3] On microscopic analysis, a peripheral blood smear will show sickle-shaped red blood cells, which are the characteristic findings of sickle cell disease. In some cases, hemoglobin C crystals may be observed. The point mutation causes cells to sickle, resulting in decreased deformability and decreased passage of red blood cells through the vasculature.^[4]

Sickle cell disease is caused by a mutation in the beta-globin gene on chromosome 11.

• Sickle cell disease must be differentiated from other diseases that cause fatigue, infection, bone pain, such as:^[5][6]

• Thalassemia
• Acute leukemia
• Autoimmune hemolytic anemia
• HbSC disease
• HbS-beta-thalassemia
• Septic arthritis
• Polycythemia vera
• Systemic lupus erythematosus

• The prevalence of sickle cell disease is approximately 160 per 100,000 individuals worldwide at birth. The actual prevalence, however, is less given that people die from the disease at an early time point.
• Approximately 1 in 12 persons of African descent have sickle cell trait.
• Approximately 100,000 persons are living with sickle cell disease in the United States.

• Age is not a risk factor for sickle cell disease since this disease is inherited at birth. Unlike other diseases that increase with age, persons with sickle cell disease are born with the condition.

• Sickle cell disease affects men and women equally. It is not an X-linked disease.

• There is a racial predilection for sickle cell disease.
  • Sickle cell disease usually affects individuals of the black race.
  • Sickle cell disease also affects persons of eastern Mediterranean descent and Middle Eastern descent.

The most potent risk factor in the development of sickle-cell disease is race, which include Africans, African Americans, Indians, and persons of Mediterranean descent. An additional risk factor is geographic location, with these locations containing the greatest occurrences of disease.^[7]

Sickle cell disease is currently a disease for which newborn screening is available, mandated, and routinely performed in the United States.^[8]

• The majority of patients with sickle cell disease remain asymptomatic until the second half of the first year of life. This is the time when fetal hemoglobin production declines such that sickled hemoglobin manifests clinically.
• If left untreated, sickle-cell disease can result in death.
• Early clinical features include painful crises, fatigue, and shortness of breath.
• Common complications include sepsis, hypoxia, tissue infarction, depression, and death.^[9]
• Prognosis is generally guarded in the United States and poor in developing nations.

• The diagnosis of sickle cell disease is made when a person has:

• The characteristic genetic mutation (glutamic acid to valine) in beta-globin
• Symptoms characteristic of sickle cell disease

• Sickle cell disease is usually symptomatic.

Symptoms of sickle-cell disease include:

• Pain and/or bone pain
• Dactylitis
• Blurry vision
• Persistent and painful erection
• Numbness
• Tingling
• Motor skill loss
• Speech deficits
• Gait disturbance
• Leg ulceration
• Jaundice

• Patients with sickle cell disease usually appear ill during times of acute exacerbation of painful crises. If patients are well controlled on their medications, they can appear clinically well.
• Physical examination may be remarkable for:

• Hypotension
• Tachycardia
• Dehydration
• Scleral icterus
• Pallor (conjunctival, mucosal, and/or skin)
• Fever
• Otitis/sinusitis
• Splenomegaly (due to extramedullary hematopoiesis)
• Heart failure
• Frontal and parietal bone bossing (due to extramedullary hematopoiesis)

The most important laboratory test for sickle cell anemia is a complete blood count (CBC), specifically hemoglobin and hematocrit. Low hemoglobin (anemia) is due to the intrinsic nature of the disease. A positive peripheral blood smear showing sickle-shaped cells is characteristic of sickle cell disease. High total bilirubin with predominantly indirect bilirubin may suggest hemolysis, since bilirubin is a breakdown production of hemoglobin. High lactate dehydrogenase (LDH) may also be seen if there is hemolysis. High reticulocyte count may be seen if the bone marrow is attempting to compensate for the anemia. Low oxygen content on arterial blood gas (ABG) may be observed.

• In some cases, plain imaging such as x ray can be useful, which may reveal subacute or chronic infarcts of the extremities or deformities.
• CT scan is useful for patients with suspected stroke due to vaso-occlusion.
• MRI can show avascular necrosis of the leg. It can also show osteomyelitis and marrow hyperplasia.

• Sickle cell disease does not require any additional diagnostic tests. Newborn screening accurately identifies patients with sickle cell disease.

• The mainstay of therapy for sickle cell disease is supportive care. Supportive care includes pain control, transfusions, antibiotics if there is infection, hydration, and oxygenation.

Specific therapies include hydroxyuea, which increases fetal hemoglobin production, exchange transfusions, and stem cell transplant.

• Surgery has no significant role in sickle cell disease.

• There are no primary preventive measures available for sickle cell disease. However, genetic counseling is an option.

Hydroxyurea can prevent sickle cell crises by increasing fetal hemoglobin. Fetal hemoglobin protects against complications of anemia.^[10][11]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2], Shyam Patel [3]

The pathophysiology of sickle cell disease is based on a mutation in the beta-globin chain of hemoglobin, which leads to red blood cell sickling and vaso-occlusive crises.

It is important to understand normal red blood cell physiology prior to understanding the pathophysiology of sickle cell disease. Normally, in healthy persons, red blood cells are deformable and flexible, allowing them to pass through vasculature.^[1] Red blood cells lose their organelles and nucleus so they can easily pass through capillaries. They have a biconcave disc structure which allows for maximum oxygen transportation and deformability. Red blood cells can pass through capillaries that have 50% of the diameter than the red blood cells themselves.

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 mutation occurs in exon 1 and changes the nucleic acid sequence from GAG to GTG.^[2] Because valine is a hydrophobic amino acid, this imparts a sticky adhesive quality and results in sickling. Glutamic acid is a negatively charged amino acid and thus prevents red blood cells from sickling. The pathophysiology involves polymerization of deoxygenated HbS, which forms long fibers within erythrocytes and thus creates distortion of cell morphology.^[3] The association of two wild-type α-globin subunits with two mutant β-globin subunits forms hemoglobin S, which polymerizes 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.

Abnormal cell adhesion underlies the cellular pathophysiology of the disease.^[1] When cells adhere to the vascular endothelium, obstruction can occur.^[1] In addition to defective red blood cells, patients with sickle cell disease have abnormal white blood cells and platelets. These cell types are also more adhesive to the vascular endothelium. Adhesion in the post-capillary venules can result in venular obstruction.^[4] Patients with sickle cell disease have a diminished vasodilatory response to nitric oxide.^[4]

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.^[5][6]

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

A recognized type of sickle crisis is the acute chest crisis, a condition characterized by fever, chest pain, labored 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.

• Aplastic crises are acute deteriorations 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, however, 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.

In people heterozygous for HgbS (carriers of sickling hemoglobin), the polymerization 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 deoxygenated 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 25% chance of their child developing the illness and a 50% 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.^[7]

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 United States, 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.

File:Autorecessive.svg

• 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.

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.