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Sickle-cell disease

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Sickle-cell Anaemia
   Classifications and external resources

   Sickle-shaped red blood cells
     ICD- 10   D 57.
     ICD- 9    282.6
      OMIM     603903
   DiseasesDB  1206
   MedlinePlus 000527
    eMedicine  emerg/26
   MeSH        C15.378.071.141.150.150

   Sickle-cell disease is a general term for 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, usually looking much like
   that of a banana, upon deoxygenation because of polymerization of the
   abnormal sickle hemoglobin. 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. The disease is chronic and lifelong. Individuals are most
   often well, but their lives are punctuated by periodic painful attacks.
   In addition to periodic pain, there may be damage of internal organs,
   such as stroke. Lifespan is often shortened with sufferers living to an
   average of 40 years. 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. Sickle-cell disease can occur
   in any individual of any colour or ethnicity, however.

Types and terminology

   "Sickle-cell anaemia" is the name of a specific form of sickle-cell
   disease in which there is homozygosity for the mutation that causes Hgb
   S. Other forms of sickle-cell disease include:
     * sickle-haemoglobin C disease
     * sickle beta-plus-thalassemia
     * sickle beta-zero-thalassemia
     * hemoglobin ss

   Unlike sickle-cell anaemia, 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
   haemoglobin gene. It is important to know that "sickle-cell anaemia" is
   the proper name of a specific type of "sickle-cell disease", and that
   "sickle-cell disease" is a non-specific term. Because the different
   forms of sickle-cell disease are quite different, one must be sure to
   specify the exact form of the disease in question.

Signs and symptoms

   Patients with sickle cell anaemia have an anaemia that varies in
   severity, with typical hemoglobin levels of 6-9 g/dl. Reticulocyte
   counts are elevated, reflecting new red blood cells replacing the
   rapidly destroyed older cells - red blood cell life span is markedly
   reduced in this disease. Often, the white blood cell and platelet
   counts are elevated, and these cells may contribute to vaso- occlusion.

Vaso-occlusive crises

   A vaso-occlusive crisis is caused by sickle-shaped red blood cells that
   obstruct capillaries and restrict bloodflow 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
   anaemia. This autosplenectomy increases the risk of infection from
   encapsulated organisms; preventive antibiotics and vaccinations are
   recommended for those with such asplenia. Liver failure may also occur
   with time.

   Bones, especially weight-bearing bones, are also a common target of
   vasoocclusive damage. Such damage may result -cell patients is also due
   to the bone ischemia.

   A recognized type of sickle crisis is the acute chest crisis, a
   condition characterized by fever, chest pain, hard breathing, and
   pulmonary infiltrate on chest X-ray. Given that pneumonia and
   intra-pulmonary sickling can both produce these symptoms, the patient
   is treated for both conditions. Treatment consists of admission,
   oxygen, close monitoring, and intravenous antibiotics.

Other sickle-cell crises

     * Aplastic crisis. An acute worsening of the patient's baseline
       anaemia producing pallor, tachycardia, and fatigue. This crisis is
       triggered by parvovirus B19, which directly affects erythropoiesis
       (production of red blood cells). 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 crisis. An acute, painful enlargement of the
       spleen. The abdomen becomes bloated and very hard. Management is
       supportive, sometimes with blood transfusion.

Complications

   Sickle-cell anaemia can lead to various complications, including:
     * Vaso-occlusive crisis (otherwise known as pain 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 minimize the development of
       atelectasis, is recommended.
     * Acute chest syndrome: Acute chest syndrome is a life-threatening
       condition characterized by chest pain, shortness of breath, fever,
       hypoxemia, 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 - 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
       hematologists continuing treatment indefinitely. Patients benefit
       today from routine vaccination for Haemophilus influenzae,
       Pneumococcus and Meningococcus.
     * Stroke - progressive vascular narrowing (occlusion) can prevent
       oxygen from reaching the brain, leading to stroke; cerebral
       infarction occurs in children, and cerebral hemorrhage in adults.
     * Cholelithiasis and cholecystitis (gallstones) - prolonged hemolysis
       may lead to excessive bilirubin production and precipitation,
       leading to gallstones
     * Avascular necrosis ( aseptic bone necrosis) of the hip
     * Decreased immune reactions due to hyposplenism (malfunctioning of
       the spleen)
     * Priapism and infarction of the penis (in men)
     * Osteomyelitis (bacterial bone infection) - salmonella is noted much
       more commonly than in the general population, but staphylococcus is
       still the most common pathogen.
     * Opioid addiction (see below)

Diagnosis

   Attacks are diagnosed clinically, i.e. there is no gold standard
   diagnostic test. Hemolysis (anaemia and jaundice) is often present,
   although for painful crises the diagnosis depends essentially on how
   the patient describes the pain.

   Abnormal hemoglobin forms are detected on hemoglobin electrophoresis, a
   form of gel electrophoresis on which the various types of hemoglobin
   move at varying speed. Sickle cell hemoglobin (HbSS) and Hemoglobin C
   with sickling (HbSC)—the two most common forms—can be identified from
   there. Genetic testing is rarely performed.

Pathophysiology

   Sickle-cell anaemia is caused by a missense 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
   ischemia.

Genetics

   Sickle-cell disease is inherited in the autosomal recessive pattern,
   depicted above.
   Enlarge
   Sickle-cell disease is inherited in the autosomal recessive pattern,
   depicted above.

   The allele responsible for sickle cell anaemia is autosomal recessive.
   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.

   The gene defect is a known mutation of a single nucleotide (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 GTG 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. In people heterozygous for HbS (carriers of sickling
   hemoglobin), the polymerization problems are minor. In people
   homozygous for HbS, 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. For those afflicted with the disease, however,
   vasocclusive events can be a painful part of life (normally they occur
   0.8 times per year per patient). This occurs when HbS becomes
   deoxygenated it undergoes an abnormal change in shape and consistency
   which can lead to a change in the shape and plasticity in the cell wall
   of the RBC, an occurrence called sickling.

   The sufferers of the illness have a reduced life span. It is believed
   that carriers ( sickle cell trait) are relatively resistant to malaria.
   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.

   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).

   Due to the above phenomenon, 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. In fact,
   sickle-cell anaemia is the most common genetic disorder among African
   Americans; about 1 in every 12 is a carrier.

   The evolution of sickle-cell anaemia is probably an example of
   Baldwinian evolution, whereby humans modify their environment and thus
   change the selective pressures. As humans in tropical areas in Africa
   and elsewhere developed agriculture and animal husbandry, they expanded
   the niche for Anopheles mosquitoes that could transmit the malaria
   parasite.

   In the USA, where there is no endemic malaria, the incidence of sickle
   cell anaemia amongst African Americans is much lower than in West
   Africa and falling. Without endemic malaria from Africa, the condition
   is purely disadvantageous, and will tend to be bred out of the affected
   population. See the Price equation article for a simplified
   mathematical model of the genetic evolution of sickle cell anaemia.

Inheritance

   Sickle cell conditions are inherited from parents in much the same way
   as blood type, hair color and texture, eye colour 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. Like most genes, hemoglobin genes are inherited in two sets,
   one from each parent.

Examples

    1. If one parent has Sickle Cell Anaemia ("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 Anaemia (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.

Treatment

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 centre) 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.

Painful (vaso-occlusive) crises

   Most patients with sickle cell disease have intensely painful episodes
   called vaso-occlusive crises. The frequency, severity, and duration of
   these crises vary tremendously, however. 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 third generation cephalosporin), 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
   anaemia, hydroxyurea, was shown to decrease the number and severity of
   attacks in a study in 1995 (Charache et al) and shown to increase
   survival time in a study in 2003. This is achieved by reactivating
   fetal hemoglobin production in place of the hemoglobin S that causes
   sickle cell anaemia. 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.

History

   The cause of this collection of clinical findings was unknown until the
   description 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 anaemia. 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
   is very occasionally called "Herrick's syndrome" for this reason.

   The disease was named "sickle cell anaemia" by Vernon Mason in 1922. In
   retrospect some elements of the disease had been recognized 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 1870's 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 Ghanian family. Also, the
   practice of using tar soap to cover blemishes caused by sickle cell
   sores was prevalent in the African American community.

   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 3000 and 6000 generations ago,
   approximately 70000-150000 years.

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