Sickle-cell disease (SCD), also known as sickle-cell anaemia (SCA), is a group of genetically passed down blood disorders.^[1] It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances.^[1] Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain ("sickle-cell crisis"), anemia, bacterial infections, and stroke.^[2] Long term pain may develop as people get older. The average life expectancy in the developed world is 50 years.^[1]

Sickle-cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent.^[3] Several subtypes exist, depending on the exact mutation in each haemoglobin gene.^[1] An attack can be set off by temperature changes, stress, dehydration, and high altitude.^[2] A person with a single abnormal copy does not usually have symptoms and is said to have sickle-cell trait.^[3] Such people are also referred to as carriers.^[4] Diagnosis is by ablood test and some countries test all babies at birth for the disease.^[5] Testing is also possible during pregnancy.^[5]

The complications of sickle-cell disease can be managed to a large extent with vaccination, preventive antibiotics, high fluid intake, folic acid supplementation, and pain medication.^[4][6] Other measures may include blood transfusion, and the medication hydroxycarbamide (hydroxyurea).^[6] A small proportion of people can be cured by a transplant of bone marrow cells.^[1]

Facts About Sickle Cell Disease

SCD is a group of inherited red blood cell disorders. Healthy red blood cells are round, and they move through small blood vessels to carry oxygen to all parts of the body. In someone who has SCD, the red blood cells become hard and sticky and look like a C-shaped farm tool called a “sickle”. The sickle cells die early, which causes a constant shortage of red blood cells. Also, when they travel through small blood vessels, they get stuck and clog the blood flow. This can cause pain and other serious problems such infection, acute chest syndrome and stroke.

Types of SCD

Following are the most common types of SCD:

HbSS

People who have this form of SCD inherit two sickle cell genes (“S”), one from each parent. This is commonly called sickle cell anemia and is usually the most severe form of the disease.

HbSC

People who have this form of SCD inherit a sickle cell gene (“S”) from one parent and from the other parent a gene for an abnormal hemoglobin called “C”. Hemoglobin is a protein that allows red blood cells to carry oxygen to all parts of the body. This is usually a milder form of SCD.

HbS beta thalassemia

People who have this form of SCD inherit one sickle cell gene (“S”) from one parent and one gene for beta thalassemia, another type of anemia, from the other parent. There are two types of beta thalassemia: “0” and “+”. Those with HbS beta 0-thalassemia usually have a severe form of SCD. People with HbS beta +-thalassemia tend to have a milder form of SCD.

There also are a few rare types of SCD:

HbSD, HbSE, and HbSO

People who have these forms of SCD inherit one sickle cell gene (“S”) and one gene from an abnormal type of hemoglobin (“D”, “E”, or “O”). Hemoglobin is a protein that allows red blood cells to carry oxygen to all parts of the body. The severity of these rarer types of SCD varies. 

Sickle Cell Trait (SCT)

HbAS

People who have SCT inherit one sickle cell gene (“S”) from one parent and one normal gene (“A”) from the other parent. This is called sickle cell trait (SCT). People with SCT usually do not have any of the signs of the disease and live a normal life, but they can pass the trait on to their children. Additionally, there are a few, uncommon health problems that may potentially be related to sickle cell trait.

Cause of SCD

SCD is a genetic condition that is present at birth. It is inherited when a child receives two sickle cell genes—one from each parent.

Diagnosis

SCD is diagnosed with a simple blood test. It most often is found at birth during routine newborn screening tests at the hospital. In addition, SCD can be diagnosed before birth.

Because children with SCD are at an increased risk of infection and other health problems, early diagnosis and treatment are important.

You can call your local sickle cell organization to find out how to get tested.

Anemia

Anemia is a very common complication of SCD. With SCD, the red blood cells die early. This means there are not enough healthy red blood cells to carry oxygen throughout the body. When this happens, a person might have:

·         Tiredness

·         Irritability

·         Dizziness and lightheadedness

·         A fast heart rate

·         Difficulty breathing

·         Pale skin color

·         Jaundice (yellow color to the skin and whites of the eyes)

·         Slow growth

·         Delayed puberty

 

Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.^[13]

Sickle-cell crisis

The terms "sickle-cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD. SCD results in anemia and crises that could be of many types including the vaso-occlusive crisis, aplastic crisis, sequestration crisis, haemolytic crisis, and others. Most episodes of sickle-cell crises last between five and seven days.^[14] "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."^[15]

Vaso-occlusive crisis

The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ resulting in ischaemia, pain,necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration, analgesics, and blood transfusion; 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 devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis^[16] or lungs are considered an emergency and treated with red-blood cell transfusions. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.^[17]

Splenic sequestration crisis

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected.^[18] It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anemia. This spleen damage increases the risk of infection from encapsulated organisms;^[19][20] preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.

Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in hemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 1–2 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient, they continue for 3–4 hours and may last for one day.^[21]

Acute chest syndrome

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia.^[22] It is the second-most common complication and it accounts for about 25% of deaths in patients with SCD, majority of cases present with vaso-occlusive crises then they develop ACS.^[23][24] Nevertheless, about 80% of patients have vaso-occlusive crises during ACS.

Aplastic crisis

Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered byparvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them.^[25] Parvovirus infection almost completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 days to one week to disappear. Most patients can be managed supportively; some need blood transfusion.^[26]

Haemolytic crisis

Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with coexistent G6PD deficiency.^[27]Management is supportive, sometimes with blood transfusions.^[17]

Other

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle-cell trait.^[28] The crisis can last up to a month.^[29] Another recognised type of sickle crisis, acute chest syndrome, is characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, the patient is treated for both conditions.^[30] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.

Sickle-cell disease is inherited in the autosomal recessive pattern.

Distribution of the sickle-cell trait shown in pink and purple^{[citation needed]}

Historical distribution of malaria (no longer endemic in Europe) shown in green^{[citation needed]}

Modern distribution of malaria^{[citation needed]}

Normally, humans have haemoglobin A, which consists of two alpha and two beta chains, haemoglobin A2, which consists of two alpha and two delta chains, and haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Of these, haemoglobin F dominates until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life.

Sickle-cell conditions have an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle-cell anaemia and the other has sickle-cell trait, then the child has a 50% chance of having sickle-cell disease and a 50% chance of having sickle-cell trait. When both parents have sickle-cell trait, a child has a 25% chance of sickle-cell disease, 25% do not carry any sickle-cell alleles, and 50% have the heterozygous condition.

Sickle-cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.^[31]

In people heterozygous for HgbS (carriers of sickling haemoglobin), the polymerisation problems are minor, because the normal allele is able to produce over 50% of the haemoglobin. In people homozygous for HgbS, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated. The sickle-cell disease occurs when the sixth amino acid, glutamic acid, is replaced by valine to change its structure and function; as such, sickle-cell anemia is also known as E6V. Valine is hydrophobic, causing the haemoglobin to collapse on itself occasionally. The structure is not changed otherwise. When enough haemoglobin collapses on itself the red blood cells become sickle-shaped.

The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism - SNP) (A to T) of the ?-globin gene, which results in glutamic acid(E/Glu) being substituted by valine (V/Val) at position 6. Note, historic numbering put this glutamic acid residue at position 6 due to skipping the methionine (M/Met) start codon in protein amino acid position numbering. Current nomenclature calls for counting the methionine as the first amino acid, resulting in the glutamic acid residue falling at position 7. Many references still refer to position 6 and both should likely be referenced for clarity. Haemoglobin S with this mutation is 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 on the coding strand, which is transcribed from the template strand into a GUG codon. Based on genetic code, GAG codon translates to glutamic acid (E/Glu) while GUG codon translates to valine (V/Val) amino acid at position 6. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of haemoglobin in conditions of normal oxygen concentration. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. The deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic side chain of the valine residue at position 6 of the beta chain in haemoglobin is able to associate with the hydrophobic patch, causing haemoglobin S molecules to aggregate and form fibrous precipitates.

HBB gene (responsible for sickle-cell anaemia) is located on the short (p) arm ofchromosome 11 at position 15.5

The allele responsible for sickle-cell anaemia can be found on the short arm of chromosome 11, more specifically 11p15.5. 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 or heterozygote. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe.^[32]

Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such asAfrica, the Mediterranean, India, and the Middle East.^[33] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.^[34]

The malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the Plasmodium parasite 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).

Scanning electron micrograph showing a mixture of red blood cells, some with round normal morphology, some with mild sickling showing elongation and bending

The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle-cell disease, low oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.

The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction.^[36] Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.^[37]

In HbSS, the complete blood count reveals haemoglobin levels in the range of 6–8 g/dl with a high reticulocyte count (as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells). In other forms of sickle-cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cellsand Howell-Jolly bodies).

Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution.

Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.^[38]

An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia, should be routinely performed.^[39]

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 fetus or a sample of amniotic fluid. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening provides not only a method of early detection for individuals with sickle-cell disease, but also allows for identification of the groups of people that carry the sickle cell trait.^[40]