Sickle cell disease


Sickle cell disease, also simply called sickle cell, is a group of inherited haemoglobin-related blood disorders. The most common type is known as sickle cell anaemia. Sickle cell anaemia results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to the red blood cells adopting an abnormal sickle-like shape under certain circumstances. With this shape, they are unable to deform as they pass through capillaries, causing blockages.
Problems in sickle cell disease typically begin around 5 to 6 months of age. Several health problems may develop, such as attacks of pain in joints, anaemia, swelling in the hands and feet, bacterial infections, dizziness and stroke. The probability of severe symptoms, including long-term pain, increases with age. Without treatment, people with sickle cell disease rarely reach adulthood, but with good healthcare, median life expectancy is between 58 and 66 years. All of the major organs are affected by sickle cell disease. The liver, heart, kidneys, lungs, gallbladder, eyes, bones, and joints can be damaged from the abnormal functions of the sickle cells and their inability to effectively flow through the small blood vessels.
Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene that make haemoglobin, one from each parent. The abnormal gene generates haemoglobin S which changes the properties of red blood cells. A sickle cell crisis occurs when red blood cells switch from the normal saucer-like shape to a sickle-like shape which can obstruct small blood vessels; an attack can be set off by temperature changes, stress, dehydration, and high altitude. A person with a single abnormal gene does not usually have symptoms and is said to have sickle cell trait, these people are also referred to as carriers. Diagnosis is by a blood test, and some countries test all babies at birth for the disease. Diagnosis of the unborn foetus is also possible during pregnancy.
The care of people with sickle cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation, and pain medication. Other measures may include blood transfusion and the medication hydroxycarbamide. In 2023, new gene therapies were approved involving the genetic modification and replacement of blood forming stem cells in the bone marrow.
, sickle cell disease is estimated to affect about 7.7 million people worldwide, directly causing an estimated 34,000 annual deaths and a contributory factor to a further 376,000 deaths. About 80% of sickle cell disease cases are believed to occur in sub-Saharan Africa. It also occurs to a lesser degree among people in parts of India, Southern Europe, West Asia, North Africa and among people of African origin living in other parts of the world. The condition was first described in the medical literature by American physician James B. Herrick in 1910. In 1949, its genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954, it was established that carriers of the abnormal gene are protected to some degree against malaria, which accounts for its persistence in populations threatened by malaria.

Signs and symptoms

Signs of sickle cell disease usually begin in early childhood. The severity of symptoms can vary from person to person, as can the frequency of crisis events. Sickle cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.

First events

When sickle cell disease presents within the first year of life, the most common problem is an episode of pain and swelling in the child's hands and feet, known as dactylitis or "hand-foot syndrome". Pallor, jaundice, and fatigue can also be early signs due to anaemia resulting from sickle cell disease.
In children older than 2 years, the most common initial presentation is a painful episode of a generalised or variable nature, while a slightly less common presentation involves acute chest pain. Dactylitis is rare or almost never occurs in children over the age of 2.

Critical events

Vaso-occlusive crisis

Also termed "sickle cell crisis" or "sickling crisis", the vaso-occlusive crisis manifests principally as extreme pain, most often affecting the chest, back, legs, and/or arms. The underlying cause is 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. Milder crises can be managed with nonsteroidal anti-inflammatory drugs. For more severe crises, patients may require inpatient management for intravenous opioids. Vaso-occlusive crisis involving organs such as the lungs or the penis are considered an emergency and treated with red blood cell transfusions.
A VOC can be triggered by anything which causes blood vessels to constrict; this includes physical or mental stress, cold, and dehydration. "After Haemoglobin S deoxygenates in the capillaries, it takes some time for HbS polymerization and the subsequent flexible-to-rigid transformation. If the transit time of RBC through the microvasculature is longer than the polymerization time, sickled RBC will lodge in the microvasculature."

Splenic sequestration crisis

The spleen is especially prone to damage in sickle cell disease due to its role as a blood filter. A splenic sequestration crisis, also known as a spleen crisis, is a medical emergency that occurs when sickled red blood cells block the spleen's filter mechanism, causing the spleen to swell and fill with blood. The accumulation of red blood cells in the spleen results in a sudden drop in circulating haemoglobin and potentially life-threatening anaemia. Symptoms include pain on the left side, swollen spleen, fatigue, dizziness, irritability, rapid heartbeat, or pale skin. It most commonly affects young children; the median age of first occurrence is 1.4 years. By the age of 5 years, repeated instances of sequestration cause scarring and eventual atrophy of the spleen.
Treatment is supportive, with blood transfusion if haemoglobin levels fall too low. Full or partial splenectomy may be necessary. Long term consequences of a loss of spleen function are increased susceptibility to bacterial infections.

Acute chest syndrome

is caused by a VOC which affects the lungs, possibly triggered by infection or by emboli which have circulated from other organs. Symptoms include wheezing, chest pain, fever, pulmonary infiltrate, and hypoxemia. After sickling crisis, it is the second-most common cause of hospitalisation, and it accounts for about 25% of deaths in patients with sickle cell disease. Most cases present with vaso-occlusive crises and then develop acute chest syndrome.

Aplastic crisis

are instances of an acute worsening of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them. 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 people with sickle cell disease results in an abrupt, life-threatening situation. Reticulocyte count drops dramatically during the disease, red cell production lapses, and the rapid destruction of existing red cells leads to acute and severe anaemia. This crisis takes four to seven days to resolve. Most patients can be managed supportively; some need a blood transfusion.

Complications

Sickle cell anaemia can lead to various complications, including: