Sickle cell disease (NORD)

Video summary

Sickle cell disease is an autosomal recessive genetic disorder, in which the beta-globin subunit of hemoglobin is misshapen, causing red blood cells to sickle when deoxygenated, which leads to their premature destruction as well as vaso-occlusion. Sickle-cell disease is associated with several acute and chronic health problems, such as severe infections, attacks of severe pain ("sickle-cell crisis"), stroke, and an increased risk of death.

Symptoms of sickle cell disease can vary and may include episodes of severe pain, fatigue, shortness of breath, anemia, and frequent infections. The severity and frequency of symptoms can vary widely among individuals with the condition, and some people may experience only mild symptoms, while others may have more severe and frequent episodes of pain and organ damage.

Treatment for sickle cell disease may involve pain management, blood transfusions, and antibiotics to prevent infections. In some cases, a bone marrow transplant may be necessary to cure the condition. Additionally, individuals with sickle cell disease may need to make lifestyle changes, such as avoiding extreme temperatures, staying hydrated, and managing stress, to help prevent and manage symptoms.

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In sickle cell disease, also known as sickle cell anemia, the term sickle cell refers to the crescent-shaped red blood cells due to abnormal hemoglobin structure.
Moreover, sickle cell disease is caused by mutations in the HPB gene and represents the most common inherited hemoglobinopathy.
Healthy red blood cells or erythrocytes have a biconcave shape looking like flattened discs. If we slice one open, you'll notice it's not completely packed, meaning there's more cell membrane than content inside.
Inside there's hemoglobin, which is the protein responsible for carrying oxygen from the lungs to the rest of the body. Imagine hemoglobin as marbles and the red blood cell membrane as a plastic bag.
If you fill the bag tightly with marbles, it won't bend or fit through narrow pipes. But if you use a much larger bag for the same number of marbles, you could easily squeeze it through.
That's exactly how red blood cells work. Their structure gives them flexibility to stretch and change shape as they squeeze through tiny capillaries without breaking.
Now let's talk about hemoglobin itself. Hemoglobin is a tetramer, meaning it's made up of 4 protein subunits arranged in two pairs.
Up until 6 months of age, most of our hemoglobin is fetal hemoglobin or hemoglobin F, which consists of 2 alpha globin chains and 2 gamma globin chains.
Around 6 months of age, the body shifts from hemoglobin F. To the dominant adult form called hemoglobin A, which consists of two alpha globin and two beta globin chains, there's also a small amount of hemoglobin A2 which contains two alpha globin and two delta globin chains.
Now in sickle cell disease, there's a mutation in the HBB gene that encodes beta globin chains of hemoglobin. If a person inherits only one mutated copy of the gene, they are a carrier and do not develop the condition.
These individuals have a sickle cell trait. However, if they inherit two mutated copies, they develop sickle cell disease.
In other words, sickle cell disease is an autosomal recessive condition. This mutation in the HBB gene affects the 6th amino acid of the beta globin chain.
Normally, glutamic acid is in this position, which is hydrophilic and loves water. However, in sickle cell disease, glutamic acid is replaced by valine, which is sticky and hydrophobic, meaning it repels water.
So instead of hemoglobin A, red blood cells are rich in hemoglobin S. While hemoglobin S can still carry oxygen, problems arise when it releases oxygen.
Once deoxygenated, valine on neighboring hemoglobin molecules starts to stick together, causing them to clump and form long, rigid polymers.
Eventually these polymers distort the shape of the red blood cells, turning them from flexible biconcave discs into stiff, crescent, or sickle shaped cells.
This process is called sickling. As a result, sickled red blood cells lose their flexibility and can no longer squeeze through tiny blood vessels.
As a result, they get stuck, causing blockages. That lead to microvascular obstruction and tissue ischemia.
But once the red cells reach the lungs, pick up oxygen, and bind it to hemoglobin S, they return to their normal shape. So initially, the sickling process is reversible.
However, each time hemoglobin S releases oxygen, Calcium rushes into the cell. While potassium and water leave the cell, leaving it dehydrated over time, these repeated cycles of sickling and desickling lead to permanent cell membrane distortion, making red blood cells prone to intravascular hemolysis.
Additionally, there's also extravascular hemolysis because macrophages within the spleen recognize these sickled red cells as abnormal, so they engulf them and destroy them.
Now, several conditions can trigger sickling. First, hypoxemia, or low oxygen levels in the blood, leaves hemoglobin in a deoxygenated state directly triggering sickling.
Similarly, acidosis encourages hemoglobin to release oxygen, also promoting the deoxygenated state and sickling. On the other hand, dehydration and hypeosmolarity cause red blood cells to lose fluid.
This makes hemoglobin more concentrated inside the cell, increasing the risk of clumping, even when oxygen levels are normal and there's no acidosis.
Moving on to clinical manifestations which typically don't appear until around 6 months of age when hemoglobin F is replaced by hemoglobin S.
Once sickling begins, it leads to two major consequences over time. First, both intravascular and extravascular hemolysis cause chronic hemolytic anemia.
Additionally, viral infections, especially panovirus B19 infection, Can trigger aplastic crisis where the bone marrow temporarily stops making new red blood cells.
Second, microvascular obstruction can result in intense pain, but also tissue and organ damage. These are known as vaso-occlusive episodes or crises, and they can occur anywhere in the body.
For example, the blockage of blood vessels in the brain can lead to an ischemic stroke, and the eye, it can result in retinal infarction.
Moreover, recurrent retinal infarctions can stimulate the growth of new blood vessels to compensate for retinal ischemia.
Over time, this can lead to proliferative retinopathy and even blindness. Sickle cells can also block lung blood vessels and cause acute chest syndrome, which is characterized by chest pain, difficulty breathing, fever, low oxygen levels, and lung infiltrates on a chest X-ray.
Often it occurs several days after a vaso-occlusive episode, and it's dangerous because low oxygen levels trigger even more sickling, which can rapidly make the situation worse.
Next, in the spleen, repeated vaso occlusions will result in infarctions and hyposplenism. The damaged spleen leaves individuals vulnerable to infections, especially by encapsulated bacteria like Streptococcus pneumonia, Haemophilus influenzae, and salmonella.
Finally, in young children, sickled red blood cells can obstruct blood vessels that supply the bones of the hands and feet and cause bone infarction, which is characterized by pain and swelling.
In severe cases, bacteria can invade the damaged bones and cause osteomyelitis. Again, the most common pathogens include encapsulated bacteria.
Most of the time, the diagnosis is made through routine newborn screening. However, if a person hasn't gone through screening, lab results will indicate signs of hemolysis.
As red blood cells break down, hemoglobin breaks down, causing bilirubin levels to rise. To compensate for the loss of red blood cells, the body responds by pumping out immature red blood cells called reticulocytes.
As a result, the lab findings will reveal low red blood cell count, hyperbilirubinemia. And reticulocytosis.
Additionally, a peripheral blood smear will reveal sickle-shaped red blood cells along with reticulocytes. Finally, to confirm the diagnosis, tests like hemoglobin electrophoresis or high performance liquid chromatography can help identify abnormal hemoglobin.
Moving on to treatment, which primarily focuses on preventing sickling, first, there's hydroxyurea, which boosts gamma globulin production and increases levels of fetal hemoglobin.
Since hemoglobin F cannot form polymers, it helps block the sickling process. Also, there are newer medications like Voxyotor and risanlizumab that help reduce hemolysis and vasoacclusive crises.
In severe cases, a bone marrow transplant may offer a potential cure. Additionally, gene therapy is an emerging option that aims to correct the underlying genetic cause to prevent sickling.
All right, as a quick recap, sickle cell disease is the most common inherited hemoglobinopathy characterized by crescent-shaped red blood cells due to abnormal hemoglobin.
The underlying cause is a mutation in the HBB gene that encodes beta globin chains of the hemoglobin, which results in the production of hemoglobin S.
When deoxygenated hemoglobin S molecules stick together. Forming rigid polymers that distort red blood cells into sickle-shaped red blood cells.
Leading to microvascular obstruction as well as intravascular and extravascular hemolysis.