Sickle Cell Disease
Sickle Cell Disease, also called SCD, is a genetic disease that affects the blood. Many people have heard of the term Sickle Cell Anemia which is the most common form of SCD and the focus of this video.
Worldwide, millions of people suffer from SCD. About 80% of all patients live in Sub-Saharan Africa. Outside of Africa, SCD is most common in SouthEast Asia, mainly India and in the Eastern Mediterranean Region. In Europe and the United States SCD is much less common and can often be found in people with African ancestors.
SCD is an autosomal recessive disorder, which means both parents must carry the mutated gene and pass it on for their child to develop the disease. Furthermore, SCD is a monogenic disease, which means only one gene is mutated and responsible for the symptoms observed.
Sickle Cell Disease is a multisystem disease which entails episodes of acute illness as well as progressive organ damage. Severity and kind of symptoms differ among patients depending on the exact kinds of mutations, also referred to as genotype, and other environmental factors. Some of the most common symptoms include: chronic anemia and acute anemic episode, painful episodes from vaso-occlusion, acute chest syndrome, and stroke. There are many more symptoms that affect different organs like the kidneys, spleen, and heart but for now let’s focus on the most common and severe symptoms.
Chronic anemia and acute anemic episodes:
Chronic anemia occurs when, on a chronic basis, there aren’t enough healthy red blood cells to carry oxygen to a person’s organs. This is often the case in SCD as the oxygen carrying molecule, hemoglobin is defective. More about that later. Acute anemic episodes differ in that it is an event where a high number of red blood cells die, leading to a lack of oxygen transport.
Painful episodes from vaso-occlusion:
Vaso-occlusion occurs when the circulation is obstructed and blood can’t flow properly. This happens in SCD when sickled red blood cells block blood vessels. The result of these obstructions is a painful event, often in extremities, feet and hands. The pain level differs but sometimes when pain is unmanageable, patients require hospitalization and treatment with intravenous opioids to find relief. More than 3 painful episodes with hospitalization per year is associated with an increased mortality in patients over 20 years. Unexplained death during painful episodes can also occur.
Acute chest syndrome:
This usually follows a painful episode and is extremely dangerous. Symptoms are fever, chest pain, wheezing, cough and hypoxia. Acute chest syndrome is a frequent cause of death in patients with SCD and sometimes culminates with multi organ failure. In children, acute chest syndrome occurs more often but is usually less severe. In adults, however, albeit rare, acute chest syndrome is highly dangerous.
Stroke:
Strokes are very common especially in kids with Sickle Cell Disease. This is because sickled red blood cells in combination with a reduction in nitric oxide damage the walls of blood vessels. When this happens in the brain, we speak of cerebral vascular damage. Together with high rates of blood flow in patients with SCD, cerebral vascular damage leads to a high risk of stroke.
So what exactly happens in Sickle Cell Disease? Let’s take a look at some background before diving into the genetics.
Humans need oxygen to survive. It is the fuel that all our organs run on. Red blood cells, also called erythrocytes are the special cell type that transports oxygen throughout our body. Erythrocytes are produced in the bone marrow and have a lifespan of about 100-120 days. Special about erythrocytes is that they don’t have a nucleus. That’s because in order to move through tiny capillaries, red blood cells have to be smaller than most other cell types in our bodies and they need as much room as possible to store hemoglobin.
Hemoglobin is the molecule that binds oxygen in the lungs and releases it in tissues. Hemoglobin consists of four individual units that are connected to each other. Those units are called globins. The composition of those globins determines the different kinds of hemoglobin. For example during fetal development, red blood cells mostly carry hemoglobin F, or HbF. HbF consists of 2 alpha and two delta units. Until babies are about 6 weeks old, HbF is the predominant form of hemoglobin. Afterwards HbF gets slowly substituted with other kinds of hemoglobin. The most common hemoglobin in adults is HbA, which consists of two alpha and two beta subunits. Other kinds of hemoglobin exist, but make up only a small percentage of the overall hemoglobin.
Erythrocytes are packed with hemoglobin molecules and each hemoglobin can bind up to 4 oxygen molecules. In oxygen rich environments, like the lungs, hemoglobin takes on a shape, or conformation, that allows the binding of oxygen molecules. When erythrocytes travel to places in the body that are in need of oxygen, the conformation of hemoglobin changes and releases the bound oxygen to the environment. Blood then travels back to the lung and the cycle repeats.
How is this process disrupted in patients with Sickle Cell Disease?
SCD is a result of mutations in the gene producing the beta units of hemoglobin. This gene is called beta-globin or HBB gene and is located on the short arm of chromosome 11. Different mutations exist leading to different kinds of sickle cell disease. The most common kind is Sickle Cell Anemia in which a patient has two identical mutations replacing the beta globin units with a mutated version called S globin. The S globin is produced when patients carry a nucleotide substitution of A-to-T in the codon for the amino acid at position 6. Instead of glutamic acid, the A-to-T transversion leads to incorporation of the amino acid valine. This seemingly small change has dramatic effects. When hemoglobin is deoxygenated, meaning it is in the state where it doesn’t carry any oxygen, it binds to other deoxygenated hemoglobins forming polymers within the erythrocyte. These polymers change the shape of red blood cells from its usual donut-like flexible disk, to a sickle shaped rigid cell.
Although the polymerization is reversible when hemoglobin binds oxygen, it causes a lot of damage. The polymers changing the cell shape cause membrane damage that with recurring events, will ultimately lead to hemolysis, the rupture and destruction of the erythrocyte. Additionally, the rigid sickle cell doesn’t flow as freely and unhindered through blood vessels which often leads to obstruction of such.
Hemolysis leads to many complications. For one, if many erythrocytes die at the same time, the patient will suffer from an acute anemic event as talked about earlier. Additionally, with hemolysis, erythrocytes secrete a protein called arginase which metabolizes arginine. This means less arginine is available in the environment and other processes that require arginine are negatively affected. For example the production of nitric oxide, NO, is dependent on arginine availability. With arginase in the bloodstream after hemolysis, less production of NO can occur leading to a lack of NO bioavailability. This has multiple downstream effects, such as hypertension, or high blood pressure, and hypertension specifically in lungs, which is called pulmonary hypertension. Pulmonary hypertension is very dangerous and can be lethal. Other symptoms of reduced NO bioavailability are priapism, which is a prolonged erection of the penis which in some cases requires immediate medical intervention, and leg ulcers, which are open wounds that allow bacterial growth.
Recurring vaso-occlusion due to sickled erythrocytes lead to progressive damage to most organs, including the brain, kidneys, lunges, bones, and cardiovascular system.
What does the prognosis for people with Sickle Cell Disease look like?
Life expectancy for people with SCD is difficult to predict as disease progression varies widely. Many children die at a young age but there are also a lot of people surviving into their 50s. Different factors influence how long a person lives and what their quality of life looks like.
For example, people who have higher percentages of fetal hemoglobin in their blood have a better prognosis compared to patients with low HbF. This is because HbF is thought to decrease polymerization.
Furthermore, people in more developed countries usually get better care. This means they have more access to medication, although not many medications are available for SCD, and other treatment options. One common and seemingly helpful treatment strategy is regular blood transfusions. You basically want to dilute the percentage of sickled erythrocytes to avoid serious complications. In some rare cases, people can receive bone marrow transplants, which are the only cure for SCD at the moment. However, only a very small percentage of patients qualify as a compatible donor is required and the procedure is dangerous leading to death in about 7% of the patients who undergo bone marrow transplants.
People in Africa usually have the most severe clinical courses of Sickle Cell Disease. Partly this is because of access to medical care, but infectious diseases also play a role. Malaria for example is a great danger for people with SCD. Interestingly, carriers of SCD, people who carry only one allele of the mutated beta-globin gene, have an advantage over people with two healthy alleles when it comes to malaria infections. This may be one reason why SCD is most prevalent in countries that were or are still exposed to malaria.
Here, I only covered Sickle Cell Anemia, which is one kind of Sickle cell disease. There are many other genotypes leading to other kinds of Sickle Cell Disease not discussed here.
Literature used
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950383/
https://pubmed.ncbi.nlm.nih.gov/9287233/
