Sickle Cell Anemia, Symptoms, Genetics, Disease, Diagnosis and Treatment
Sickle cell disease also called sickle cell anemia is a genetic disease, where red blood cells can take the shape of a crescent or sickle, and that change allows them to more easily be destroyed causing anemia among other things. Sickle cell disease is caused by defective hemoglobin, which is the oxygen carrying protein in red blood cells. Hemoglobin is actually made up of four peptide chains, each bond to a heme group.
Different hemoglobins have diffrent combination of these chains. Hemoglobin-A or Hb-A made up of two α-globin and two
β-globin peptide chains. This is the primary hemoglobin affected in the sickle cell. Specifically, the
β-globin chains end up misshapen. This is because of a mutation in the beta globin gene or Hb-B gene.
Sickle cell is an autosomal recessive disease so a mutation in both copies of the beta globin gene is needed to get the disease; if the person has just one copy of the mutation and one normal Hb-B gene, then they are a sickle cell carrier, also called sickle trait. Having sickle trait doesn't cause health problems unless the person is exposed to extreme conditions like high altitude or dehydration.
Where some sickle cell disease like symptoms can crop up what it does do is decrease the severity of infection by plasmodium falsiparum malaria, so in part of the world with a high malaria burden, like Africa and pockets of southern Asia, those with sickle trait actually have no evolutionary advantage. This phenomenon is called heterozygote advantage, and it's unfortunate consequence is a high rate of sickle cell disease in people from these part of the world.
Almost always sickle cell mutation is a non-conservative missense mutation that happens into the 6th amino acid of beta globin being a valine instead of glutamic acid. A non conservative substitution means that the new amino acid valine, which is hydrophobic has different properties than the one it replaced glutamic acid, which is hydrophilic.
A hemoglobin tetramer with two alpha-globin and two mutated beta-globin proteins is called sickle hemoglobin or Hb-S. Hb-S carries oxygen perfectly well, but when deoxygenated Hb-S change it's shape, which allows it to aggregate with other Hb-S proteins and form long polymers that distort the red blood cell into a crescent shape, a process called sickling. Conditions favorable for sickling include acidosis, which decreases hemoglobins affinity for oxygen and small low flow vessels where red blood cell's hemoglobin molecules have plenty of time to dump lots of oxygen molecules. Repeated sickling of red blood cell damages their cell membranes and promotes premature destruction, since this happens within the vasculature, its called intra vascular hemolysis.
Symptoms and sign
This destruction of red blood cells not only leads to anemia, which is a deficiency in red blood cells or loss of the normal levels of hemoglobin, but also means a lot of hemoglobin spilling out. Free hemoglobin in the plasma is bound by a molecule called haptoglobin and gets recycled; which is why a low haptoglobin levels is a sign of intro vascular hemolysis recycling of that heme group yields unconjugated bilirubin, which at high concentration can cause scleral icterus, jaundice and bilirubin gallstones.
To counter the anemia of sickle cell disease the bone marrow makes increased numbers of reticulocytes, which are immature red blood cells. This ends up causing new bone formation and the modulatory cavities of the skull can expand out ward, which causes enlarged cheeks and a 'hair-on-end' appearance on skull x-ray. Extra medullary hematopoiesis, which is red blood cell production cut side of the bone marrow can also happen, most often in the liver which can causes hepatomegaly.
In sickled from red blood cells tend to get stuck in capillaries, called vasco-occlusion. starting in infancy, they can clog up blood flow in bones of the hands and the feet, causing dactylitis, or swelling and pain of the digits. Later, they get stuck in other bone, causing a sickle cell pain crisis or a vascular necrosis of the bone. Red blood cells can also clog up the spleen, which can lead to an infarct of the spleen as well as an enormous back up of blood in the spleen called splenic sequestration, a life threatening complications.
Over time, splenic infarcts might can lead to an auto-splenectomy, where the spleen scars down and fibrosis to basically nothing. Having an absent or non functional spleen makes a person susceptible to encapsulated bacteria like streptococcus pneumonia, haemophilus influenza, Neisseria meningitis, and salmonella species, since encapsulated bacteria are normally opsonized and phagocytosed by macrophages in the spleen. It also leaves a person with Howell jolly bodies. Basophilic nuclear remnants in red blood cells, which can be seen on a peripheral blood cells, which can be seen on a peripheral blood smear. Sickled red blood cells can get stuck in the cerebral vasculature, causing vessel damage resulting in strokes.
Extensive sickle cell damage to the brain vessels may resulting Moya-Moya disease, which is named for the "puff-of-smoke". Collateral vessels that by pass blocked arteries they can also get stuck in the blood vessels of the lungs, leading to acute chest syndrome. This is particularly dangerous because it sets up a vicious cycle of preventing other red blood cells from getting oxygen, and this is made worse by the lung's natural tendency for hypoxia vasoconstriction, which is blood vessel.
Constriction in ares of the lungs that are lower in oxygen. In addition, clogging in the renal papillae can cause necrosis which can manifest as hematuria and proteinuria-blood and protein spilling out into take urine and in men, clogging the of the vasculature of the penis can cause priapism, a painful and prolonged erection.
Diagnosis
Given all of these symptoms, it's important to diagnose sickle cell anemia. So it's included in the new born blood spot screen in some countries and can also be identified with a blood smear looking for sickle cells or by identifying Hb-S using protein electrophoresis.
Treatments of sickle cell anemia
The factor that cause red blood cell to sickle, which are hypoxia, dehydration and/or acidosis, can be improved with oxygen and fluids, which are mainstays of treatment. In addition, opioids are usually used to manage pain and antibiotics are used to treat any underlying bacterial infections causing acute chest syndrome. Occasionally blood transfusion are also used built the risk of multiple transfusions include iron overload and risk of developing new antibodies against future blood transfusion.
Finally, children with sickle cell typically get prophylaxis with penicillin and an additional polysaccharide vaccine against streptococcus pneumonia, to help prevent sepsis and meningitis with encapsulated bacteria, which works by increasing the amount of gamma globin, which results in more fetal hemoglobin (Hb-F). Fetal hemoglobin is made up of two alpha and two gamma globin chains, so it doesn't include the mutated beta globins.
Since it can't polymerase, it gets in the way of Hb-S polymers being made and prevents sickling. Hb-F is the primary hemoglobin at birth, which explains why sickle cell symptoms don't happen until a few months of life when adult hemoglobin starts to predominate, which contains the mutated beta globin.more rarely bone marrow transplants have been used in some patients and given that sickle cell involves a single point mutation Gene Therapy is another option being researched.
