Sickle cell disease (NORD)

Sickle cell disease, also called sickle cell anemia or just “sickle cell,” 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 bound to a heme group.

Different hemoglobins have different combinations of these chains. Hemoglobin A (or HbA), made up of two α-globin and two β-globin peptide chains, is the primary hemoglobin affected in sickle cell.

Specifically, the β-globin chains end up misshapen. This is because of a mutation in the beta globin gene, or HBB 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 HBB gene, then they’re 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 falciparum malaria, so in parts of the world with a high malaria burden, like Africa and pockets of southern Asia, those with sickle trait actually have an 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 parts of the world.

Almost always, the sickle cell mutation is a nonconservative missense mutation that results in the 6th amino acid of beta globin being a valine instead of glutamic acid.

A nonconservative substitution means that the new amino acid—valine, which is hydrophobic—has different properties that the one it replaced—glutamic acid, which is hydrophilic.

A hemoglobin tetramer with two α-globin and two mutated β-globin proteins is called sickle hemoglobin, or HbS.

HbS carries oxygen perfectly well, but when de-oxygenated, HbS changes its shape, which allows it to aggregate with other HbS 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 hemoglobin’s affinity for oxygen, and small, low-flow vessels where red blood cells’ hemoglobin molecules have plenty of time to dump lots of oxygen molecules.

Repeated sickling of red blood cells damages their cell membranes and promotes premature destruction; since this happens within the vasculature, it’s called intravascular hemolysis.

This destruction of red blood cells not only leads to anemia—which is a deficiency in red blood cells, 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 level is a sign of intravascular hemolysis.

Recycling of that heme group yields unconjugated bilirubin, which at high concentration can cause scleral icterus, jaundice, and bilirubin gallstones.

To counteract 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 medullary cavities of the skull caan expand outward, which causes enlarged cheeks and a ‘hair-on-end’ appearance on skull X-ray.

Extramedullary hematopoiesis—which is red blood cell production outside of the bone marrow—can also happen, most often in the liver which can cause hepatomegaly.