Sickle cell anemia – causes, symptoms, diagnosis, treatment & pathology

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 than 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
deoxygenated, 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 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
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 can
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. In sickled form, red blood cells tend to get
stuck in capillaries, called vaso-occlusion. Starting in infancy, they can clog up blood
flow in the bones of the hands and the feet, causing dactylitis, or swelling and pain of
the digits. Later, they get stuck in other bones, causing a sickle cell pain crisis or
avascular 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 complication. 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 nonfunctional spleen makes
a person susceptible to encapsulated bacteria, like Streptococcus pneumoniae, Haemophilus
influenzae, Neisseria meningitidis, 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 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 result in Moya-moya disease which is named for the “puff-of-smoke”
collateral vessels that bypass 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 congested, de-oxygenated red blood cells preventing other red blood
cells from getting oxygen, and this is made worse by the lung’s natural tendency for
hypoxic vasoconstriction, which is blood vessel constriction in areas of the lungs that are
low 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 the urine, and
in men, clogging the of the vasculature of the penis can cause priapism, a painful and
prolonged erection. Given all of these symptoms, it’s important
to diagnose sickle cell as early as possible, so it’s included in the newborn blood spot
screen in some countries and can also be identified with a blood smear looking for sickled cells
or by identifying HbS using protein electrophoresis. The factors that cause red blood cells 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 transfusions are also used, but the risk of multiple transfusions
include iron overload and the risk of developing new antibodies against future blood transfusions.
Finally, children with sickle cell typically get prophylaxis with penicillin and an additional
polysaccharide vaccine against Streptococcus pneumoniae, to help prevent sepsis and meningitis
with encapsulated bacteria, Another preventative medicine is hydroxyurea,
which works by increasing the amount of gamma globin, which results in more fetal hemoglobin,
or HbF. 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 polymerize, it gets in the way of
HbS polymers being made and prevents sickling. HbF 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. Alright, as a quick recap, sickle cell disease
is an autosomal recessive genetic disease where the beta-globin subunit of hemoglobin
is misshapen, which causes red blood cells to sickle when deoxygenated, and this leads
to their premature destruction as well as vaso-occlusion. Further, multiorgan damage
is the end result from ongoing sickling and hypoxic damage to the body’s important organs,
resulting in a shortened life span.