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Sickle cell disease (NORD)





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Sickle cell disease (NORD)


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High Yield Notes
13 pages

Sickle cell disease (NORD)

17 flashcards

USMLE® Step 1 style questions USMLE

3 questions

A 35-year-old man comes to the primary care office complaining of mild fatigue and shortness of breath. The patient has a past medical history significant for episodes of jaundice and intermittent right upper quadrant abdominal pain, which he has never been to the doctor for before. Temperature is 37.2°C (98.9°F), pulse is 72/min, respirations are 18/min, and blood pressure is 128/88 mmHg. Physical examination shows splenomegaly. Laboratory tests are obtained, and the results are shown below.  

Peripheral blood smear shows hexagonal crystals and target cells. This patient’s disease is most likely caused by a substitution of glutamic acid with which of the following amino acids?

External References

Content Reviewers:

Rishi Desai, MD, MPH


Tanner Marshall, MS

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.


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.