A 15-year-old African-American female presents to the emergency room with complaints of bilateral thigh and hip pain. The pain has been present for 1 day and is steadily increasing in severity. Acetaminophen and ibuprofen have not relieved her symptoms. She denies any recent trauma or excessive exercise. She does report feeling fatigued and has been having burning with urination along with urinating frequently. She reports having similar pain episodes in the past, sometimes requiring hospitalization. On examination, she is afebrile (without fever) and in no acute distress. No one in her family has similar episodes. Her conjunctiva and mucosal membranes are slightly pale in coloration. She has nonspecific bilateral anterior thigh pain with no abnormalities appreciated. The remainder of her examination is completely normal. Her white blood cell count is elevated at 17,000/mm3 and her hemoglobin (Hb) level is decreased at 7.1 g/dL. The urinalysis demonstrated an abnormal number of numerous bacteria.
Based on blood smear report and the clinical features, the patient has been diagnosed with sickle-cell disease. The molecular event triggering this disease is which of the following?
A. A loss of quaternary structure of the hemoglobin molecule
B. An increase in oxygen binding to hemoglobin
C.A gain of ionic interactions, stabilizing the “T” form of hemoglobin
D. An increase in hydrophobic interactions between deoxyhemoglobin molecules
E. An alteration in hemoglobin secondary structure leading to loss of the “α” helix
The answer is D: An increase in hydrophobic interactions between deoxyhemoglobin molecules.
The patient is suffering from sickle-cell disease.
In sickle-cell disease, valine (a hydrophobic amino acid) is substituted for glutamate (a charged, hydrophilic amino acid) in the sixth position in the β-globin chain of hemoglobin (Hb).
This change, from a negatively charged amino acid side chain (glutamate) to a hydrophobic side chain (valine), allows deoxygenated hemoglobin to polymerize and form long rods within the red blood cell (figure-1). Deoxygenated hemoglobin has a hydrophobic patch on its surface (created by A70, F85, and L88), which the valine in position 6 on another hemoglobin chain can associate with via hydrophobic interactions (this does not occur in normal hemoglobin as there is a charged glutamate residue at this position, which will not interact with a surface hydrophobic patch)- figure-1.The binding of hemoglobin molecules to each other results in the polymerization. This causes the red blood cell to have less distensibility and thus to sickle, leading to rupture of the red blood cell (hemolysis) and blockage in small capillaries. The sludging in small capillaries leads to poor oxygen delivery, ischemia, and pain (figure-2).
Figure- 1-Basic pathophysiological mechanism of sickle-cell disease: the polymerization of deoxy-HbS. The replacement of a glutamic acid by a valine residue at position 6 in the β-globin polypeptide chain characterizes the abnormal haemoglobin of SCD: HbS. At low oxygen pressure, deoxy-HbS polymerises and gets organised in long polymer fibres that deform, stiffen, and weaken the red blood cell (not shown). This process represents the basic mechanisms leading to haemolytic anaemia and to vaso-occlusive events in the microcirculation.
Oxygenated hemoglobin does not present a hydrophobic surface to other hemoglobin molecules, so polymerization is much less likely in the oxygenated state. The polymerization is not caused by a loss of quaternary structure, an increase in oxygen binding (which would actually reduce sickling), a gain of ionic interactions, or the loss of any α-helical structure in the final conformation of the protein.
This 15-year-old female’s description of her pain is typical of a sickle-cell pain crisis. Many times, infection is a trigger, most commonly pneumonia or a urinary tract infection. This case is consistent with a urinary tract infection, indicated by her symptoms of urinary frequency, and burning with urination (dysuria). Her white blood cell count is elevated in response to the infection. The low hemoglobin level is consistent with sickle-cell anemia (figure-2).
Figure-2- Biochemical basis of clinical manifestations in Sickle cell disease.
The diagnosis can be established with hemoglobin electrophoresis. Treatment includes searching for an underlying cause of crisis (infection, hypoxia, fever, excessive exercise, and extreme changes in temperature), administration of oxygen, intravenous fluids for hydration, pain management, and consideration of a blood transfusion.
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