Clinical Cases (Biochemistry)
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.
^ What is the most likely diagnosis?
^ What is the molecular genetics behind this disorder?
^ What is the pathophysiologic mechanism of her symptoms?
ANSWERS TO CASE 1: SICKLE CELL DISEASE
Summary: A 15-year-old African-American female with recurrent bilateral thigh and hip pain, anemia, and symptoms and laboratory evidence of a urinary tract infection.
^ Most likely diagnosis: Sickle cell disease (pain crisis).
^ Biochemical mechanism of disease: Single amino acid substitution on hemoglobin beta chain, inherited in an autosomal recessive fashion (1 of 12 African Americans in United States are carriers of the trait).
^ Pathophysiologic mechanism of symptoms: The sickled red blood cells cause infarction of bone, lung, kidney, and other tissue from vasoocclusion.
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. Since she is homozygous (both genes coding for sickle hemoglobin), both her parents have sickle cell trait (heterozygous) and thus do not have symptoms. 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.
APPROACH TO SICKLE CELL DISEASE
1. Understand the primary, secondary, tertiary, and quaternary levels of protein structure.
2. Be able to describe the structure of hemoglobin and its role in oxygen binding and dissociation.
3. Be able to describe the mechanism that amino acid substitution results in sickle cell hemoglobin.
Allosteric effectors: Molecules that bind to enzymes or protein carriers at sites other than the active or ligand binding site. On binding, allosteric effectors either positively or negatively affect the enzymatic activity or capability of the protein to bind its ligand.
Globin: The globular proteins that are the polypeptide components of myoglobin and hemoglobin.