, Question 1
A missense mutation substitutes valine for glutamic acid at position 6 of the
-globin chain. Which pathophysiologic consequence most directly explains the
premature destruction of erythrocytes in this disorder?
A. Impaired globin chain synthesis leading to microcytic hypochromic
anemia
B. Polymerization of deoxygenated hemoglobin distorting the cell into a
rigid sickle shape
C. Autoantibody-mediated complement fixation on the red cell membrane
D. Defective heme synthesis causing ringed sideroblasts in the marrow
Correct Answer: B - Polymerization of deoxygenated hemoglobin
distorting the cell into a rigid sickle shape
RATIONALE
The valine substitution creates a hydrophobic interaction site that,
upon deoxygenation, polymerizes HbS into rigid fibers, deforming the
cell and causing membrane damage and splenic sequestration.
Impaired synthesis (A) describes thalassemia; autoantibodies (C)
describe autoimmune hemolysis; defective heme synthesis (D)
describes sideroblastic anemia.
Question 2
In a patient with a complement deficiency, which pattern of infections most
strongly suggests a defect in the terminal membrane attack complex (C5-C9)?
A. Recurrent encapsulated bacterial infections (e.g., Streptococcus
pneumoniae)
B. Recurrent Neisseria species infections (e.g., meningitidis,
gonorrhoeae)
C. Chronic mucocutaneous candidiasis
D. Severe viral infections with impaired cytotoxic T-cell responses
Correct Answer: B - Recurrent Neisseria species infections (e.g.,
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,meningitidis, gonorrhoeae)
RATIONALE
Terminal complement components are critical for lysing
Gram-negative Neisseria; deficiency predisposes to recurrent
disseminated Neisseria infections. Encapsulated bacteria (A) suggest
antibody or early complement (C1-C4) defects; candidiasis (C)
suggests T-cell defects; viral infections (D) suggest cellular
immunodeficiency.
Question 3
A tumor suppressor gene is inactivated by a nonsense mutation in one allele
and a chromosomal deletion in the other. This mechanism best exemplifies
which genetic concept?
A. Haploinsufficiency
B. Dominant-negative effect
C. Loss of heterozygosity (two-hit hypothesis)
D. Genomic imprinting
Correct Answer: C - Loss of heterozygosity (two-hit hypothesis)
RATIONALE
The two-hit hypothesis requires biallelic inactivation; a germline
mutation plus somatic loss of the second allele constitutes loss of
heterozygosity. Haploinsufficiency (A) involves one functional copy
being insufficient; dominant-negative (B) involves a mutant protein
interfering with wild-type; imprinting (D) is parent-of-origin
silencing.
Question 4
Which hemodynamic change best explains the development of high-output
heart failure in a patient with chronic severe anemia?
A. Increased afterload from systemic vasoconstriction
B. Compensatory tachycardia and reduced blood viscosity decreasing
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, systemic vascular resistance
C. Impaired myocardial contractility due to iron deposition
D. Pericardial effusion restricting diastolic filling
Correct Answer: B - Compensatory tachycardia and reduced
blood viscosity decreasing systemic vascular resistance
RATIONALE
Chronic anemia reduces oxygen-carrying capacity, triggering
compensatory tachycardia and decreased viscosity, which lowers SVR
and increases cardiac output, eventually leading to high-output failure.
Afterload increase (A) is not typical; iron deposition (C) causes
restrictive cardiomyopathy; pericardial effusion (D) causes diastolic
restriction, not high-output state.
Question 5
A patient with acute respiratory distress syndrome (ARDS) has refractory
hypoxemia. Which pathophysiologic mechanism most directly accounts for the
hypoxemia?
A. Increased alveolar dead space due to pulmonary embolism
B. Intrapulmonary shunting from alveolar flooding and collapse
C. Hypoventilation from opioid-induced respiratory depression
D. Diffusion limitation from thickened alveolar-capillary membrane
Correct Answer: B - Intrapulmonary shunting from alveolar
flooding and collapse
RATIONALE
ARDS causes heterogeneous alveolar flooding and collapse, creating
true intrapulmonary shunt where blood bypasses non-ventilated
alveoli, leading to refractory hypoxemia. Dead space (A) impairs CO2
elimination more than oxygenation; hypoventilation (C) responds to
supplemental oxygen; diffusion limitation (D) is a minor contributor
in ARDS.
Page 4
A missense mutation substitutes valine for glutamic acid at position 6 of the
-globin chain. Which pathophysiologic consequence most directly explains the
premature destruction of erythrocytes in this disorder?
A. Impaired globin chain synthesis leading to microcytic hypochromic
anemia
B. Polymerization of deoxygenated hemoglobin distorting the cell into a
rigid sickle shape
C. Autoantibody-mediated complement fixation on the red cell membrane
D. Defective heme synthesis causing ringed sideroblasts in the marrow
Correct Answer: B - Polymerization of deoxygenated hemoglobin
distorting the cell into a rigid sickle shape
RATIONALE
The valine substitution creates a hydrophobic interaction site that,
upon deoxygenation, polymerizes HbS into rigid fibers, deforming the
cell and causing membrane damage and splenic sequestration.
Impaired synthesis (A) describes thalassemia; autoantibodies (C)
describe autoimmune hemolysis; defective heme synthesis (D)
describes sideroblastic anemia.
Question 2
In a patient with a complement deficiency, which pattern of infections most
strongly suggests a defect in the terminal membrane attack complex (C5-C9)?
A. Recurrent encapsulated bacterial infections (e.g., Streptococcus
pneumoniae)
B. Recurrent Neisseria species infections (e.g., meningitidis,
gonorrhoeae)
C. Chronic mucocutaneous candidiasis
D. Severe viral infections with impaired cytotoxic T-cell responses
Correct Answer: B - Recurrent Neisseria species infections (e.g.,
Page 2
,meningitidis, gonorrhoeae)
RATIONALE
Terminal complement components are critical for lysing
Gram-negative Neisseria; deficiency predisposes to recurrent
disseminated Neisseria infections. Encapsulated bacteria (A) suggest
antibody or early complement (C1-C4) defects; candidiasis (C)
suggests T-cell defects; viral infections (D) suggest cellular
immunodeficiency.
Question 3
A tumor suppressor gene is inactivated by a nonsense mutation in one allele
and a chromosomal deletion in the other. This mechanism best exemplifies
which genetic concept?
A. Haploinsufficiency
B. Dominant-negative effect
C. Loss of heterozygosity (two-hit hypothesis)
D. Genomic imprinting
Correct Answer: C - Loss of heterozygosity (two-hit hypothesis)
RATIONALE
The two-hit hypothesis requires biallelic inactivation; a germline
mutation plus somatic loss of the second allele constitutes loss of
heterozygosity. Haploinsufficiency (A) involves one functional copy
being insufficient; dominant-negative (B) involves a mutant protein
interfering with wild-type; imprinting (D) is parent-of-origin
silencing.
Question 4
Which hemodynamic change best explains the development of high-output
heart failure in a patient with chronic severe anemia?
A. Increased afterload from systemic vasoconstriction
B. Compensatory tachycardia and reduced blood viscosity decreasing
Page 3
, systemic vascular resistance
C. Impaired myocardial contractility due to iron deposition
D. Pericardial effusion restricting diastolic filling
Correct Answer: B - Compensatory tachycardia and reduced
blood viscosity decreasing systemic vascular resistance
RATIONALE
Chronic anemia reduces oxygen-carrying capacity, triggering
compensatory tachycardia and decreased viscosity, which lowers SVR
and increases cardiac output, eventually leading to high-output failure.
Afterload increase (A) is not typical; iron deposition (C) causes
restrictive cardiomyopathy; pericardial effusion (D) causes diastolic
restriction, not high-output state.
Question 5
A patient with acute respiratory distress syndrome (ARDS) has refractory
hypoxemia. Which pathophysiologic mechanism most directly accounts for the
hypoxemia?
A. Increased alveolar dead space due to pulmonary embolism
B. Intrapulmonary shunting from alveolar flooding and collapse
C. Hypoventilation from opioid-induced respiratory depression
D. Diffusion limitation from thickened alveolar-capillary membrane
Correct Answer: B - Intrapulmonary shunting from alveolar
flooding and collapse
RATIONALE
ARDS causes heterogeneous alveolar flooding and collapse, creating
true intrapulmonary shunt where blood bypasses non-ventilated
alveoli, leading to refractory hypoxemia. Dead space (A) impairs CO2
elimination more than oxygenation; hypoventilation (C) responds to
supplemental oxygen; diffusion limitation (D) is a minor contributor
in ARDS.
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