Hereditary Hemochromatosis MCQ — NEET PG Practice Question | NEETPGAI
Hereditary Hemochromatosis
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stethoscope Medicine
A 45-year-old man of Northern European descent presents with progressive fatigue, arthralgia in the second and third metacarpophalangeal joints, and hepatomegaly. Laboratory studies show transferrin saturation of 52% and serum ferritin of 580 ng/mL. HFE genotyping confirms C282Y homozygosity. The inheritance pattern marked **C** in the diagram represents the genetic basis of this patient's condition. Which of the following best explains the molecular pathophysiology underlying iron overload in this autosomal recessive disorder?
A. Loss-of-function mutation in the ferroportin gene preventing iron export from enterocytes and macrophages
B. Impaired HFE protein folding leading to inappropriately low hepcidin production, causing unchecked intestinal iron absorption and macrophage iron release
C. Mutation in the transferrin receptor gene causing increased iron uptake by hepatocytes and reduced iron excretion
D. Defective ceruloplasmin synthesis resulting in impaired ferroxidase activity and iron accumulation in the reticuloendothelial system
Explanation
Why option 1 is right
Hereditary hemochromatosis type 1 (HFE-HH) is caused by mutations in the HFE gene on chromosome 6p21, most commonly C282Y homozygosity. The impaired HFE protein folding results in inappropriately low hepcidin production by hepatocytes. Since hepcidin normally degrades ferroportin on enterocytes and macrophages, low hepcidin levels cause unchecked intestinal iron absorption and macrophage iron release, leading to progressive parenchymal iron deposition. This is the pathophysiologic hallmark of autosomal recessive HFE-HH (Harrison 21e; AASLD Hemochromatosis Guideline 2011).
Why each distractor is wrong
Option 2: Transferrin receptor mutations do not cause hereditary hemochromatosis. Transferrin receptor 2 (TFR2) mutations cause a rare autosomal recessive form (HFE-HH type 3), not the common type 1 disease anchored in this question.
Option 3: Ceruloplasmin deficiency causes Wilson disease (autosomal recessive copper overload), not iron overload. While both are autosomal recessive, the pathophysiology and metal involved are entirely different.
Option 4: Ferroportin mutations cause autosomal dominant hemochromatosis (HFE-HH type 4, ferroportin disease), not autosomal recessive HFE-HH. Additionally, ferroportin loss-of-function would trap iron intracellularly, not cause unchecked absorption.
High-YieldNEET PG
HFE-HH type 1 = C282Y homozygosity → low hepcidin → high ferroportin activity → iron overload; most common autosomal recessive disorder in Northern Europeans (~1 in 200–300).
Harrison 21e; AASLD Hemochromatosis Guideline 2011
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