Hereditary hemochromatosis
USMLE Step 1Difficulty: easyLast updated:
A 52-year-old man of Northern European ancestry is evaluated for fatigue, joint pain in both hands, and erectile dysfunction. He was diagnosed with diabetes mellitus 1 year ago. He drinks alcohol rarely. Examination shows hepatomegaly. Serum ferritin is 1,850 ng/mL and transferrin saturation is 78%. Viral hepatitis serologies are negative.
Which of the following is the most likely underlying genetic abnormality?
Answer and explanation
Correct answer: A. Homozygous C282Y mutation of the HFE gene
Markedly elevated ferritin and transferrin saturation together with liver involvement, diabetes, arthropathy, and erectile dysfunction indicate systemic iron overload. The source lists systemic symptoms, liver disorders, cardiomyopathy, diabetes, erectile dysfunction, and arthropathy as manifestations, and states that diagnosis is by elevated ferritin, iron, and transferrin saturation confirmed by gene assay. Classic (type 1a, HFE-related) hereditary hemochromatosis is autosomal recessive, and more than 80% of cases are caused by homozygosity for the C282Y mutation; the homozygous frequency is about 1:200 in people of Northern European ancestry. The source notes that homozygous H63D or S65C mutations do not cause clinically significant iron overload, so a single (heterozygous) H63D allele would not explain this degree of iron loading.
Each option explained
- A. Homozygous C282Y mutation of the HFE geneCorrect. Homozygous HFE C282Y causes more than 80% of classic hereditary hemochromatosis.
- B. Biallelic mutations of the ATP7B geneIncorrect. ATP7B mutations cause Wilson disease, a disorder of copper (not iron) overload that typically presents in younger patients.
- C. Homozygous Z allele (PiZZ) of the SERPINA1 geneIncorrect. PiZZ alpha-1 antitrypsin deficiency causes liver disease and emphysema, not systemic iron overload with diabetes and hypogonadism.
- D. Heterozygous H63D mutation of the HFE geneIncorrect. Even homozygous H63D does not cause clinically significant iron overload; a heterozygous H63D allele alone would not explain this picture.
- E. Point mutation in the beta-globin geneIncorrect. A beta-globin mutation (e.g., thalassemia) can cause transfusional or ineffective-erythropoiesis iron overload, but there is no anemia or transfusion history here.
Key point
Classic hereditary hemochromatosis is autosomal recessive and usually due to homozygous HFE C282Y; screen with ferritin and transferrin saturation.
From the source
“Type 1a is classic hereditary hemochromatosis, also termed HFE -related hemochromatosis, and more than 80% of cases are caused by the homozygous C282Y mutation.”