Hereditary Hemochromatosis
A 47-year-old man has 6 months of fatigue, right upper quadrant discomfort and darkening bronze skin. He also reports reduced libido and aching second and third metacarpophalangeal joints. He drinks no alcohol. Fasting glucose is 9.1 mmol/L, ALT 78 U/L, serum ferritin 1450 µg/L and transferrin saturation 62 percent. His father died of liver cirrhosis. What is the most appropriate confirmatory test?
- A.Abdominal ultrasound with hepatic Doppler
- B.Liver biopsy with Perls iron staining
- C.Serum ceruloplasmin measurement
- D.HFE gene mutation analysisCorrect
Explanation
Bronze pigmentation, diabetes, arthropathy of the second and third metacarpophalangeal joints, hypogonadism and hepatic dysfunction with a ferritin above 1000 µg/L and a transferrin saturation above 45 percent make hereditary hemochromatosis the diagnosis, and the ACG guideline directs that HFE genotyping for C282Y and H63D is the confirmatory test after abnormal iron studies. C282Y homozygosity accounts for most cases in people of northern European descent and impairs hepcidin production, so ferroportin remains active on enterocytes and macrophages and iron absorption continues unchecked. Excess iron is deposited in liver, pancreatic islets, heart, pituitary, joints and skin, producing cirrhosis, diabetes, cardiomyopathy, hypogonadism, arthropathy and pigmentation from both iron and increased melanin. A transferrin saturation of 45 percent or more identifies almost all C282Y homozygotes and is the most sensitive screening threshold, while ferritin reflects total body iron stores. Ferritin is nonetheless an acute phase reactant and rises in inflammation, alcohol excess and metabolic dysfunction-associated steatotic liver disease, so genotyping is needed before committing a patient to lifelong therapy. Liver biopsy is no longer required for diagnosis and is reserved for staging fibrosis when ferritin exceeds 1000 µg/L or transaminases are raised, and MRI can quantify hepatic iron non-invasively. Ceruloplasmin screens for Wilson disease, which presents at a younger age with neuropsychiatric features and Kayser-Fleischer rings. Ultrasound may show hepatomegaly or cirrhosis but cannot detect iron overload. Treatment is repeated phlebotomy until ferritin falls to 50 to 100 µg/L, with chelation reserved for those who cannot tolerate venesection.
Why each option
- A.
- Ultrasound may show hepatomegaly or cirrhosis but cannot detect or confirm iron overload.
- B.
- Liver biopsy is now used for fibrosis staging rather than diagnosis, and MRI can quantify hepatic iron non-invasively.
- C.
- Ceruloplasmin screens for Wilson disease, which presents younger with neuropsychiatric signs and Kayser-Fleischer rings.
- D.
- Correct. HFE genotyping for C282Y and H63D confirms hereditary hemochromatosis once transferrin saturation and ferritin are raised.
Reference: ACG Clinical Guideline: Hereditary Hemochromatosis, American Journal of Gastroenterology, 2019
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