In primary (hereditary) hemochromatosis, which of the following statements is correct: reduced hepcidin expression, association with diabetes mellitus, association with chronic obstructive pulmonary disease, childhood onset with liver failure, or treatment of liver damage with chelating agents?

Primary Hemochromatosis: Correct Statement Analysis

The correct answer is (b): there is an association with diabetes mellitus. Primary hemochromatosis classically presents with the triad of cirrhosis, diabetes, and skin pigmentation—historically termed "bronze diabetes"—though this full phenotype is now seen in fewer than 10% of genetically susceptible individuals. 1

Analysis of Each Statement

Statement A: Reduced Hepcidin Expression (Correct Mechanism, Incorrect Terminology)

• Reduced hepcidin expression (not "epsidin") is indeed the central pathophysiologic mechanism in hereditary hemochromatosis, particularly in HFE-related disease. 1, 2
• The HFE C282Y mutation, which accounts for >90% of cases, causes inappropriately low hepcidin levels, leading to excessive dietary iron absorption. 2
• When hepcidin is reduced, ferroportin (the iron export protein on enterocytes and macrophages) is not degraded, resulting in unregulated iron absorption from the intestine and release from macrophages. 1
• However, the question uses the term "epsidin" rather than "hepcidin," making this statement technically incorrect as written.

Statement B: Association with Diabetes Mellitus (CORRECT)

• Diabetes mellitus is a well-established clinical manifestation of advanced hereditary hemochromatosis. 1
• The American Association for the Study of Liver Diseases documents that clinical diabetes was present in 6-55% of symptomatic hemochromatosis patients across multiple case series. 1
• Iron deposition in the pancreas leads to beta-cell dysfunction and insulin deficiency. 1
• Diabetes is one of the classic triad features (cirrhosis, diabetes, skin pigmentation) that define fully expressed disease. 1
• This association is so strong that the historical term for advanced hemochromatosis was "bronze diabetes." 1

Statement C: Association with COPD (INCORRECT)

• There is no established association between primary hemochromatosis and chronic obstructive pulmonary disease. 1
• The principal clinical features documented by the American Association for the Study of Liver Diseases include hepatomegaly, cirrhosis, diabetes, arthralgias, cardiac manifestations, skin pigmentation, and hypogonadism—but not pulmonary disease. 1
• Iron deposition occurs primarily in the liver, pancreas, heart, joints, and pituitary gland, not the lungs. 3, 4

Statement D: Childhood Onset with Liver Failure (INCORRECT for Most Cases)

• Most hereditary hemochromatosis does NOT manifest in childhood. 1, 2
• The typical HFE-related hemochromatosis (C282Y homozygosity) presents in the fourth to fifth decade of life, with men developing symptoms earlier than women. 2
• By the 1990s, approximately 75% of identified patients were asymptomatic and detected through screening or family studies. 1
• Juvenile hemochromatosis (caused by HJV or HAMP mutations) is a rare exception that presents before age 30 with cardiac or endocrine manifestations, but this represents a distinct minority of cases. 2, 5
• Even among C282Y homozygotes, fewer than 10% develop end-organ damage such as cirrhosis. 1, 2

Statement E: Chelating Agents for Treatment (INCORRECT)

• Therapeutic phlebotomy, not chelating agents, is the first-line treatment for hereditary hemochromatosis. 2, 6
• The American Association for the Study of Liver Diseases recommends weekly removal of approximately 500 mL of blood (containing ~250 mg iron) until ferritin falls below 50 ng/mL, followed by maintenance phlebotomy every 2-4 months. 2
• Chelation therapy (e.g., deferoxamine) is reserved only for patients who cannot tolerate phlebotomy due to anemia or cardiac disease. 2
• This contrasts sharply with beta-thalassemia major, where iron chelation is mandatory because patients require ongoing transfusions and cannot undergo phlebotomy. 2

Critical Clinical Pearls

• Incomplete penetrance is crucial to understand: Only 58-70% of C282Y homozygotes develop progressive iron overload, and fewer than 10% progress to end-organ damage. 2, 6
• Screening strategy: Transferrin saturation ≥45% plus elevated ferritin should prompt HFE genetic testing for C282Y and H63D mutations. 2, 6
• Normal CBC distinguishes hemochromatosis from thalassemia: Patients with hereditary hemochromatosis have normal hemoglobin and red cell indices, unlike iron-loading anemias. 2
• Serum ferritin is the best prognostic marker for disease severity and guides phlebotomy frequency. 6