MKSAP 19 "Quiz Me!" Question: Answer and Critique


D: No intervention

Educational Objective

Manage newly diagnosed hereditary hemochromatosis


This patient does not require any intervention currently (Option D). She has hereditary hemochromatosis, with heterozygous C282Y mutation of the HFE gene. Mutations in the HFE gene comprise the most prevalent form of hereditary hemochromatosis, with a prevalence of 1 in 250 persons of northern European descent. The C282Y, H63D, and S65C mutations are the three most common, and homozygosity for C282Y accounts for 80% to 90% of patients with hemochromatosis who have a genetic mutation. Heterozygosity is common in patients of European ancestry. Iron overload is extremely rare in heterozygous individuals, and evidence of elevated iron indices (ferritin level >1000 ng/mL [1000 μg/L], transferrin saturation >45%) should raise suspicion for a concomitant rare mutation that may not be detected with standardized testing. The 2019 guideline from the American College of Gastroenterology (ACG) recommends treatment in patients with homozygous C282Y mutations with serum ferritin greater than 300 ng/mL (300 μg/L) in men and greater than 200 ng/mL (200 μg/L) in women, along with a transferrin saturation of 45% or more. Other sources recommend observation for serum ferritin levels less than 500 ng/mL (500 μg/L) regardless of genotype. This patient has a heterozygous C282Y mutation without elevated iron indices; therefore, without symptoms, no intervention or ongoing surveillance is required.

Chelation with agents such as deferasirox is reserved for patients with iron overload who cannot undergo phlebotomy because of concomitant anemia (Option A). This patient is not experiencing iron overload, so iron chelation is not necessary.

Phlebotomy is preferred for lowering iron levels in patients with hereditary hemochromatosis who require treatment (Option B). However, phlebotomy is unnecessary in those who are asymptomatic, have a ferritin level less than 500 ng/mL (500 μg/L) (or less than 300 ng/mL [300 μg/L] in men and 200 ng/mL [200 μg/L] in women, according to the ACG), and have no evidence of organ iron deposition even with an HFE homozygous genetic mutation. However, those patients should be monitored for symptoms and have periodic evaluation of iron levels (Option C). This patient, with a heterozygous C282Y mutation and normal iron stores, does not require monitoring.

Key Points

The C282Y, H63D, and S65C mutations are the three most common in patients with hereditary hemochromatosis, and homozygosity for C282Y accounts for 80% to 90% of patients who have a genetic mutation.

Iron overload is extremely rare in persons with hereditary hemochromatosis and a heterozygous HFE mutation, so without symptoms or elevated iron indices, no treatment or monitoring is necessary in these patients.


Kowdley KV, Brown KE, Ahn J, Sundaram V. ACG clinical guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019;114:1202-1218. PMID: 31335359 doi:10.14309/ajg.0000000000000315

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