A 63-year-old woman dies of congestive heart failure. Autopsy shows a dilated heart with brownish pigmentation of the myocardium. Light microscopy of her liver after Prussian blue staining is shown in the image below: The patient's brother died of profuse upper gastrointestinal bleeding at age 43. Assuming this patient's disorder is hereditary, which of the following most likely contributed to the delayed onset of her disease compared to her brother?

Question

A 63-year-old woman dies of congestive heart failure.  Autopsy shows a dilated heart with brownish pigmentation of the myocardium.  Light microscopy of her liver after Prussian blue staining is shown in the image below:  The patient's brother died of profuse upper gastrointestinal bleeding at age 43.  Assuming this patient's disorder is hereditary, which of the following most likely contributed to the delayed onset of her disease compared to her brother?

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11ec160b_3adf_0b67_9249_299b0097a1d5_MD0001_00 This patient has cardiomyopathy with visible brown discoloration, which could represent lipofuscin (age-related pigment) or hemosiderin (iron deposition). However, her liver specimen shows diffuse infiltration of iron (visible as blue pigment granules after Prussian blue staining), confirming a diagnosis of iron overload. Given that her brother likely developed cirrhosis complicated by variceal hemorrhage in his 40s, the most probable underlying cause is hereditary hemochromatosis (HH). Total iron stores in the body are tightly regulated at the point of intake, with gastrointestinal absorption adjusted to match daily losses. HH is an autosomal recessive disorder characterized by increased intestinal iron absorption; because there is no specific mechanism to excrete unneeded iron, the excess iron (typically 0.5-1.0 g/yr) accumulates in the parenchymal organs (eg, liver, heart). HH is usually silent in early adulthood, manifesting only after >20 g of iron has accumulated in the body. Men typically begin to develop symptoms in their 30s and 40s. However, premenopausal women have ongoing blood (and iron) losses due to menstruation, which partially offsets the excess iron absorption. Women therefore develop manifestations later, typically several years after menopause (ie, variable expressivity based on sex). (Choices A and C) Most patients with HH have inactivating mutations in the HFE gene that cause impaired hepcidin secretion. Disease development requires biallelic genetic mutations (ie, affecting both alleles); heterozygotes are unaffected. Although biallelic HFE inactivation is necessary to develop the condition, most patients (>70%) with biallelic mutations never develop HH (ie, the disease exhibits incomplete penetrance) due to genetic and environmental modifiers. However, this patient developed HH manifestations at a typical age for women, which would not be explained by heterozygosity or incomplete penetrance. (Choice B) Ascorbic acid (vitamin C) and citric acid enhance the absorption of inorganic iron in the gastrointestinal tract and therefore might lead to earlier disease manifestations instead of slowing its onset. (Choice E) Frequent blood transfusions can also lead to iron overload and hemosiderosis (iron accumulation in parenchymal tissues). The opposite, therapeutic phlebotomy, is the preferred treatment for HH and has been shown to slow its progression. Educational objective: Hereditary hemochromatosis is characterized by increased intestinal iron absorption with deposition of excess iron in parenchymal tissues. Men typically develop manifestations in their 30s and 40s. However, premenopausal women have ongoing blood and iron losses due to menstruation, which partially offsets the excess iron absorption and delays the onset of symptoms.

A 63-Year-Old Woman Dies of Congestive Heart Failure