Severe Hepatic Iron Overload and Cirrhosis in an HFE C282Y Heterozygote With Autoimmune Hepatitis: A Case of Genotype-Phenotype Discordance

Hereditary hemochromatosis is a disorder of iron metabolism characterized by increased intestinal iron absorption and progressive parenchymal iron deposition, most commonly associated with homozygous mutations in the HFE gene. In contrast, heterozygous carriers of HFE mutations are generally considered to have low clinical penetrance and are not expected to develop clinically significant iron overload or advanced liver disease. However, iron homeostasis may be substantially altered in the presence of chronic liver inflammation and immune-mediated hepatic injury. We present the case of a woman in her early 60s with a heterozygous HFE C282Y mutation who developed marked hyperferritinemia, biopsy-confirmed hepatic iron overload, and established cirrhosis in the setting of autoimmune hepatitis treated with mycophenolate mofetil. Her clinical course was notable for wide fluctuations in ferritin levels over several years, with a peak exceeding 3,800 ng/mL, and subsequent sustained reduction following therapeutic phlebotomy. Management was complicated by anemia, requiring individualized phlebotomy thresholds and transition to a maintenance strategy. This case highlights the diagnostic challenges of interpreting iron indices in patients with inflammatory liver disease and demonstrates that clinically significant iron overload may occur in HFE heterozygotes when additional disease modifiers are present. It underscores the importance of histologic confirmation of iron overload in cases of genotype-phenotype discordance and reinforces the need for individualized management strategies in complex iron-loading conditions.