Introduction: Hereditary hemochromatosis (HH) is a genetic disorder in which excessive gastrointestinal absorption of iron results in iron-mediated damage to the liver and other organs. HH is inherited in an autosomal recessive fashion and is characterized by mutations in the HFE gene; however, due to low penetrance, many patients with two abnormal copies of HFE do not exhibit clinical iron overload. The most common pathologic mutations of HFE are C282Y and H63D. Over 90% of HH cases are due to homozygosity for C282Y, with the remainder attributed to C282Y/H63D compound heterozygosity, H63D homozygosity, or S65C mutation. We discuss a rare case of newly diagnosed HH in a patient with H63D homozygosity and family history of iron overload.
Case Description/Methods: A healthy 67-year-old Caucasian male with history of hyperlipidemia presented for abnormal iron studies which were checked after he reported that his father used to require phlebotomy. He drinks two alcoholic beverages daily and denies any clinical complaints. Laboratory tests were notable for serum ferritin of 1240 ng/mL, transferrin saturation of 45.6%, hemoglobin 15.5 g/dL, ALT 91 units/L, and AST 43 units/L. Genetic testing revealed homozygosity for H63D. Due to his markedly elevated ferritin, liver biopsy was performed and showed diffusely increased iron deposition, predominantly in hepatocytes. Moderate steatosis and portal fibrosis (fibrosis stage 1/4) were also seen. He was diagnosed with HH and is scheduled for phlebotomy with goal ferritin less than 50 ng/mL.
Discussion: Patients homozygous for H63D make up fewer than 10% of all HH cases and clinically significant iron overload is far less common. The likelihood of iron overload for a particular genotype is higher if a first-degree relative had iron overload which may explain our patient’s phenotype. Although our patient did not have cirrhosis on biopsy, his HH in addition to hepatic steatosis puts him at higher risk of liver disease. This risk can be mitigated with control of his ferritin via phlebotomy and modification of other risk factors. Our case highlights the importance of evaluating for HH and hepatic fibrosis in patients with family history, irrespective of genotype, if they present with phenotypic signs of iron overload.
