Episode one of the Inherited Liver Diseases chapter takes hereditary hemochromatosis and reasons from the molecular lesion outward: lose the HFE signal, lose the hepcidin brake, and iron pours in unchecked for decades. The organizing move is that genotype alone is a substrate, not a disease, so diagnosis rests on biochemistry plus genotype, not a positive C282Y result by itself. Iron regulation, the C282Y and H63D alleles, incomplete sex-skewed penetrance, the two-tier diagnostic framework, phlebotomy to a ferritin target, and the reversibility line all run through the episode. The recurring trap is the healthy homozygote with normal iron studies who is surveyed, not treated. Topics covered Iron regulation: hepcidin, ferroportin, and HFE C282Y and H63D genotypes Non-HFE hemochromatosis and ferroportin disease Biopsy iron distribution and quantitative thresholds Incomplete, sex-skewed penetrance Carrier and homozygote frequencies Diagnostic criteria and the two-tier framework Phlebotomy to a ferritin target Reversibility, cirrhosis, and HCC surveillance Key decisions C282Y homozygosity is the classical disease genotype; an isolated H63D allele or compound heterozygosity rarely causes overload and does not warrant phlebotomy or surveillance. Diagnose on biochemistry plus genotype: a fasting transferrin saturation of at least forty-five percent in men or forty in women plus a ferritin over three hundred in men or two hundred in women, then HFE genotyping for homozygosity. A high ferritin with a normal transferrin saturation in alcohol, fatty liver, or inflammation is secondary hyperferritinemia and is not treated with phlebotomy; treat the upstream driver instead. Induction phlebotomy removes about five hundred milliliters of whole blood (roughly two hundred fifty milligrams of iron) weekly to a target ferritin of fifty to a hundred, holding the session if hemoglobin is under eleven. Homozygotes with normal iron studies are substrates, not patients, and get iron studies repeated every couple of years to catch late conversion. Once cirrhosis is established, liver cancer risk is high (about a third of cirrhotic patients), so ultrasound every six months continues for life, and phlebotomy does not reverse established cirrhosis, diabetes, or hypogonadism. Counsel patients to avoid vitamin C supplements and raw shellfish (fulminant Vibrio risk) and reduce red meat; siblings of a proband carry a one-in-four risk and are screened first. For the full chapter with MCQs, tables, and primary-guideline references, visit www.boardpearls.com. Questions or feedback: [email protected]. (00:00) - Introduction: the two metal-handling diseases (00:46) - Iron loop: hepcidin, ferroportin, and HFE (02:06) - The classical genotype and the non-HFE forms (03:36) - Biopsy pattern and hyperferritinemia mimics (04:36) - Incomplete penetrance and carrier frequencies (05:52) - Diagnostic criteria: biochemistry plus genotype (06:57) - Phlebotomy to target and dietary counseling (08:14) - Reversibility, cirrhosis risk, and cancer surveillance (09:47) - One-line summary

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“What did the council decide on item 42?” — answered with the speaker and the moment.

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