Inherited Liver Diseases: Hereditary Hemochromatosis

0:00Welcome to Board Pearls. This is episode one of three of the Inherited Liver Diseases chapter, in the Liver Disease module. This episode is hereditary hemochromatosis: its gene, its low biochemical penetrance, and phlebotomy to a ferritin target.

0:16Iron and copper are the two metals the liver handles in trace amounts and excretes with precision. Hemochromatosis is what happens when the iron brake fails; Wilson disease, next episode, is what happens when the copper exit fails. Each has its own genotype, biochemical fingerprint, and therapy, and the unifying move is to reason from the molecular lesion outward, so the diagnosis and treatment fall out.

0:40Start with hemochromatosis, the cleaner example. Dietary iron enters at the duodenal brush border, is reduced and carried into the enterocyte, and is exported across the basolateral membrane by ferroportin into portal blood. The brake on that loop is hepcidin, made by the liver, which internalizes and degrades ferroportin, so when body iron is adequate hepcidin rises and shuts the export channel and when stores are low it falls and the channel opens, and the signal telling the hepatocyte to make hepcidin comes through the HFE protein binding the transferrin receptor in the iron-replete state. Lose the HFE signal and you lose the brake, so ferroportin stays on the membrane regardless of iron load, dietary iron pours in unchecked, and the parenchyma accumulates iron for decades. Worth holding the mirror image: inflammatory cytokines, especially interleukin-6, drive the same hepcidin promoter independently of iron, which is the molecular basis of anemia of chronic disease, where hepcidin is high, ferroportin is degraded, and iron is sequestered in macrophages despite erythropoietic demand. Same molecule, opposite direction: hemochromatosis is hepcidin too low, anemia of chronic disease is hepcidin too high.

1:53The classical genotype is C282Y homozygosity, a substitution that destabilizes the HFE protein so with two copies the feedback is disabled and the brake is gone. The other allele, H63D, is a partial-loss variant, and compound heterozygosity rarely produces significant overload by itself, doing so only when a cofactor amplifies the partial defect, daily alcohol, metabolic fatty liver, or chronic hepatitis C, which is why an H63D allele alone doesn't warrant phlebotomy or surveillance, and a stem handing you a healthy person with only that allele is asking you to refuse to medicalize the result. The non-HFE forms each pick a different point on the same loop: the juvenile form bypasses HFE with mutations in hemojuvelin or hepcidin itself, so the signal collapses from childhood and patients load iron severely and present young with cardiomyopathy and hypogonadism rather than the indolent later course, the transferrin-receptor-2 form loses the iron-sensing arm and mirrors HFE disease but with negative HFE genotyping, and ferroportin disease splits along its mutation, loss-of-function variants trapping iron in macrophages with low transferrin saturation and gain-of-function variants escaping hepcidin degradation to behave like HFE disease. The biopsy pattern follows the mechanism, which makes it useful: primary hemochromatosis delivers iron through absorption to portal blood, so it deposits first in the periportal hepatocyte, staining strongly on iron stain, with quantitative thresholds of a hepatic iron concentration over four thousand or an iron index over one point nine, while secondary overload comes through macrophage processing of red cells and infused iron and deposits in the Kupffer cells, with a broad differential including transfusion-dependent anemia, alcohol, and cirrhosis of any cause. Two mimics of unexplained ferritin elevation sit here too, aceruloplasminemia with ferritin elevation but low transferrin saturation and neurologic disease, and hyperferritinemia-cataract syndrome with isolated ferritin elevation and cataracts but no actual iron overload.

3:49Penetrance is incomplete and sex-skewed, which is where genotype-only thinking misleads: on screening, abnormal iron studies appear in most male homozygotes but only about half of female homozygotes because menstruation and pregnancy partially protect women, and while many homozygotes develop biochemical overload, only a minority develop disease-associated morbidity and cirrhosis in under a quarter, so a positive genotype is a substrate for disease, not a guarantee. Allele frequency varies sharply by ancestry, common in Northern European descent and essentially absent in East Asian populations, which is why hemochromatosis is the most common Mendelian disease of Northern Europeans, with homozygote prevalence around one in two hundred to four hundred, and homozygosity accounts for most phenotypic disease. The carrier-frequency stacking the boards favor goes in pairs: the HFE heterozygote around one in ten, the alpha-one antitrypsin heterozygote one in thirty, and the Wilson carrier around one in ninety, with the corresponding homozygote frequencies hemochromatosis around one in two hundred fifty, alpha-one antitrypsin around one in sixteen hundred to two thousand, and Wilson around one in thirty thousand.

5:00Now the diagnostic criteria, because the genotype alone isn't the disease. The framework opens with a fasting transferrin saturation, at least forty-five percent in men or forty in women, and an elevated ferritin, over three hundred in men or two hundred in women, then HFE genotyping confirms homozygosity. The two-tier framework exists because a high ferritin with a normal transferrin saturation in alcohol, fatty liver, or inflammation is secondary hyperferritinemia, acute-phase synthesis rather than iron loading, and doesn't warrant phlebotomy, so the upstream driver gets treated instead. Homozygotes with normal iron studies aren't patients yet, they're substrates who get iron studies repeated every couple of years to catch late conversion, and a minority of phenotypic patients have negative standard HFE testing and need non-HFE genotyping, with MRI iron quantitation reserving biopsy for HFE-negative overload or unexplained ferritin. Induction phlebotomy de-irons the patient, with five hundred milliliters of whole blood removing about two hundred fifty milligrams of iron, done weekly to a target ferritin of fifty to a hundred, with hemoglobin checked before each session and the session held if it's under eleven because the transient anemia of aggressive de-ironing is the rate-limiting step, so if the patient becomes anemic after just a few phlebotomies the diagnosis was probably wrong, then maintenance a few times a year with ferritin checked periodically. Dietary counseling lands on a few mechanism-driven points: avoid vitamin C supplements because they enhance non-heme iron absorption, avoid raw shellfish because iron-loaded patients are susceptible to fulminant Vibrio infection that thrives on iron, and reduce red meat because its heme iron is highly bioavailable. Family screening matters because the disease is autosomal recessive, so siblings of a proband have a one-in-four risk and get tested first, and the spouse gets tested because their carrier status makes the proband's children obligate compound heterozygotes. Iron chelators are reserved for patients who can't tolerate phlebotomy because of anemia or heart failure.

7:09The reversibility framework drives the counseling: phlebotomy reverses the elevated liver tests, early fibrosis, hepatomegaly, cardiomyopathy, hyperpigmentation, hypothyroidism, and pre-diabetes, but it does not reverse established cirrhosis, established diabetes, hypogonadotropic hypogonadism, the chondrocalcinotic arthropathy, or the cancer risk. Advanced fibrosis is predicted by older age and a ferritin over a thousand, cirrhosis is rare in homozygotes with low ferritin and normal transaminases, and biopsy is reserved for genuine uncertainty, triggered by transaminases over twice normal, age over forty with a high ferritin, low platelets, or a non-C282Y genotype. Heavy alcohol is the single largest cofactor for cirrhosis, with most cirrhotic patients being heavy drinkers, so abstinence is part of treatment. And liver cancer risk in hemochromatosis cirrhosis is high, about a third of cirrhotic patients, roughly two hundred times the general population, persisting despite iron depletion because the fibrotic substrate persists, so ultrasound every six months continues for life once cirrhosis is established. After transplant, the donor liver carries functioning HFE and normalizes hepcidin, so the disease doesn't recur, and the pre-transplant concern shifts to cardiac iron evaluation because perioperative arrhythmia is the dominant complication.

8:31So hemochromatosis in one line: the driver is hepcidin too low, the genotype is C282Y homozygous, the diagnosis is biochemistry plus genotype rather than genotype alone, the therapy is phlebotomy to a ferritin of fifty to a hundred, and the reversibility framework draws the line between what de-ironing rescues and what it can't. The penetrance is the recurring trap, because a positive genotype with normal iron studies is a substrate to survey, not a patient to treat.

9:00The next episode takes the other metal-handling disease, Wilson, where the toxin is copper, the gene is ATP7B, and the diagnostic logic is harder because no single test stands alone, so an integrated score does the work and the chelator choice turns on the speed and site of copper movement.

9:18For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode one of three of chapter twenty-two, and I'll see you in the next one.