Inherited Liver Diseases: Inherited Liver Diseases: Hereditary Iron Overload

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, from diagnosis to family screening. A man with knuckle pain and a high ferritin shows why iron builds up and what hepcidin has to do with it, which two results make the diagnosis, which genotypes load iron, and what incomplete penetrance means for his brother. A woman with fatty liver disease shows a high ferritin that isn't hemochromatosis, and a young man with heart failure shows the forms that a negative HFE test misses, along with what the biopsy adds. Then a woman with cirrhosis shows who needs staging first, how phlebotomy is done and when to hold it, what to avoid, what reverses and what doesn't, why her cancer surveillance never ends, what transplant offers, and who in the family gets tested.

0:51Here's the first patient. A forty-eight-year-old man of Irish descent has pain in the knuckles of both hands, fatigue, and low libido. His ferritin is eight hundred sixty, and his fasting transferrin saturation is seventy-two percent. His alanine aminotransferase, ALT, is fifty-eight. He drinks two beers a night. His brother asks whether he should be tested too.

1:13A high ferritin with a transferrin saturation of seventy-two percent, knuckle arthropathy, and Irish ancestry point to hereditary hemochromatosis, iron overload from a genetic failure to limit iron absorption. It's driven by an inappropriately low hepcidin, which removes the brake on ferroportin and speeds the absorption of dietary iron.

1:34The absorption pathway shows where that brake acts. In the duodenum, duodenal cytochrome b reduces dietary ferric iron to ferrous iron at the brush border, and divalent metal transporter one, DMT1, carries it into the enterocyte. It leaves across the basolateral membrane through ferroportin, paired with hephaestin, which re-oxidizes it so it can load onto transferrin. Hepcidin controls the ferroportin step. Normally, HFE binds transferrin receptor one when iron stores are adequate and raises hepatic hepcidin, which internalizes and degrades ferroportin and limits iron entry. In hemochromatosis that signal fails, hepcidin stays low, and ferroportin keeps exporting iron whatever the stores.

2:18Inflammation does the opposite, which is why an inflammatory high ferritin looks different on the labs. Interleukin-6, IL-6, and other cytokines raise hepcidin regardless of iron, trapping iron in macrophages and enterocytes, and that's the basis of the anemia of chronic disease.

2:36Two HFE genotypes matter. C282Y homozygosity, cysteine to tyrosine at amino acid two eighty-two, destabilizes HFE, disables the hepcidin signal almost completely, and accounts for about eighty to eighty-five percent of phenotypic hemochromatosis. H63D, histidine to aspartate at amino acid sixty-three, is a milder allele with partial loss of function. Compound heterozygosity for C282Y and H63D accounts for about five percent of phenotypic disease, and it rarely causes significant overload without a cofactor such as daily alcohol, metabolic dysfunction-associated steatotic liver disease, MASLD, or chronic hepatitis C. H63D alone doesn't warrant phlebotomy or surveillance.

3:27Ancestry shapes who carries it. C282Y is carried by about six to ten percent of people of Northern European descent and is very rare in Native American, Hispanic, Black, and especially Asian populations. That makes hemochromatosis the most common single-gene disease of Northern European descent, with homozygotes at about one in two hundred to four hundred, and effectively absent in East Asians. His Irish descent puts him in the group at risk.

3:56His diagnosis needs two things. The American College of Gastroenterology, ACG, approach, endorsed by the European Association for the Study of the Liver, EASL, requires a fasting transferrin saturation of at least forty-five percent in men or forty percent in women, plus a ferritin over three hundred in men or two hundred in women, followed by HFE genotyping for C282Y homozygosity. An unsaturated iron-binding capacity under twenty-six micromoles per liter is an alternative signal when the saturation can't be calculated. Both the iron studies and the genotype are needed, because each misleads alone. C282Y homozygosity without overload doesn't need phlebotomy, and a high ferritin without a high saturation, from alcohol, MASLD, or inflammation, is secondary hyperferritinemia, treated by fixing its cause.

4:51His saturation of seventy-two percent and ferritin of eight hundred sixty lead to HFE testing, which shows C282Y homozygosity. His knuckle arthropathy, his fatigue, and his low libido from hypogonadism all fit. His two beers every night are daily alcohol, a cofactor that adds to the injury. Had his genotype been C282Y with H63D, that same overload would have pointed to the alcohol as the cofactor driving it, because the genotype gives the susceptibility and the iron studies decide whether to act.

5:25His brother's question turns on what a positive genotype means, because penetrance is incomplete and lower in women. In population screening of C282Y homozygotes, abnormal iron studies were found in most men but only about half of women, partly because of menstrual and pregnancy losses. Homozygotes carry a forty-two to seventy-five percent risk of biochemical overload, a ten to thirty-three percent risk of illness from hemochromatosis, and less than a twenty-five percent risk of cirrhosis. A homozygote with normal iron studies isn't phlebotomized, but has iron studies and a ferritin repeated every two to three years. His brother has a twenty-five percent chance of being homozygous, so he should have iron studies and HFE testing, and if he's a homozygote with normal iron studies, he's watched, not treated.

6:12The second patient has a high ferritin with another cause. A fifty-two-year-old woman with obesity, diabetes, and MASLD has a ferritin of six hundred forty and a transferrin saturation of twenty-eight percent. Her saturation under forty makes this secondary hyperferritinemia from fatty liver disease, so she needs neither HFE testing nor phlebotomy. Her treatment is her MASLD, covered in chapter twenty-one.

6:39The third patient shows that a negative HFE test doesn't end the workup when the overload is clear. A thirty-four-year-old man has a saturation of eighty-five percent, a ferritin of two thousand, early heart failure, and negative HFE testing. About ten to twenty percent of phenotypic hemochromatosis is HFE-negative, and three non-HFE forms matter. Juvenile hemochromatosis, type two, comes from mutations in HJV, hemojuvelin, or HAMP, the hepcidin gene, which remove hepcidin or the co-receptor that drives it. It causes severe loading from childhood, with cardiomyopathy and hypogonadism by the second decade. TfR2 hemochromatosis, type three, is autosomal recessive, from mutations in transferrin receptor two, and presents at thirty to forty with loading of the liver, endocrine glands, and heart that mirrors HFE disease.

7:32Ferroportin disease, type four, is autosomal dominant and comes in two forms. The classic loss-of-function form traps iron in macrophages, with a low or normal saturation. The non-classical gain-of-function form escapes hepcidin and behaves like HFE disease, with a high saturation and iron in the liver cells. His age and heart failure fit a non-HFE form, so he needs testing for HJV, HAMP, TfR2, and SLC40A1, the ferroportin gene, plus magnetic resonance imaging, MRI, to quantify his liver iron. MRI quantification now reserves biopsy for HFE-negative overload or an unexplained ferritin. And when the diagnosis is still unclear after iron studies and genetic testing, a therapeutic trial of phlebotomy is reasonable, because it's cheap and low-risk. Anemia after fewer than five sessions suggests the diagnosis was wrong, because a truly loaded patient can give many units first.

8:31When a biopsy is done, where the iron sits separates primary from secondary overload. Genetic hemochromatosis deposits iron in periportal hepatocytes, the first cells to take up dietary iron from the sinusoids, staining two-plus to four-plus with Perls Prussian blue. A hepatic iron concentration over four thousand micrograms per gram of dry weight, or a hepatic iron index over one point nine, supports genetic overload. Secondary overload deposits iron mainly in Kupffer cells, the macrophages that process old red cells and infused iron. Its causes include transfusion-dependent anemia, parenteral iron on dialysis, thalassemia, sickle cell disease, sideroblastic anemia, chronic alcohol use, dysmetabolic iron overload, established cirrhosis of any cause, chronic hepatitis C, metabolic dysfunction-associated steatohepatitis, MASH, portosystemic shunting, and porphyria cutanea tarda.

9:31Two rarities raise the ferritin without true overload. In aceruloplasminemia, loss of a ferroxidase traps iron inside cells, with a low saturation and neurologic disease. In hyperferritinemia-cataract syndrome, a ferritin gene mutation causes an isolated high ferritin with bilateral cataracts.

9:51Once the diagnosis is made, treatment starts by staging the liver, and the fourth patient shows why. A fifty-eight-year-old postmenopausal woman is a C282Y homozygote. Her ferritin is one thousand six hundred, her saturation eighty-one percent, her ALT ninety, and her platelets one hundred thirty thousand. She has type two diabetes and arthritis in her second and third knuckles. She drinks three glasses of wine a night and takes a vitamin C supplement for her immune system. She asks whether removing the iron will cure her diabetes and her joints.

10:25She has symptomatic hemochromatosis with a ferritin over one thousand, and her liver is staged before treatment. Advanced fibrosis is predicted by older age and a ferritin over one thousand, and cirrhosis is rare in C282Y homozygotes with a low ferritin and normal aminotransferases. So biopsy or elastography is reserved for an ALT over twice normal, age over forty with a ferritin over one thousand, low platelets, or a genotype other than C282Y homozygosity with diagnostic doubt. She meets three of those triggers, and her elastography and biopsy show cirrhosis.

11:04Her wine matters as much as her iron. Heavy alcohol is the largest cofactor for cirrhosis in hemochromatosis, and in one cohort most patients with hemochromatosis and cirrhosis drank more than sixty grams a day. Her three glasses are about forty grams a day, close to three hundred grams a week, so her wine stops as part of her treatment.

11:24A younger patient shows when staging isn't needed. A thirty-nine-year-old C282Y homozygote has a ferritin of four hundred twenty, a high saturation, and a normal ALT and platelet count. He meets no trigger, so he starts phlebotomy without a biopsy, and any early fibrosis he has is the kind that treatment reverses.

11:46Her treatment is phlebotomy. Induction is five hundred milliliters of whole blood weekly, each removing roughly two hundred fifty milligrams of iron, until the ferritin falls to fifty to one hundred. A normal adult holds three to four grams of body iron and a heavily loaded patient more than twenty, so removing four grams takes about sixteen sessions, and induction can last up to two years. The hemoglobin is checked before every session, and the session is held if it's under eleven, because transient anemia is the step that limits the pace of induction, and pushing through it only makes the patient anemic. A hemoglobin of ten point six at her eighth session means holding that week and rechecking, not abandoning the plan. Once the ferritin reaches fifty to one hundred, maintenance is one to two units every two to four months, about three to four times a year, with a ferritin every six to twelve months.

12:36Her habits need changing too. Vitamin C supplements raise non-heme iron absorption by reducing ferric to ferrous iron in the duodenum, so hers stops. Raw shellfish is dangerous, because Vibrio vulnificus thrives on iron, and iron-loaded patients are susceptible to fulminant infection. Excess iron-fortified foods are avoided, and eating less red meat helps, because the heme iron in beef has the highest bioavailability, and a modest reduction can save half a liter to a liter and a half of blood removal over the course of induction. And alcohol stops entirely for her.

13:11Some patients can't tolerate phlebotomy, because of severe anemia or heart failure, and for them iron chelators are the alternative. Deferoxamine is given by injection and has retinal and hearing toxicity. Oral deferiprone causes neutropenia and agranulocytosis. Oral deferasirox causes gastrointestinal upset, rash, raised aminotransferases, and kidney toxicity. Each toxicity needs monitoring, while phlebotomy removes iron directly, cheaply, and at low risk, so phlebotomy stays first line. She tolerates it, stops drinking and stops her vitamin C, reaches a ferritin of eighty after fourteen months, and moves to maintenance.

13:51Her question has a mixed answer. Phlebotomy reverses raised liver tests, early hepatic fibrosis, hepatomegaly, cardiomyopathy and conduction abnormalities, skin hyperpigmentation, hypothyroidism, and prediabetes. It doesn't reverse established cirrhosis, established type two diabetes, hypogonadotropic hypogonadism or testicular atrophy, or the chondrocalcinotic arthropathy of hemochromatosis, and it doesn't remove the risk of liver cancer. Her diabetes, arthropathy, and cirrhosis will stay. What phlebotomy does is stop further iron damage and protect her heart and the rest of her liver. Early fibrosis in a younger patient can reverse, which is the argument for finding these patients early.

14:34Her cirrhosis also brings a lasting cancer risk. The risk of liver cancer in hemochromatosis with cirrhosis is high and persists after the iron is gone. About thirty percent develop it, roughly two hundred times the general population's risk, and a ferritin over one thousand, ongoing alcohol, and tobacco amplify it. She has surveillance every six months for life once cirrhosis is present, and a normal ferritin on maintenance doesn't end it. Chapter twenty-four covers surveillance.

15:05If her cirrhosis decompensates, transplant cures the iron problem. HFE iron overload doesn't recur after liver transplant, because the donor liver makes hepcidin normally. Her heart is evaluated for iron first, and some centers do an endomyocardial biopsy, because perioperative arrhythmia is the dominant transplant complication when there's iron in the heart. Chapter twenty-three covers decompensated cirrhosis.

15:30The family closes the loop, and it goes back to the first man's brother. Inheritance is autosomal recessive, so the siblings of a proband are tested first, each with a twenty-five percent chance of being homozygous. The spouse is tested too, because if the spouse is heterozygous, the children are at real risk and need iron studies every several years through adulthood. The first man's brother turns out to be a C282Y homozygote with early loading, so he starts phlebotomy before his liver is damaged.

16:02Here are the traps the boards set in these patients. HFE testing isn't sent for a high ferritin with a normal saturation, and the saturation has to be fasting. C282Y homozygosity with normal iron studies isn't a disease to treat. H63D alone isn't phlebotomized. Alcohol and MASLD are the cofactors that load iron in compound heterozygotes. A negative HFE test doesn't end the workup when overload is clear. And Kupffer cell iron on biopsy isn't hereditary hemochromatosis.

16:35The treatment traps follow. A ferritin over one thousand, a raised ALT, or low platelets calls for staging, but not every homozygote needs a biopsy. Phlebotomy is held for a hemoglobin under eleven, and the ferritin target isn't overshot. Phlebotomy won't reverse cirrhosis, diabetes, hypogonadism, or arthropathy. Liver cancer surveillance continues after the iron is removed. Vitamin C supplements, raw shellfish, and alcohol are avoided. The heart is evaluated before transplant. And the spouse is tested along with the siblings.

17:11So, start to finish. Hemochromatosis is a low hepcidin letting ferroportin release iron unchecked. Diagnose it with a fasting saturation of forty-five percent or more, or forty in women, plus a raised ferritin, then HFE testing. C282Y homozygosity is the usual genotype, and H63D alone, or compound heterozygosity without a cofactor, rarely loads iron. Penetrance is incomplete and lower in women, so a homozygote with normal iron studies is rechecked every two to three years. A high ferritin with a normal saturation is secondary. Suspect juvenile, TfR2, or ferroportin disease when overload is clear and HFE is negative, and on biopsy, hepatocyte iron means primary overload and Kupffer cell iron secondary.

18:03Stage the liver with a ferritin over one thousand after forty, an ALT over twice normal, or low platelets. Phlebotomize five hundred milliliters weekly to a ferritin of fifty to one hundred, holding for a hemoglobin under eleven, then maintain with one to two units every two to four months. Avoid raw shellfish, vitamin C supplements, and alcohol.

18:27Phlebotomy reverses early fibrosis, cardiomyopathy, and prediabetes, but not cirrhosis, established diabetes, hypogonadism, or arthropathy, and cirrhosis means liver cancer surveillance for life. Overload doesn't recur after transplant, but the heart is checked first. And test the siblings and the spouse.

18:46Episode two is Wilson disease: who to suspect, why no single test is enough, the Leipzig score, and treatment for life.

18:56For 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.