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Hematology›Condition·Updated Jul 11, 2026·v1

Hereditary Hemochromatosis

Hereditary hemochromatosis is a common genetic iron overload disorder most often due to HFE C282Y homozygosity. Diagnosis relies on elevated transferrin saturation and ferritin, confirmed by HFE genotyping. Management centers on therapeutic phlebotomy to achieve a ferritin target <50 ng/mL, with iron chelation reserved for phlebotomy-intolerant patients. Key complications include cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes, arthropathy, and increased infection risk. Early detection and treatment prevent progression and normalize life expectancy, but established organ damage is often irreversible. Asymptomatic C282Y homozygotes benefit from regular blood donation to prevent disease.

High Evidence111 references·9,333 words·38 min read·v1
hereditary hemochromatosisHFEiron overloadhemochromatosishepcidinphlebotomygenetic disorderC282Yferritintransferrin saturation

Quick Reference

RxDrug of choiceTherapeutic phlebotomy (500 mL whole blood weekly until ferritin <50 ng/mL, then maintenance every 3-4 months to keep ferritin 50-100 ng/mL)
AltAlternativesDeferasirox (20-40 mg/kg/day PO) or deferoxamine (40-50 mg/kg/day SC/IV) for phlebotomy-intolerant patients; pantoprazole 40 mg daily as adjunct to reduce phlebotomy frequency
⊘AvoidAvoid iron supplements, high-dose vitamin C, raw shellfish, and alcohol. In acute cardiac iron overload, avoid aggressive diuretics and inotropes. Non-dihydropyridine CCBs are not specifically contraindicated but should be used with caution in cirrhosis.
DxTest of choiceTransferrin saturation (TSAT) >45% is the most sensitive screening test; HFE genotyping (C282Y, H63D) confirms diagnosis; MRI R2*/T2* quantifies liver and cardiac iron overload
ScKey scoreHepatic iron index >1.9 (by MRI or biopsy) discriminates HFE-related iron overload with AUC 0.94; serum ferritin >1000 μg/L predicts advanced fibrosis
→When to referHepatology for cirrhosis or HCC surveillance; cardiology for cardiac iron overload (T2* <10 ms); endocrinology for hypogonadism or diabetes; orthopedics for arthropathy; transplant center for decompensated cirrhosis or HCC
Suspect HH in any patient with unexplained elevated TSAT and ferritin, especially with family history or MCP joint pain. Confirm with HFE genotyping, quantify iron burden with MRI, and initiate phlebotomy to ferritin <50 ng/mL. Abstain from alcohol, avoid iron supplements, and monitor for cirrhosis, HCC, and infection. Blood donation twice yearly can prevent disease in asymptomatic C282Y homozygotes.
Hereditary hemochromatosis (HH) is a common genetic disorder of iron metabolism, most often due to HFE C282Y homozygosity, that leads to progressive iron overload and end-organ damage. The disease has incomplete penetrance, only ~20% of homozygotes develop clinical iron overload, but untreated disease can cause cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes, arthropathy, and increased infection risk. The cornerstone of management is therapeutic phlebotomy to achieve and maintain serum ferritin below 50 ng/mL, which prevents progression and reverses some manifestations. Early diagnosis through transferrin saturation screening and HFE genotyping, followed by risk-adapted surveillance, is essential for preventing complications.

Overview and Recommendations

Background

  • •Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism caused by mutations that lead to hepcidin deficiency, most commonly homozygosity for the HFE C282Y variant. Hepcidin deficiency results in unregulated ferroportin-mediated iron absorption from the gut and release from macrophages, causing progressive iron loading in parenchymal organs, liver, heart, pancreas, skin, while sparing macrophages.
  • •The disease predominantly affects individuals of Northern European descent, with a C282Y homozygote frequency of approximately 1 in 200-300. However, penetrance is incomplete: only 20-38% of homozygotes develop biochemical iron overload, and just 10-33% progress to clinical disease. Men are affected earlier and more severely, with clinical onset typically after age 40; women present more often after menopause.
  • •Untreated HH carries significant morbidity: cirrhosis develops in a subset of patients with ferritin >1000 μg/L, and the risk of hepatocellular carcinoma (HCC) is markedly increased even in the absence of cirrhosis. Cardiac iron overload can cause cardiomyopathy and arrhythmias, while pancreatic iron deposition leads to diabetes. Arthropathy, especially of the second and third metacarpophalangeal joints, is common and often irreversible.
  • •Beyond HFE-related HH (type 1), four other types are recognized: juvenile HH (type 2, due to HJV or HAMP mutations) presents before age 30 with severe cardiac and endocrine involvement; type 3 (TFR2 mutations) has intermediate severity; and type 4 (ferroportin disease, SLC40A1) is autosomal dominant with macrophage iron trapping, low transferrin saturation, and often mild disease. Non-HFE forms should be suspected in young patients, those of non-European ancestry, or when iron overload persists despite negative HFE testing.
  • •The molecular basis of the hepcidin deficiency in HFE-HH involves impaired BMP/SMAD signaling: the C282Y mutant HFE fails to stabilize ALK3 on hepatocyte membranes, reducing hepcidin transcription. Genetic modifiers such as CYBRD1 and TMPRSS6 variants, as well as environmental factors like alcohol consumption and blood donation, contribute to the wide variability in clinical expression. Blood donation twice a year can reduce the risk of clinical disease in C282Y homozygotes by 80%.

Evaluation

  • •Suspect HH in any patient with unexplained fatigue, arthralgias (especially bilateral metacarpophalangeal joint pain), erectile dysfunction, or skin hyperpigmentation. A family history of liver disease, diabetes, arthritis, or cardiomyopathy should raise suspicion.
  • •Ask about alcohol intake, iron or vitamin C supplementation, blood donation history, and prior transfusions. In women, note menopausal status as ferritin rises sharply after menopause.
  • •Examine for bronze or slate-gray skin hyperpigmentation on sun-exposed areas, hepatomegaly, testicular atrophy, and stigmata of chronic liver disease (spider angiomas, palmar erythema, caput medusae). Evidence of arthritis (MCP joint swelling, limited range of motion) is a key clue.
  • •The most sensitive screening test is transferrin saturation (TSAT). A fasting TSAT >45% is the threshold for further evaluation; TSAT >60% in men or >50% in women with elevated ferritin (≥300 μg/L in men, ≥200 μg/L in women) warrants genetic testing. Serum ferritin alone is not diagnostic as it can be elevated in inflammation, metabolic syndrome, or alcohol use.
  • •Order HFE genotyping for the C282Y and H63D variants. C282Y homozygosity or compound heterozygosity (C282Y/H63D) with iron overload confirms the diagnosis. If HFE testing is negative but iron overload is confirmed (by MRI or biopsy), proceed to a non-HFE gene panel including HJV, HAMP, TFR2, and SLC40A1.
  • •Quantify liver iron concentration noninvasively with MRI R2* or T2* relaxometry, which can also assess cardiac iron. A hepatic iron index >1.9 (by biopsy or MRI) is highly specific for HFE-related iron overload. Liver biopsy is reserved for cases with discordant serology, suspected additional liver disease, or when ferroportin disease is considered (shows Kupffer cell iron trapping).
  • •Assess for end-organ damage: liver function tests, fasting glucose, echocardiogram with strain imaging, and bone density scan (DXA) at diagnosis. In patients with cirrhosis, perform semiannual HCC surveillance with ultrasound and alpha-fetoprotein.
  • •Evaluate for iron deficiency in the setting of anemia; if present, consider gastrointestinal blood loss as a cause of iron deficiency separate from HH. Do not attribute all iron overload to HH without excluding secondary causes such as transfusional iron overload, dyserythropoietic anemias, and chronic liver disease.
  • •In a patient with acute decompensation (dyspnea, hypotension, fever), obtain an urgent cardiac T2* MRI. A value <10 ms indicates life-threatening cardiac iron overload requiring immediate chelation. Simultaneously, evaluate for sepsis, keeping in mind that HH patients have a 1.7-fold increased risk of sepsis and are susceptible to siderophilic organisms like Yersinia and Vibrio.
  • •Diagnostic criteria for HH: evidence of increased iron stores (elevated TSAT and ferritin, or MRI/biopsy evidence) plus either homozygosity for C282Y or compound heterozygosity for C282Y/H63D. In non-HFE types, the genetic defect defines the subtype. A normal TSAT (<45%) effectively excludes hepcidin-deficient HH, even with hyperferritinemia.

Management

  • •Initiate therapeutic phlebotomy as first-line therapy for all patients with iron overload. Induction: remove 500 mL of whole blood (≈200 mg iron) weekly or biweekly until serum ferritin falls below 50 ng/mL. Maintain hemoglobin ≥11 g/dL; defer phlebotomy if lower. The typical induction course requires 20-40 sessions over 6-12 months.
  • •After iron depletion, transition to maintenance phlebotomy every 3-4 months to keep serum ferritin between 50 and 100 ng/mL. For asymptomatic C282Y homozygotes without iron overload, regular blood donation at least twice a year reduces the risk of developing clinical disease to that of a low-risk compound heterozygote.
  • •Iron chelation (deferasirox 20-40 mg/kg/day orally or deferoxamine 40-50 mg/kg/day subcutaneously) is reserved for patients who cannot tolerate phlebotomy due to severe anemia (Hb persistently <11 g/dL), poor venous access, or advanced cirrhosis with thrombocytopenia. Chelation is less effective and more expensive than phlebotomy.
  • •In acute cardiac iron overload (T2* <10 ms), start continuous intravenous deferoxamine at 40-50 mg/kg over 24 hours without interruption. Do not use aggressive diuretics or inotropes, as the high-output state in chronic anemia makes these patients sensitive to volume shifts. Add oral deferiprone (75 mg/kg/day divided TID) as augmentation if needed. Continue until cardiac T2* improves to >10 ms.
  • •For suspected sepsis in HH, obtain blood cultures and start empiric antibiotics covering Yersinia enterocolitica and Vibrio vulnificus: ceftriaxone 2 g IV daily plus doxycycline 100 mg IV twice daily. Consider temporarily withholding deferoxamine if Yersinia infection is confirmed, as it may act as a siderophore. The infection risk persists even with normal ferritin.
  • •Advise all patients to abstain from alcohol completely, as alcohol accelerates hepatic fibrosis and increases cirrhosis risk. Avoid iron supplements, high-dose vitamin C (which enhances iron absorption and oxidative stress), and raw shellfish. A balanced diet low in red meat is reasonable. Ilex paraguariensis (yerba mate) tea can inhibit non-heme iron absorption.
  • •Consider adjunctive pantoprazole 40 mg daily in patients with high phlebotomy requirements; it reduces dietary iron absorption by increasing gastric pH and may decrease the frequency of phlebotomy.
  • •Monitor patients on maintenance therapy: serum ferritin and TSAT every 3-6 months, plus annual liver function tests, fasting glucose, and joint assessment. In patients with cirrhosis, perform semiannual HCC surveillance with ultrasound and alpha-fetoprotein. Repeat cardiac MRI every 1-2 years if there is evidence of myocardial iron deposition.
  • •Manage hypogonadotropic hypogonadism with testosterone replacement if symptomatic. Treat osteoporosis (DXA-confirmed) with bisphosphonates or denosumab, and ensure adequate calcium and vitamin D intake. Refer to an endocrinologist for complex cases.
  • •For arthropathy, provide symptomatic treatment with NSAIDs or acetaminophen; consider orthopedic referral as joint replacement is more common in HH (6.3% of patients undergo arthroplasty). Iron-mediated arthropathy progresses faster than osteoarthritis.
  • •Anticoagulation for atrial fibrillation follows standard CHA₂DS₂-VASc risk assessment, but use direct oral anticoagulants with caution in patients with cirrhosis and avoid in decompensated disease. Portal vein thrombosis in cirrhosis requires anticoagulation per general guidelines.
  • •What NOT to do: Do not use iron chelation as first-line therapy; do not ignore alcohol counseling; do not perform phlebotomy in patients with hemoglobin <11 g/dL without evaluating the cause of anemia; do not supplement with vitamin C without monitoring iron status; do not use aggressive diuretics in acute cardiac iron overload; do not withhold antibiotics while awaiting cultures in a febrile HH patient.
  • •Refer to hepatology for cirrhosis or HCC, cardiology for cardiac iron overload, endocrinology for hypogonadism or diabetes, orthopedics for arthropathy, and a transplant center for end-stage liver disease. For pregnant women with HH, defer phlebotomy unless severe overload; avoid iron supplementation unless documented iron deficiency. Postpartum, reassess ferritin, especially after menopause.

Board Review — High Yield

  • •C282Y homozygosity, Most common genotype in HH; 1 in 200-300 Northern Europeans; penetrance only ~20%
  • •TSAT >45%, Most sensitive screening test; a normal TSAT effectively excludes hepcidin-deficient HH
  • •Ferritin >1000 μg/L, Strongest predictor of advanced fibrosis; urgent phlebotomy indicated
  • •Phlebotomy first-line, Induction weekly 500 mL until ferritin <50 ng/mL; maintenance every 3-4 months
  • •Blood donation twice yearly, Reduces risk of clinical HH in C282Y homozygotes by 80% (to level of compound heterozygote)
  • •Alcohol abstinence, Essential to prevent fibrosis progression; alcohol is a major cofactor
  • •Infection risk persists, C282Y homozygotes have HR 1.40 for any infection, 1.69 for sepsis, even with normal iron indices
  • •Juvenile HH (HJV/HAMP), Onset <30 years; severe cardiomyopathy and hypogonadism; requires early aggressive treatment
  • •Postmenopausal ferritin surge, 3.6-fold increase in 10 years in C282Y homozygotes; proactive phlebotomy needed
  • •Cardiac T2 <10 ms*, Indicates acute cardiac iron overload; treat with continuous IV deferoxamine 40-50 mg/kg/24h, avoid diuretics

Deep Dive — Evidence Details

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