Hemochromatosis

Order serum ferritin and transferrin saturation (TSAT) together in patients with suspected iron overload, including those with unexplained liver enzyme abnormalities, arthropathy, diabetes, cardiomyopathy, hypogonadism, suggestive family history, or prior abnormal iron studies. Ferritin reflects iron stores but also rises with inflammation and liver injury; TSAT identifies increased circulating iron availability and is an early phenotypic abnormality in HFE hemochromatosis. PubMed+1PubMedHFE Genotype, Ferritin Levels and Transferrin Saturation in Patients with Suspected Hereditary HemochromatosisPubMedHFE-Related Hemochromatosis - GeneReviews® - NCBI Bookshelf

Persistent ferritin elevation with TSAT greater than 45% should trigger HFE genotyping for C282Y and H63D variants. Conversely, normal ferritin—less than 300 ng/mL in men or less than 200 ng/mL in women—together with normal TSAT has a reported 97% negative predictive value for iron overload. ASH+1ASHDiagnosis and Management of Non-HFE Hemochromatosis | The Hematologist | American Society of HematologyPubMedLaboratory Evaluation of Hereditary Hemochromatosis - StatPearls - NCBI Bookshelf

Do not diagnose hereditary hemochromatosis from ferritin alone. Isolated hyperferritinemia with normal TSAT is rarely iron overload and should redirect evaluation toward alternate causes, particularly metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, inflammatory states, or hematologic disorders. NAFLD and alcohol-associated liver disease commonly produce elevated ferritin with normal TSAT, although overlap with hemochromatosis can occur. ASH+2ASHDiagnosis and Management of Non-HFE Hemochromatosis | The Hematologist | American Society of HematologyPubMedDiagnosis and Treatment of Genetic HFE-Hemochromatosis: The Danish AspectPubMedLaboratory Evaluation of Hereditary Hemochromatosis - StatPearls - NCBI Bookshelf

C282Y homozygosity is the predominant genotype associated with clinically symptomatic HFE hemochromatosis and confers the greatest risk of progressive biochemical iron overload. In a patient with elevated TSAT and ferritin, C282Y homozygosity is consistent with HFE-related hemochromatosis and generally does not require further genetic testing to establish the common HFE diagnosis. Nature+1NatureHighly accurate molecular genetic testing for HFE hereditary hemochromatosis: results from 10 years of blinded proficiency surveys by the College of American Pathologists | Genetics in MedicineASHDiagnosis and Management of Non-HFE Hemochromatosis | The Hematologist | American Society of Hematology

Do not equate C282Y homozygosity with inevitable end-organ disease. Phenotypic expression has been reported in approximately 70% of C282Y homozygotes, whereas expression is less than 10% with other mutations; clinical classification should therefore distinguish biochemical iron overload from iron-overload-related organ injury. NEJM+1NEJMHemochromatosis: Practice Guidelines Update | NEJM ClinicianPubMedHFE-Related Hemochromatosis - GeneReviews® - NCBI Bookshelf

C282Y/H63D compound heterozygosity, H63D homozygosity, other HFE combinations, or absent common HFE variants do not independently prove hereditary hemochromatosis. When TSAT and ferritin remain abnormal in these settings, quantify hepatic iron—usually with MRI—and exclude secondary iron loading before making a presumptive diagnosis of non-HFE hemochromatosis. ASH+1ASHDiagnosis and Management of Non-HFE Hemochromatosis | The Hematologist | American Society of HematologyPubMedLaboratory Evaluation of Hereditary Hemochromatosis - StatPearls - NCBI Bookshelf

Consider non-HFE hemochromatosis particularly with young presentation and biochemical plus clinical evidence of iron overload. Non-HFE forms, especially HJV- or HAMP-mediated disease, have earlier onset and a greater propensity for cardiac and gonadal involvement; this phenotype should accelerate assessment for organ involvement and referral for specialized genetic evaluation after hepatic iron is documented. ASHASHDiagnosis and Management of Non-HFE Hemochromatosis | The Hematologist | American Society of Hematology

Use quantitative hepatic MRI as the preferred noninvasive method to document and quantify hepatic iron deposition when HFE results are non-diagnostic, hyperferritinemia has an uncertain cause, or biopsy is not feasible. MRI can also assess iron in the spleen, pancreas, heart, and brain, which is useful when extrahepatic involvement is suspected. PubMed+1PubMedHFE-Related Hemochromatosis - GeneReviews® - NCBI BookshelfPubMedLaboratory Evaluation of Hereditary Hemochromatosis - StatPearls - NCBI Bookshelf

Assess hepatic fibrosis in every patient with confirmed iron overload using noninvasive testing or biopsy when clinical risk is substantial. Ferritin greater than 1,000 µg/L, abnormal liver tests, clinical evidence of cirrhosis, heavy alcohol exposure, viral hepatitis, or another coexisting liver disease should lower the threshold for fibrosis staging and liver biopsy when histology will clarify diagnosis or prognosis. PubMed+2PubMedClinical practice guidelines on hemochromatosis: Asian Pacific ...PubMedHFE-Related Hemochromatosis - GeneReviews® - NCBI BookshelfPubMedLaboratory Evaluation of Hereditary Hemochromatosis - StatPearls - NCBI Bookshelf

Liver biopsy is no longer required to diagnose typical HFE hemochromatosis when iron indices and genotype are concordant, but remains useful when the diagnosis is unclear, when NAFLD, dysmetabolic iron overload syndrome, or alcohol-associated liver disease confounds interpretation, and when direct fibrosis assessment will change management. PubMed+1PubMedHFE-Related Hemochromatosis - GeneReviews® - NCBI BookshelfPubMedLaboratory Evaluation of Hereditary Hemochromatosis - StatPearls - NCBI Bookshelf

In HFE hemochromatosis cohorts, APRI greater than 0.44 and FIB-4 greater than 1.1 each identified biopsy-validated advanced fibrosis with 81% diagnostic accuracy. These lower thresholds are disease-contextual rather than general chronic-liver-disease cutoffs and should be integrated with ferritin, liver tests, elastography, imaging, and clinical findings rather than used in isolation. PubMedPubMedClinical practice guidelines on hemochromatosis: Asian Pacific ...

Initiate therapeutic phlebotomy for patients with HFE-related hemochromatosis and biochemical or clinical iron overload. Standard induction removes 300 to 500 mL of blood at 1- to 2-week intervals until ferritin is below 100 µg/L; each 400- to 500-mL removal eliminates approximately 200 to 250 mg of iron. jacc+1jaccIron Overload Cardiomyopathy: Better Understanding of an Increasing DisorderPubMedDiagnosis and Treatment of Genetic HFE-Hemochromatosis: The Danish Aspect

Check hemoglobin before every phlebotomy and remeasure ferritin after every fourth procedure during induction. Once depleted, transition to individualized maintenance phlebotomy based on recurrent ferritin elevation; maintenance commonly requires three to four procedures annually in men and one to two annually in women, although frequency must follow serial hemoglobin and ferritin rather than a fixed calendar schedule. jacc+1jaccIron Overload Cardiomyopathy: Better Understanding of an Increasing DisorderPubMedDiagnosis and Treatment of Genetic HFE-Hemochromatosis: The Danish Aspect

Published targets vary. One source describes ferritin below 100 µg/L for induction, while AASLD-derived targets cited in a recent trial report ferritin 50 to 100 ng/mL and TSAT below 50% in men or below 45% in women. Use a consistent local target and avoid iatrogenic anemia through preprocedure hemoglobin monitoring. Nature+2NatureA phase 1b randomised clinical trial evaluating BBI-001, a non-absorbed oral therapeutic for the treatment of iron overload | Scientific ReportsjaccIron Overload Cardiomyopathy: Better Understanding of an Increasing DisorderPubMedDiagnosis and Treatment of Genetic HFE-Hemochromatosis: The Danish Aspect

Phlebotomy is not feasible in substantial anemia, some malignancy settings, or hemodynamic instability. Iron chelation is an alternative when phlebotomy is contraindicated or impossible, but available agents—deferoxamine, deferasirox, and deferiprone—carry drug toxicity and are generally reserved for selected patients rather than routine HFE hemochromatosis. Nature+1NatureA phase 1b randomised clinical trial evaluating BBI-001, a non-absorbed oral therapeutic for the treatment of iron overload | Scientific ReportsjaccIron Overload Cardiomyopathy: Better Understanding of an Increasing Disorder

After iron depletion, follow ferritin and TSAT with hemoglobin to determine maintenance phlebotomy timing. Genotype-positive individuals without iron overload should receive biochemical follow-up rather than empiric treatment, but available guidance does not establish a single evidence-based interval. Nature+1NatureEMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH) | European Journal of Human GeneticsjaccIron Overload Cardiomyopathy: Better Understanding of an Increasing Disorder

Offer evaluation to first-degree relatives, especially siblings, of patients with hereditary hemochromatosis. Family-based testing is clinically useful because siblings may share genetic risk, whereas broad population HFE screening is not recommended because of low and variable penetrance. Nature+1NatureHighly accurate molecular genetic testing for HFE hereditary hemochromatosis: results from 10 years of blinded proficiency surveys by the College of American Pathologists | Genetics in MedicineCDCAbout Hereditary Hemochromatosis | Hereditary Hemochromatosis | CDC

At diagnosis of clinically meaningful iron overload, document potentially affected systems with liver biochemical testing, diabetes screening, and targeted joint imaging. In patients with established organ injury, iron depletion should proceed alongside management of the organ-specific disease rather than being treated as a substitute for hepatic, cardiac, endocrine, or musculoskeletal care. PubMedPubMedHFE-Related Hemochromatosis - GeneReviews® - NCBI Bookshelf