What is the management approach for a patient with elevated iron parameters, negative HFE (Human Ferritin Encoding) testing, and suspected iron overload?

Management of Elevated Iron Parameters with Negative HFE Testing

In patients with elevated iron parameters and negative HFE testing, you must first use MRI to quantify hepatic iron concentration to confirm true iron overload, then systematically investigate for secondary causes including hematologic disorders, chronic liver disease, metabolic syndrome, and alcohol excess before considering phlebotomy. 1

Confirm True Iron Overload

Serum iron parameters alone are insufficient to diagnose iron overload because ferritin is an acute-phase reactant and can be markedly elevated without true tissue iron accumulation. 1

• Obtain hepatic MRI with R2 quantification* to non-invasively measure liver iron concentration in all patients with unclear hyperferritinemia, elevated transferrin saturation and ferritin, or negative HFE testing. 1
• MRI can also assess extrahepatic organ involvement including spleen, pancreas, heart, and brain, which helps differentiate between different iron overload disorders. 1
• The pattern of iron distribution is diagnostically important: predominant hepatic iron with minimal splenic involvement suggests hemochromatosis or aceruloplasminemia, while increased splenic iron suggests ferroportin disease or transfusional overload. 1

Investigate Secondary Causes of Iron Overload

When HFE testing is negative (not C282Y homozygous or C282Y/H63D compound heterozygous), you must systematically evaluate for secondary causes before attributing iron overload to non-HFE genetic hemochromatosis. 1, 2

Hematologic Disorders

• Screen for compensated iron-loading anemias including thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, and pyruvate kinase deficiency. 2
• Obtain complete blood count with reticulocytes and peripheral blood smear. 3
• These conditions cause iron overload through ineffective erythropoiesis and/or transfusional iron accumulation. 2

Metabolic and Liver Disease Factors

• Evaluate for metabolic syndrome components (obesity, diabetes, dyslipidemia, hypertension) as these are common cofactors that can contribute to hepatic iron accumulation. 1
• Assess alcohol consumption history carefully, as excessive alcohol intake elevates transferrin saturation and increases risk of fibrosis and hepatocellular malignancy when combined with elevated iron parameters. 1
• Screen for chronic liver diseases including non-alcoholic fatty liver disease (NAFLD), chronic hepatitis B/C, and cirrhosis, which can cause secondary iron accumulation. 1, 2
• Obtain liver function tests (ALT, AST, bilirubin) and consider non-invasive fibrosis scores (APRI, FIB-4). 3

Inflammatory and Malignant Conditions

• Exclude inflammatory conditions that cause hyperferritinemia without true iron overload, including chronic infections, rheumatologic diseases (adult-onset Still's disease), and hemophagocytic lymphohistiocytosis. 2
• Screen for malignancy, particularly lymphomas, which can markedly elevate ferritin. 1, 2
• Check inflammatory markers (CRP, ESR) to contextualize ferritin elevation. 4

Consider Non-HFE Genetic Testing

Genetic testing for non-HFE hemochromatosis genes should only be pursued after confirming true iron overload by MRI or liver biopsy AND excluding secondary causes. 1

• Consider testing for mutations in TFR2, SLC40A1 (ferroportin), HAMP (hepcidin), and HJV (hemojuvelin) genes. 1
• This testing is most appropriate when iron excess has been proven by direct assessment and other hepatic and hematological disorders have been ruled out. 1
• Referral to a specialized center or research laboratory may be necessary for comprehensive genetic evaluation. 1

Management Decisions for Confirmed Iron Overload

When to Initiate Phlebotomy

Phlebotomy is indicated for patients with confirmed tissue iron overload (by MRI or liver biopsy) even without C282Y homozygosity, but requires individualized assessment based on the degree of overload and contributing factors. 1

• Management of environmental risk factors is crucial before or concurrent with phlebotomy: weight loss through dietary modification and increased physical activity for fatty liver disease, and alcohol cessation for excessive drinkers. 1
• Between 14-30% of patients referred for phlebotomy are compound heterozygotes or have other non-classical genotypes. 1
• The benefits of phlebotomy in non-C282Y homozygotes are largely unclear from evidence, so treatment decisions must weigh the confirmed degree of iron overload against potential risks. 1

Assessing for Advanced Liver Disease

Liver biopsy should be considered to assess for cirrhosis if serum ferritin >1,000 μg/L or liver enzymes are elevated. 1, 3

• The combination of ferritin >1,000 μg/L, elevated ALT/AST, and platelet count <200 predicts cirrhosis in 80% of cases. 5, 3
• Liver biopsy also helps determine the cellular distribution of iron (parenchymal vs. mesenchymal), which aids in differential diagnosis. 1
• In patients with otherwise clear diagnosis of cirrhosis, liver biopsy is not recommended. 1

Monitoring During Treatment

• Monitor serum ferritin monthly and adjust phlebotomy frequency based on trends. 1
• If ferritin falls below 1,000 μg/L at two consecutive visits, consider dose reduction of phlebotomy frequency. 1
• Interrupt phlebotomy if ferritin falls below 500 μg/L and continue monthly monitoring. 1
• Evaluate the need for ongoing chelation therapy in patients whose conditions no longer require regular interventions. 1

Critical Pitfalls to Avoid

• Never diagnose hemochromatosis based on genotype alone—diagnosis requires both genetic findings AND phenotypic evidence of iron overload. 1
• Do not assume elevated ferritin equals iron overload—ferritin can be falsely elevated by inflammation, liver disease, malignancy, and other conditions. 1, 4
• Avoid initiating phlebotomy without confirming tissue iron overload by MRI or liver biopsy, especially in patients with metabolic syndrome or chronic liver disease where evidence for benefit is lacking. 1
• Do not overlook cardiac involvement—obtain ECG and echocardiography in patients with severe iron overload, and cardiac MRI if signs of heart disease are present. 3
• Screen for extrahepatic complications including joint disease (particularly 2nd and 3rd metacarpophalangeal joints), endocrine abnormalities (diabetes, hypogonadism), and perform baseline auditory and ophthalmic examinations. 3