What is the management approach for a patient with elevated transferrin saturation (TSAT) and suspected hemochromatosis?

Differential Diagnosis of Elevated Transferrin Saturation

When transferrin saturation is elevated (≥45%), the primary concern is hemochromatosis and iron overload disorders, not iron deficiency—this requires immediate HFE genetic testing and assessment for secondary causes of iron overload. 1

Initial Diagnostic Algorithm

Step 1: Confirm the Elevation and Measure Key Parameters

• Obtain fasting transferrin saturation (TS) and serum ferritin simultaneously, as both tests together provide optimal diagnostic accuracy 1
• TS ≥45% is the diagnostic threshold that triggers further evaluation for hemochromatosis 1, 2
• Measure complete blood count, liver enzymes (ALT, AST), and platelet count to assess for hepatic involvement 2

Step 2: Order HFE Genetic Testing

• Proceed immediately to HFE mutation analysis for C282Y and H63D mutations when TS ≥45% or ferritin is elevated 1, 2
• C282Y homozygosity (C282Y/C282Y) confirms hereditary hemochromatosis and is present in approximately 90% of cases 2
• Compound heterozygosity (C282Y/H63D) or H63D homozygosity requires individualized assessment, as these genotypes have lower penetrance and may not cause significant iron overload 1, 2

Step 3: Assess Disease Severity

• If ferritin >1,000 μg/L with elevated liver enzymes (ALT/AST) and platelet count <200, cirrhosis is present in approximately 80% of C282Y homozygotes 2
• Ferritin <1,000 μg/L accurately excludes cirrhosis 2
• Consider liver biopsy when ferritin >1,000 μg/L, elevated liver enzymes, hepatomegaly, age >40 years, or platelet count <200 to assess for cirrhosis 1, 2

Differential Diagnosis When HFE Testing is Negative

Secondary Causes of Iron Overload to Investigate

• Hematologic disorders: Thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, pyruvate kinase deficiency 3
• Chronic liver diseases: Alcoholic liver disease, non-alcoholic fatty liver disease, chronic hepatitis C—these can elevate both TS and ferritin independent of genetic hemochromatosis 1, 3
• Iatrogenic causes: Multiple blood transfusions, excessive iron supplementation 3
• Increased alcohol consumption: This is an alternative cause of elevated transferrin saturation beyond hemochromatosis 1

Advanced Imaging When Diagnosis Remains Unclear

• MRI with R2 sequences should be used to quantify hepatic iron concentrations when the cause of elevated TS and ferritin is unclear or when HFE testing is negative* 1
• MRI can differentiate patterns: predominant hepatic iron with minimal spleen involvement suggests hemochromatosis or aceruloplasminemia, while increased spleen iron suggests ferroportin disease or transfusional overload 1
• Cardiac MRI should be performed in patients with signs of heart disease or in juvenile forms of hemochromatosis 1

Causes of Hyperferritinemia WITHOUT True Iron Overload

When Ferritin is Elevated but TS is Normal or Low

• Inflammatory conditions: Infections, rheumatologic diseases (adult-onset Still's disease, hemophagocytic lymphohistiocytosis) 3
• Malignancy: Lymphomas and other cancers 1, 3
• Chronic liver disease: Necroinflammatory liver disease of any cause 1, 3
• Kidney failure: Chronic kidney disease can cause hyperferritinemia 3

Management Based on Genotype

C282Y Homozygotes (C282Y/C282Y)

• Initiate therapeutic phlebotomy immediately—remove one unit (500 mL) of blood weekly or biweekly until ferritin reaches 50-100 μg/L 1, 2
• Monitor hemoglobin/hematocrit before each phlebotomy and serum ferritin every 10-12 phlebotomies 2
• Maintain ferritin at 50-100 μg/L during maintenance phase, but also monitor transferrin saturation, as persistently elevated TS ≥50% for >6 years independently predicts worsened joint symptoms, decreased athletic ability, and reduced quality of life despite normal ferritin 4

Compound Heterozygotes (C282Y/H63D) or H63D Homozygotes

• Phlebotomy may be considered only if confirmed iron overload is present on MRI or liver biopsy, as these genotypes rarely cause significant iron accumulation 1, 2
• Investigate for additional environmental risk factors (alcohol, metabolic syndrome, fatty liver disease) or other genetic causes if iron overload is confirmed 1
• If no iron overload is present, annual monitoring of TS and ferritin is sufficient 2

Negative HFE Testing with Confirmed Iron Overload

• Treat the underlying secondary cause (e.g., discontinue unnecessary iron supplementation, manage hematologic disorder, address alcohol consumption) 1, 3
• Phlebotomy can be used for iron reduction, but evidence for benefit in non-HFE iron overload is limited 1

Critical Pitfalls to Avoid

• Do not assume elevated transferrin alone (TIBC) means iron overload—elevated transferrin typically indicates iron deficiency, not excess 5, 6
• Do not rely on ferritin alone, as it is falsely elevated by inflammation, liver disease, malignancy, and chronic conditions—always interpret ferritin in the context of TS 1, 2
• Do not assume normal ferritin means adequate control in treated hemochromatosis—persistently elevated TS ≥50% for >6 years causes progressive symptoms despite ferritin <50 μg/L 4
• Do not perform population-wide screening for hemochromatosis, but do screen first-degree relatives of confirmed cases with both genetic testing and iron studies 2
• Do not overlook cardiac evaluation in hemochromatosis patients being considered for liver transplantation, as cardiac complications are a major cause of mortality 1

Family Screening Recommendations

• Screen all first-degree relatives of C282Y homozygotes with HFE genetic testing and iron studies (TS and ferritin) 2
• Provide genetic counseling before testing regarding implications for insurance, employment, and psychological impact 2