What are the next steps in managing a patient with severely elevated ferritin levels?

Management of Severely Elevated Ferritin Levels

The first critical step is to measure transferrin saturation alongside ferritin to distinguish between true iron overload and the numerous non-iron overload causes of hyperferritinemia, as ferritin is an acute phase reactant that rises with inflammation, infection, malignancy, liver disease, and metabolic conditions. 1

Initial Diagnostic Workup

Measure Transferrin Saturation Immediately

• Transferrin saturation is essential to differentiate absolute iron overload from functional iron deficiency or inflammatory conditions 1
• If transferrin saturation is ≥45% in females or ≥50% in males, proceed with HFE genetic testing for hereditary hemochromatosis 1
• If transferrin saturation is <20-25% despite elevated ferritin, this suggests either functional iron deficiency or an inflammatory block 1

Exclude Common Non-Iron Overload Causes

Over 90% of hyperferritinemia cases are due to conditions other than iron overload 1, 2:

• Check inflammatory markers (CRP, ESR) to identify acute or chronic inflammation 1, 2
• Assess for cell necrosis with AST, ALT, CK, and bilirubin 1, 2
• Screen for metabolic syndrome components: blood pressure, BMI, fasting glucose, triglycerides, cholesterol 1, 2
• Evaluate for chronic alcohol consumption through history and liver function tests 1, 3
• Consider malignancy if clinical suspicion exists, as it is the most common cause of markedly elevated ferritin (153/627 cases in one series) 4
• Review for chronic liver disease, particularly non-alcoholic fatty liver disease (NAFLD) 1, 2

Risk Stratification Based on Ferritin Level

Ferritin <1000 μg/L

• The risk of advanced liver fibrosis or cirrhosis is very low when ferritin is below this threshold, particularly with normal transaminases and no hepatomegaly 1, 2
• Continue monitoring every 6-12 months if transferrin saturation is normal and secondary causes are addressed 2

Ferritin 1000-2500 μg/L

• Consider liver biopsy or non-invasive fibrosis assessment (transient elastography/FibroScan) if liver enzymes are elevated or hepatomegaly is present 1
• If transferrin saturation is elevated (≥45%), complete HFE genetic testing 1
• Refer to hepatology or hematology for further evaluation 3

Ferritin >2500 μg/L

• Strongly consider hereditary hemochromatosis, malignancy, or severe inflammatory conditions 4
• In one large series, the average ferritin in adult-onset Still's disease, systemic juvenile idiopathic arthritis, or hemophagocytic lymphohistiocytosis was 14,242 μg/L 4
• Urgent referral to appropriate specialist is warranted 3

Genetic Testing Strategy

When to Order HFE Testing

• Only order HFE genetic testing if transferrin saturation is elevated (≥45% females, ≥50% males) 1
• Testing for C282Y and H63D mutations should be performed 1
• Do not diagnose hemochromatosis based on C282Y homozygosity alone—evidence of increased iron stores is required 1

Interpreting HFE Results

• C282Y homozygotes with elevated ferritin and transferrin saturation: Diagnosis of HFE hemochromatosis confirmed; initiate phlebotomy therapy 1
• C282Y/H63D compound heterozygotes or H63D homozygotes: These genotypes rarely cause significant iron overload; investigate other causes of hyperferritinemia first 1
• Negative HFE testing with persistent iron overload: Consider non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) only after confirming iron excess by MRI or liver biopsy 1

Advanced Imaging When Indicated

MRI for Hepatic Iron Quantification

• Use MRI with R2 sequences to non-invasively quantify hepatic iron concentration* in patients with unclear diagnosis, elevated transferrin saturation, or ferritin >1000 μg/L 1
• MRI can assess extrahepatic iron deposition in heart, pancreas, and spleen 1
• Cardiac MRI should be performed in patients with signs of heart disease or juvenile hemochromatosis 1

Non-Invasive Fibrosis Assessment

• Transient elastography (FibroScan) can rule out advanced fibrosis if liver stiffness is <6.4 kPa 1
• FIB-4 score is the best-validated serum marker for fibrosis assessment, though thresholds may differ in hemochromatosis 1

Management Based on Underlying Cause

If Iron Overload Confirmed (Elevated Transferrin Saturation + Ferritin)

• Initiate therapeutic phlebotomy to reduce iron stores 1
• Target serum ferritin 50-100 μg/L for maintenance 1
• Monitor ferritin monthly during de-ironing phase, then every 3-6 months during maintenance 1

If Functional Iron Deficiency (Low Transferrin Saturation + Elevated Ferritin)

• In chronic kidney disease patients on erythropoiesis-stimulating agents (ESAs), consider trial of IV iron 50-125 mg weekly for 8-10 doses 1
• Even with ferritin 500-1200 μg/L, IV iron can increase hemoglobin if transferrin saturation is <25% 1
• Monitor closely for iron overload; withhold iron if ferritin exceeds 1000 μg/L or transferrin saturation exceeds 50% 1

If Inflammatory/Metabolic Cause Identified

• Address the underlying condition: optimize diabetes control, initiate statin therapy for dyslipidemia, promote weight loss for metabolic syndrome 2
• Treat chronic liver disease (NAFLD, alcohol-related liver disease) as primary intervention 1, 2
• Recheck ferritin in 3-6 months after addressing underlying conditions 2

Critical Pitfalls to Avoid

• Never diagnose hemochromatosis based on elevated ferritin alone—transferrin saturation must be elevated 1
• Do not perform HFE testing in patients with normal transferrin saturation—it wastes resources and may lead to misdiagnosis 1
• Recognize that ferritin >1000 μg/L is more commonly due to malignancy or infection than iron overload 4
• Avoid phlebotomy in patients with elevated ferritin but low/normal transferrin saturation—this represents functional iron deficiency or inflammation, not iron overload 1, 3
• In elderly patients and children, monitor more frequently for toxicity if iron chelation therapy is considered, as serious adverse events are more common in these populations 5