Management of Hyperferritinemia
When ferritin levels are elevated, a systematic diagnostic evaluation should be performed to determine the underlying cause, followed by appropriate targeted management based on the etiology. 1
Initial Diagnostic Approach
Step 1: Assess Transferrin Saturation (TSAT)
- TSAT >45% suggests true iron overload disorders
- TSAT <45% suggests non-iron overload causes of hyperferritinemia
Step 2: Evaluate for Common Causes Based on TSAT Results
If TSAT >45% (Possible Iron Overload):
- Hemochromatosis screening: Consider genetic testing for HFE mutations
- Secondary iron overload: Assess for history of multiple transfusions, chronic liver disease
- Diagnostic thresholds: TSAT >50% and ferritin >300 μg/L for males and postmenopausal women; TSAT >45% and ferritin >200 μg/L for premenopausal females 1
If TSAT <45% (Non-Iron Overload Causes):
- Inflammatory conditions: Check CRP, ESR
- Liver disease: Assess liver enzymes, hepatitis serology, ultrasound
- Metabolic syndrome/NAFLD: Check BMI, lipid profile, glucose
- Malignancy: Consider appropriate cancer screening based on age/risk factors
- Rare conditions: Consider adult-onset Still's disease, hemophagocytic lymphohistiocytosis if clinically suspected 2
Management Based on Ferritin Level and Cause
For True Iron Overload (TSAT >45%)
Therapeutic Phlebotomy
- Initiate when: Ferritin ≥300 μg/L in men, ≥200 μg/L in women 3
- Protocol: Remove 1 unit (450-500 mL) of blood weekly until ferritin reaches 10-20 μg/L
- Maintenance: Periodic phlebotomy to maintain ferritin at 50-100 μg/L and TSAT <45% 1, 3
Iron Chelation Therapy
- Consider when: Ferritin >1000 μg/L with evidence of iron overload and TSAT >45%, especially in transfusion-dependent patients 4
- Prior to starting: Evaluate baseline renal function, liver function, auditory and ophthalmic examinations 4
- Monitoring: Monthly assessment of ferritin, blood counts, liver and renal function 4
- Dose adjustment: Reduce dose if ferritin falls below 1000 μg/L at two consecutive visits; interrupt therapy if ferritin falls below 500 μg/L 4
For Non-Iron Overload Causes (TSAT <45%)
Inflammatory Conditions
- Treat underlying inflammatory condition 1
- Monitor ferritin levels every 3 months until normalized
Metabolic Syndrome/NAFLD
- Weight loss: Through dietary modification and increased physical activity
- Lifestyle modifications: Limit alcohol intake, reduce consumption of processed foods and sugar 1
Liver Disease
- Manage underlying liver condition
- Avoid alcohol
- Consider referral to hepatologist if liver enzymes are elevated 1, 5
Referral Recommendations
- Ferritin >1000 μg/L: Refer to gastroenterologist or hematologist 1, 5
- TSAT >45% with elevated ferritin: Consider referral to hematologist for evaluation of hemochromatosis 1
- Elevated liver enzymes: Refer to hepatologist 1
- Unclear cause after initial workup: Refer to specialist with interest in iron disorders 5
Advanced Diagnostic Testing
- MRI for hepatic iron concentration: Non-invasive method to quantify iron overload, especially useful when cause remains unclear 6
- Liver biopsy: Consider if ferritin >1000 μg/L to assess for cirrhosis (20-45% risk) 1
Monitoring
- Monitor serum ferritin monthly during active treatment 1, 4
- Adjust therapy based on ferritin trends every 3-6 months 4
- For iron chelation therapy, monitor blood counts, liver function, renal function monthly 4
Common Pitfalls to Avoid
Assuming all hyperferritinemia is due to iron overload: 90% of elevated ferritin cases are due to non-iron overload conditions 5
Missing underlying malignancy: Malignancy is a common cause of markedly elevated ferritin 2
Inappropriate phlebotomy: Avoid in non-iron overload conditions as it may worsen anemia without addressing the underlying cause
Overlooking rare but serious causes: Very high ferritin levels (>10,000 μg/L) may indicate conditions like adult-onset Still's disease or hemophagocytic lymphohistiocytosis 2
Excessive iron depletion: Monitoring is essential to prevent iron deficiency from overtreatment 4, 3