What is the management approach for elevated ferritin levels?

Management of Elevated Ferritin

The first step in managing elevated ferritin is to measure transferrin saturation (TS) alongside ferritin to distinguish between true iron overload (TS ≥45%) and inflammatory/liver conditions (TS <45%), followed by risk stratification based on ferritin thresholds of 1000 μg/L. 1

Initial Diagnostic Workup

Measure transferrin saturation immediately when ferritin is elevated, as this single test determines your entire diagnostic pathway 1:

• If TS ≥45%: Suspect iron overload disorders and proceed directly to HFE genetic testing for hereditary hemochromatosis 1
• If TS <45%: Consider inflammatory conditions, anemia of chronic disease, liver disease (alcoholic, viral hepatitis, NAFLD), malignancy, or infection 1, 2

Risk Stratification by Ferritin Level

The 1000 μg/L threshold is critical for determining both prognosis and management intensity 1:

• Ferritin <1000 μg/L: Lower risk of organ damage; no patient in validation studies had cirrhosis at this level 1
• Ferritin ≥1000 μg/L: 20-45% prevalence of cirrhosis in C282Y homozygotes; strongly consider liver biopsy if liver enzymes are also elevated 1

Common pitfall: Ferritin >2000 μg/L is most frequently associated with malignancy and infectious diseases in hospitalized patients, not iron overload 2, 3. The highest ferritin levels (mean >14,000 μg/L) occur with rheumatologic/inflammatory conditions like adult-onset Still's disease and macrophage activation syndrome 2, 3.

Management Algorithm Based on Etiology

For Confirmed Hemochromatosis (C282Y Homozygotes with Iron Overload)

Therapeutic phlebotomy is the definitive treatment 1:

• Induction phase: Weekly phlebotomy removing 500 mL blood until ferritin reaches 50-100 μg/L 1
• Maintenance phase: Ongoing phlebotomy to maintain ferritin between 50-100 μg/L 1
• Monitoring during phlebotomy: Check hemoglobin/hematocrit before each procedure and ferritin every 10-12 phlebotomies 1
• Dietary restrictions: Avoid vitamin C supplements and iron supplements 1

Screen all first-degree relatives with iron studies and HFE mutation analysis (Grade 1A recommendation) 1. Failure to screen relatives is a common and serious pitfall 1.

For Transfusional Iron Overload

Iron chelation with deferasirox is indicated when patients have transfused ≥100 mL/kg packed red blood cells AND serum ferritin consistently >1000 μg/L 4:

• Starting dose: 14 mg/kg/day orally once daily for patients ≥2 years with eGFR >60 mL/min/1.73 m² 4
• Dose adjustments: Make changes in 3.5 or 7 mg/kg increments every 3-6 months based on monthly ferritin trends 4
• Maximum dose: 28 mg/kg/day; doses above this are not recommended 4
• Target: Reduce ferritin to <1000 μg/L, then consider dose reduction especially if dose >17.5 mg/kg/day 4
• Interrupt therapy if ferritin falls below 500 μg/L 4

Critical safety monitoring for deferasirox 4:

• Monthly monitoring of serum ferritin, blood counts, liver function, and renal function 4
• Baseline and periodic auditory/ophthalmic testing 4
• Interrupt immediately in pediatric patients with volume depletion (vomiting, diarrhea, decreased oral intake) due to risk of fatal renal toxicity 4
• Overchelation warning: Continued dosing at 14-28 mg/kg/day when iron burden approaches normal range can cause life-threatening adverse events 4

For Non-Iron Overload Causes (TS <45%)

Address the underlying condition rather than pursuing iron reduction 1:

• Inflammatory/infectious diseases: Treat the primary condition; ferritin will normalize as inflammation resolves 1, 2
• Liver disease: Manage both the liver condition and any concurrent iron overload if present 1
• Malignancy: Elevated ferritin does not predict mortality but signals need for cancer evaluation when ferritin >2000 μg/L 3

Referral indications 5:

• Ferritin >1000 μg/L warrants referral to gastroenterology, hematology, or iron overload specialist 5
• Ferritin ≥1000 μg/L with markedly elevated transaminases requires immediate evaluation including consideration of liver biopsy 1

Special Populations

Elderly patients: Monitor more frequently for toxicity with any iron chelation therapy, as serious and fatal adverse reactions occur predominantly in this population 4

Pediatric patients: Particularly vulnerable to volume depletion complications; interrupt deferasirox during acute illnesses and monitor renal function closely 4

Prognostic Considerations

With early diagnosis and treatment before cirrhosis develops, prognosis is excellent for hereditary hemochromatosis, and therapeutic phlebotomy prevents cirrhosis, hepatocellular carcinoma, and other complications 1. However, ferritin >1500 μg/L before allogeneic stem cell transplant predicts worse overall survival, progression-free survival, and infection-related mortality 6.