Elevated Ferritin: Causes and Management
Primary Causes of Elevated Ferritin
Elevated ferritin most commonly results from malignancy, iron overload syndromes, chronic inflammation, liver disease, or infection—not simply from excess iron stores. 1
Major Etiologies in Clinical Practice
Malignancy is the most frequent cause of markedly elevated ferritin (>1000 μg/L), accounting for approximately 24% of cases, including hematologic malignancies (Hodgkin's disease, leukemias, multiple myeloma) and solid tumors (breast, gastric, pancreatic carcinomas) 1, 2
Iron overload syndromes represent the second most common cause (22% of cases), including hereditary hemochromatosis and transfusional iron overload 1, 3
Chronic inflammatory conditions elevate ferritin as an acute phase reactant, independent of actual iron stores—this includes chronic liver disease (alcoholic liver disease, chronic hepatitis B/C, NAFLD), chronic kidney disease, and rheumatologic conditions 3
Infection and sepsis can dramatically increase ferritin levels through inflammatory pathways 3, 1
Transfusional iron overload occurs in patients with myelodysplastic syndromes, thalassemia, sickle cell disease, or other chronic transfusion-dependent anemias 3
Critical Interpretation Pitfall
Ferritin acts as an acute phase reactant, generating false elevations in inflammatory states—patients with chronic inflammation and ferritin ≥50 μg/L could still be iron deficient despite the elevated level. 3 When inflammation is suspected, measure C-reactive protein or transferrin saturation to distinguish true iron overload from inflammatory ferritin elevation 3.
Diagnostic Approach
Initial Assessment
Measure transferrin saturation (TS) alongside ferritin—TS >45% with elevated ferritin suggests true iron overload, while normal TS with elevated ferritin suggests inflammation or other non-iron causes 3
In hemochromatosis screening, serum ferritin >1000 μg/L predicts advanced fibrosis and cirrhosis with high specificity 3
For transfusional iron overload, ferritin >1000 ng/mL indicates need for chelation therapy consideration 3
Specific Clinical Contexts
In chronic kidney disease patients on dialysis, maintain ferritin targets of 200-500 ng/mL when using erythropoiesis-stimulating agents—levels >500 ng/mL may indicate iron overload, though safety data for IV iron administration up to ferritin 1200 ng/mL exist in selected patients with low transferrin saturation 3
In NAFLD patients, elevated ferritin (>350 μg/L in males, >150 μg/L in females) associates with more advanced fibrosis, higher NAFLD activity scores, and significantly increased long-term mortality (HR 1.10 per year) 4
In myelodysplastic syndromes, ferritin >1000 ng/mL combined with transfusion dependence (≥2 units/month for >1 year) indicates need for chelation therapy in patients with life expectancy >1 year 3
Treatment Strategies
For Hereditary Hemochromatosis
Initiate therapeutic phlebotomy when ferritin reaches ≥300 μg/L in men or ≥200 μg/L in women, regardless of symptoms. 5
- Remove 1 unit (450-500 mL) of blood weekly until ferritin reaches 10-20 μg/L 5
- Maintain ferritin at ≤50 μg/L thereafter with periodic phlebotomy 5
- This prevents complications including cirrhosis, hepatocellular carcinoma, diabetes, hypogonadism, arthropathy, and cardiomyopathy when initiated before severe iron overload develops 5
For Transfusional Iron Overload
Begin iron chelation therapy when ferritin reaches 1000 ng/mL in transfusion-dependent patients requiring ≥2 units/month for >1 year, or when organ preservation is needed. 3
- Available chelators include deferoxamine, deferiprone, and deferasirox—choice depends on regional availability and physician discretion 3
- Monitor ferritin monthly during chelation to prevent overchelation 6
- Reduce deferasirox dose if ferritin falls below 1000 mcg/L on two consecutive visits, especially if dose >17.5 mg/kg/day 6
- Interrupt chelation if ferritin falls below 500 mcg/L and continue monthly monitoring 6
- Continue chelation as long as transfusion therapy continues and iron overload remains clinically relevant 3
For Patients Undergoing Stem Cell Transplantation
Consider chelation therapy pre-transplant in patients with ferritin >1000 ng/mL—elevated ferritin before conditioning associates with significantly worse overall survival (HR 2.5), progression-free survival (HR 2.4), and particularly infection-related mortality (HR 3.9) 7, 3
Post-transplant, prefer phlebotomy over chelation in patients with stable hemoglobin >1 year after transplant to avoid overlapping renal toxicity with immunosuppression 3
When Chelation is NOT Indicated
- Patients with life expectancy <1 year (iron complications take >1 year to manifest) 3
- Patients with platelet counts <50 × 10⁹/L (contraindication to deferasirox) 6
- When ferritin elevation is purely inflammatory without true iron overload 3
- Patients with volume depletion until rehydrated 6
Monitoring Requirements
- Assess serum ferritin every 3 months minimum in transfusion-dependent patients, monthly if possible 3
- Monitor renal function, hepatic function, and complete blood counts regularly during chelation therapy 6
- Perform auditory and ophthalmic testing before starting deferasirox and every 12 months thereafter 6
- In dialysis patients receiving IV iron with ferritin 500-1200 ng/mL and low transferrin saturation, closer monitoring is warranted given limited safety data 3