What is the management approach for elevated ferritin levels?

Management of Elevated Ferritin Levels

Measure transferrin saturation (TS) alongside ferritin immediately, as this combination distinguishes true iron overload from inflammatory causes and guides all subsequent management decisions. 1

Initial Diagnostic Workup

When ferritin is elevated, the following tests are essential:

• Obtain fasting transferrin saturation to differentiate iron overload (TS ≥45%) from inflammatory conditions (TS <45%) 1, 2
• Measure serum ferritin and TS together as recommended by the American Association for the Study of Liver Diseases, since ferritin alone is highly sensitive but poorly specific 2
• Check liver enzymes (ALT, AST) and bilirubin to assess for hepatocellular injury 1
• Obtain inflammatory markers (CRP, ESR) if TS <45% to evaluate for chronic inflammatory conditions 2

Diagnostic Algorithm Based on Transferrin Saturation

If TS ≥45% with Elevated Ferritin (Suggests Iron Overload)

• Proceed directly to HFE genotype testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis 1, 2
• This combination strongly suggests true iron overload disorders, particularly hemochromatosis 3
• Normal ferritin levels essentially rule out iron overload in hemochromatosis, making it an excellent negative predictor 2

If TS <45% with Elevated Ferritin (Suggests Secondary Causes)

• Consider inflammatory conditions including rheumatologic diseases, acute phase responses 1, 2
• Evaluate for liver disease: alcoholic liver disease, viral hepatitis, NAFLD 1, 2
• Assess for malignancy, which is the most frequent cause of markedly elevated ferritin in hospitalized patients 4
• Consider infection, which was the second most common cause in patients with ferritin >2000 ng/mL 5

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L

• Lower risk of organ damage, particularly advanced liver fibrosis 1
• In validation studies, no patient with ferritin <1000 μg/L had cirrhosis 1
• If TS ≥45% and C282Y homozygote confirmed, therapeutic phlebotomy can proceed without liver biopsy if age <40 years and transaminases are normal 2

Ferritin 1000-10,000 μg/L

• Critical threshold indicating 20-45% prevalence of cirrhosis in C282Y homozygotes 1, 2
• Strongly consider liver biopsy if accompanied by elevated liver enzymes or platelet count <200,000/μL to assess for cirrhosis 1, 2
• Liver biopsy has 100% sensitivity and 70% specificity for identifying cirrhosis at this threshold 1
• Refer to gastroenterologist, hematologist, or iron overload specialist for evaluation 2
• Assess for evidence of organ damage with cardiac evaluation (ECG/echocardiography) if severe iron overload suspected 2

Ferritin >10,000 μg/L

• Suggests life-threatening conditions requiring urgent specialist referral 2
• Consider adult-onset Still's disease (average ferritin 14,242 μg/L in these cases) 2, 4
• Evaluate for hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), which had the highest mean ferritin values among all diagnoses 5, 6
• A ferritin threshold of 9,083 μg/L showed 92.5% sensitivity and 91.9% specificity for HLH/MAS in critically ill patients 6

Management of Confirmed Hereditary Hemochromatosis

Initial Phlebotomy Protocol

• Therapeutic phlebotomy is the cornerstone of treatment for confirmed hemochromatosis 1, 3
• Weekly removal of 500 mL blood (containing approximately 200-250 mg iron) until target ferritin reached 1, 3
• Target ferritin level: 50-100 μg/L 1, 3
• Check hemoglobin/hematocrit before each procedure and ferritin every 10-12 phlebotomies 1

Maintenance Therapy

• Maintenance phlebotomy 3-4 times per year once target ferritin achieved to keep ferritin between 50-100 μg/L 1, 3
• Use the minimum effective dose to maintain iron burden in target range 1

Dietary Modifications

• Avoid vitamin C supplements and iron supplements in confirmed iron overload 1
• Take deferasirox (if used) on empty stomach or with light meal containing <7% fat content 7

Management of Secondary Iron Overload

Iron Chelation Therapy Indications

• Consider iron chelation when serum ferritin reaches 1,000 ng/mL or transfusion need is ≥2 units/month for >1 year 3
• Deferasirox therapy should only be considered with evidence of chronic transfusional iron overload: at least 100 mL/kg packed RBCs transfused AND serum ferritin consistently >1000 mcg/L 7
• Starting dose of deferasirox: 14 mg/kg body weight orally once daily for patients ≥2 years with eGFR >60 mL/min/1.73 m² 7
• Maximum dose: 28 mg/kg/day; doses above this are not recommended 7

Monitoring During Chelation

• Monitor serum ferritin monthly and adjust dose every 3-6 months based on trends 7
• If ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if dose >17.5 mg/kg/day 7
• If ferritin falls below 500 mcg/L, interrupt deferasirox therapy and continue monthly monitoring 7

Special Population: Chronic Kidney Disease

• For dialysis patients with ferritin 500-1200 ng/mL but TS <25%, intravenous iron may still be beneficial, especially if receiving erythropoietin therapy 2, 3
• This represents functional iron deficiency despite elevated ferritin 3
• Withhold iron therapy when ferritin exceeds 1000 ng/mL or TS exceeds 50% 2, 3

Family Screening

• Screen all first-degree relatives with serum ferritin, transferrin saturation, and HFE genetic testing if proband has confirmed hemochromatosis 1, 3
• Siblings have a 25% chance of being affected if the proband has hereditary hemochromatosis 3
• Penetrance is higher in family members than the general population 2

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload 2
• Do not overlook the need for liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 2
• Interrupt deferasirox in pediatric patients with acute illnesses causing volume depletion (vomiting, diarrhea, decreased oral intake) 7
• Do not continue deferasirox at 14-28 mg/kg/day range when body iron burden is approaching normal range, as this can result in life-threatening adverse events 7
• Failing to screen first-degree relatives of patients with HFE-related hemochromatosis 1
• Do not delay treatment while awaiting cardiac MRI in patients with severe hemochromatosis and signs of heart disease 2

Monitoring During Treatment

• Monitor ferritin monthly during active treatment 1, 3
• Check blood counts, liver function, and renal function monthly during chelation therapy 7
• Perform auditory and ophthalmic testing before starting deferasirox and every 12 months thereafter 7
• Evaluate the need for ongoing chelation for patients whose conditions no longer require regular blood transfusions 7