What is the approach to investigating and managing elevated ferritin levels?

Investigating High Ferritin

Initial Laboratory Evaluation

Always measure both serum ferritin and transferrin saturation (TS) simultaneously—using ferritin alone is a critical diagnostic error. 1, 2

Obtain the following tests at initial evaluation:

• Fasting transferrin saturation (most critical for determining iron overload vs. secondary causes) 2
• Complete blood count with differential 2
• Liver enzymes (ALT, AST) and bilirubin 1, 2
• Inflammatory markers (CRP, ESR) 1
• Serum creatinine and electrolytes 3

Diagnostic Algorithm Based on Transferrin Saturation

If TS ≥ 45%: Suspect Primary Iron Overload

• Proceed directly to HFE genetic testing for C282Y and H63D mutations 1, 2
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis 2
• If HFE testing is negative but iron overload suspected, consider non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) 2

If TS < 45%: Secondary Causes Are Most Likely

Over 90% of elevated ferritin cases are due to non-iron overload conditions 2, 4, including:

• Chronic alcohol consumption (most common) 2
• Metabolic syndrome/NAFLD 1, 2
• Inflammatory conditions (rheumatologic diseases, infections) 1, 2
• Liver disease (viral hepatitis B/C, acute hepatitis) 2
• Malignancy (solid tumors, lymphomas, hepatocellular carcinoma) 2, 5
• Cell necrosis (muscle, liver damage) 2

Risk Stratification by Ferritin Level

Ferritin < 1000 μg/L

• Low risk of organ damage (94% negative predictive value for advanced liver fibrosis) 1, 2
• If C282Y homozygote with elevated TS, initiate therapeutic phlebotomy targeting ferritin < 50 μg/L 1
• If secondary causes identified, treat the underlying condition rather than the ferritin 1

Ferritin 1000-10,000 μg/L

• Critical threshold requiring specialist evaluation 1, 4
• Refer to gastroenterologist, hematologist, or iron overload specialist 1
• Obtain platelet count: if < 200,000/μL with elevated liver enzymes, 80% risk of cirrhosis in C282Y homozygotes 1, 2
• Consider liver biopsy or non-invasive fibrosis assessment (MRI for hepatic iron concentration) 1, 2
• Assess for organ damage with ECG/echocardiography if severe iron overload suspected 1

Ferritin > 10,000 μg/L

• Urgent specialist referral required—rarely represents simple iron overload 1, 2
• Consider life-threatening conditions:
  • Adult-onset Still's disease (average ferritin 14,242 μg/L) 5
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 1, 5
  • Severe infection or malignancy 5

Special Clinical Contexts

Chronic Kidney Disease with Anemia

• Elevated ferritin (500-1200 μg/L) with low TS (< 25%) may still warrant IV iron therapy 6, 1
• In the DRIVE study, patients with ferritin 500-1200 μg/L and TS < 25% showed significant hemoglobin improvement with IV iron (16 g/L vs 11 g/L, P=0.028) 6
• Caution: Ferritin > 7500 ng/mL with TS > 88% indicates risk of liver cell damage 1

Inflammatory Conditions

• Ferritin rises as an acute phase reactant—interpret in clinical context 2, 7
• In inflammatory bowel disease: ferritin > 100 μg/L with low TS suggests anemia of chronic disease 2
• Active infection causes ferritin elevation; treat the infection, not the ferritin 2

Management Based on Etiology

Hereditary Hemochromatosis (Confirmed)

• Initiate therapeutic phlebotomy targeting ferritin < 50 μg/L 1
• If ferritin > 1000 μg/L with elevated liver enzymes and platelets < 200,000/μL, evaluate for cirrhosis 1
• Screen first-degree relatives 2

Secondary Causes

• Treat the underlying condition, not the elevated ferritin 1
• Avoid iron supplementation 1
• Monitor ferritin based on the underlying disease activity 1

Iron Chelation Therapy (When Indicated)

• Consider deferasirox only when ferritin consistently > 1000 μg/L with documented transfusional iron overload 3
• Starting dose: 14 mg/kg/day for patients with eGFR > 60 mL/min/1.73 m² 3
• Critical warning: Interrupt therapy if ferritin falls < 500 μg/L to avoid overchelation 3

Critical Pitfalls to Avoid

• Never diagnose iron overload using ferritin alone without measuring transferrin saturation 1, 2
• Do not overlook liver biopsy in patients with ferritin > 1000 μg/L and abnormal liver tests 1, 2
• Do not assume iron overload when TS < 45%—secondary causes are far more likely 2
• Do not delay specialist referral when ferritin > 1000 μg/L regardless of TS 1
• In pediatric patients or elderly, interrupt therapy during volume depletion (vomiting, diarrhea) and monitor more frequently 3