What are the next steps for a patient with significantly elevated ferritin (iron storage protein) levels?

Management of Ferritin Level 669 ng/mL

A ferritin of 669 ng/mL is moderately elevated but does not indicate iron overload in most cases—you must immediately check a fasting transferrin saturation to determine if this represents true iron overload or a secondary cause such as inflammation, liver disease, alcohol use, or metabolic syndrome. 1, 2

Immediate Next Step

Measure transferrin saturation (TS) simultaneously with repeat ferritin to distinguish between iron overload and secondary hyperferritinemia. 1, 2

• If TS ≥45%: Proceed with iron overload evaluation (see below) 1, 2
• If TS <45%: Iron overload is unlikely; focus on identifying secondary causes 2

Understanding This Ferritin Level

This ferritin level (669 ng/mL) falls well below the threshold for organ damage risk (>1000 ng/mL for liver fibrosis, >7500 ng/mL for documented organ damage). 2

• Over 90% of elevated ferritin cases are caused by non-iron overload conditions including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD—not hereditary hemochromatosis 2, 3
• Ferritin is an acute phase reactant that rises with inflammation, infection, and liver disease independent of actual iron stores 1, 2

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45% (Suggests Possible Iron Overload):

Order HFE genetic testing for C282Y and H63D mutations 1, 2

• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis 1, 2
• If genetic testing is negative but TS remains elevated, consider non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1, 2
• At this ferritin level (<1000 ng/mL), liver biopsy is NOT recommended even if hemochromatosis is confirmed, as the negative predictive value for cirrhosis is 94% 1, 2
• Consider liver MRI with R2* quantification to assess hepatic iron concentration if diagnosis remains unclear 1

If TS <45% (Secondary Hyperferritinemia—Most Likely):

Systematically evaluate for common secondary causes: 2, 3

1. Alcohol consumption: Obtain detailed alcohol history; even moderate consumption elevates ferritin and TS 1, 2

2. Metabolic syndrome/NAFLD: Check BMI, waist circumference, fasting glucose, lipid panel, blood pressure 1, 2

3. Liver disease: Measure ALT, AST, bilirubin, alkaline phosphatase; screen for viral hepatitis B and C 1, 2

4. Inflammation/infection: Check CRP, ESR; evaluate for active infection or inflammatory conditions 2, 4

5. Malignancy: Age-appropriate cancer screening; consider CT imaging if constitutional symptoms present 2, 4

6. Cell necrosis: Check CK for muscle injury; review recent trauma or rhabdomyolysis 2

Management Strategy

For Confirmed Iron Overload (TS ≥45% + Genetic Confirmation):

Initiate therapeutic phlebotomy even at this ferritin level if patient is C282Y homozygote with elevated TS 1, 2

• Target ferritin 50-100 ng/mL to prevent organ damage 1
• Weekly phlebotomy of 500 mL until target reached, then maintenance every 2-4 months 1
• Screen first-degree relatives with HFE genetic testing 2

For Secondary Hyperferritinemia (TS <45%):

Treat the underlying condition, not the elevated ferritin: 2

• NAFLD/metabolic syndrome: Weight loss through dietary modification and increased physical activity 1, 2
• Alcohol-related: Alcohol cessation counseling 1, 2
• Inflammatory conditions: Disease-specific anti-inflammatory therapy 2
• Malignancy: Oncologic treatment 2

Do NOT perform phlebotomy for secondary hyperferritinemia—there is no conclusive evidence supporting iron depletion in these patients 1

Monitoring Recommendations

• Recheck ferritin and TS in 3 months if initial workup is unrevealing 1, 2
• If ferritin continues to rise or exceeds 1000 ng/mL, refer to gastroenterology or hematology 3
• Monitor liver enzymes and platelet count if ferritin approaches 1000 ng/mL 1, 2

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload—this is the most common diagnostic error 2
• Do not assume iron overload when TS <45%—secondary causes are far more likely 1, 2
• Do not perform liver biopsy at this ferritin level (<1000 ng/mL) unless liver enzymes are significantly elevated 1
• Do not overlook alcohol consumption—patients often underreport intake, and alcohol is a major cause of elevated ferritin with elevated TS 1, 2
• Recognize that extremely high ferritin (>10,000 ng/mL) rarely represents simple iron overload—this would warrant urgent evaluation for hemophagocytic lymphohistiocytosis, severe infection, or malignancy 2, 4, 5