What is the appropriate management for a patient with elevated ferritin levels?

Management of Elevated Ferritin

Initial Diagnostic Approach

The first and most critical step is to measure fasting transferrin saturation (TS) alongside ferritin, as over 90% of elevated ferritin cases are NOT due to iron overload but rather inflammation, liver disease, malignancy, or metabolic conditions. 1, 2

Essential Initial Laboratory Tests

• Fasting transferrin saturation (TS) - the single most important test to distinguish true iron overload from secondary causes 1, 2
• Complete metabolic panel including ALT, AST to assess hepatocellular injury 1, 2
• Inflammatory markers (CRP, ESR) to detect occult inflammation 1, 2
• Complete blood count with differential to assess for anemia, polycythemia, or hematologic malignancy 2

Algorithmic Management Based on Transferrin Saturation

If TS ≥ 45% (Suggests Iron Overload)

Proceed immediately to HFE genotype testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis 1, 2

Risk Stratification by Ferritin Level:

Ferritin < 1000 μg/L:

• Low risk of advanced liver fibrosis (negative predictive value 94%) 1, 2
• If C282Y homozygote with normal liver enzymes, age <40 years, and no hepatomegaly: proceed directly to therapeutic phlebotomy without liver biopsy 1, 2
• Target ferritin: 50-100 μg/L 1, 2

Ferritin > 1000 μg/L:

• Critical threshold - 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 1, 2
• This combination predicts cirrhosis in 80% of C282Y homozygotes 2
• Mandatory referral to gastroenterologist or hepatologist 1

Ferritin > 10,000 μg/L:

• Rarely represents simple iron overload 1, 2
• Urgent specialist referral required to evaluate for life-threatening conditions including adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 1, 2

If TS < 45% (Secondary Causes Predominate)

Iron overload is unlikely - focus on identifying secondary causes: 1, 2

Most Common Causes (>90% of cases):

• Chronic alcohol consumption - increases iron absorption and causes hepatocellular injury 1, 3
• Inflammatory conditions - ferritin is an acute phase reactant 1, 2, 4
• Liver disease - alcoholic liver disease, viral hepatitis B/C, NAFLD/metabolic syndrome 1, 2, 3
• Malignancy - solid tumors, lymphomas, hepatocellular carcinoma 1, 3, 4, 5
• Cell necrosis - muscle injury, hepatocellular necrosis 1, 3
• Chronic kidney disease - especially with anemia 1, 2
• Metabolic syndrome/NAFLD - ferritin reflects hepatocellular injury and insulin resistance 1, 2

Specific Diagnostic Considerations:

If ferritin 4,000-10,000 μg/L with persistent fever:

• Consider adult-onset Still's disease 1, 2
• Measure glycosylated ferritin fraction - <20% is 93% specific for AOSD 1, 3

If ferritin >5,000 μg/L with cytopenias, fever, multiorgan dysfunction:

• Consider hemophagocytic lymphohistiocytosis/macrophage activation syndrome 2, 4

If elevated ferritin with low TS (<20%):

• Represents anemia of chronic inflammation where iron is sequestered in storage sites 2, 3
• Do NOT supplement iron - will not improve anemia and may worsen outcomes 2

Management Strategy

For Confirmed Hereditary Hemochromatosis:

Therapeutic Phlebotomy Protocol: 1, 2

• Remove 500 mL blood weekly or biweekly as tolerated
• Check hemoglobin/hematocrit before each procedure
• Allow hemoglobin to fall no more than 20% from baseline
• Check ferritin every 10-12 phlebotomies
• Target ferritin: 50-100 μg/L for induction phase endpoint

Maintenance Phase: 1, 2

• Continue phlebotomy every 2-4 months to maintain ferritin 50-100 μg/L
• Monitor ferritin monthly initially, then every 3 months once stable

Family Screening: 1, 2

• Screen ALL first-degree relatives with both HFE genotype testing and phenotype (ferritin and TS)

Critical Dietary Restrictions: 1, 2

• Avoid vitamin C supplements - accelerates iron mobilization and increases oxidative stress
• Avoid iron supplements entirely
• Avoid raw shellfish - risk of Vibrio vulnificus infection in iron-overloaded patients

For Secondary Causes:

Treat the underlying condition, NOT the elevated ferritin itself 1, 2

• NAFLD/metabolic syndrome: Weight loss, metabolic syndrome management 2
• Inflammatory conditions: Disease-specific anti-inflammatory therapy 2
• Malignancy: Oncologic treatment 2
• Chronic kidney disease with functional iron deficiency: Consider IV iron if ferritin 500-1200 μg/L with TS <25%, especially if receiving erythropoietin therapy 1, 2

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload - ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy independent of iron stores 1, 2, 3
• Do not assume iron overload when TS <45% - in the general population, iron overload is NOT the most common cause of elevated ferritin 1, 2, 6
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 1, 2
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1, 2
• Do not delay specialist referral when ferritin >1000 μg/L regardless of TS 1, 2

Special Population Considerations

Chronic Kidney Disease: 1, 2

• Elevated ferritin (500-1200 μg/L) with low TS (<25%) may represent functional iron deficiency that responds to IV iron therapy
• Withhold iron therapy when ferritin exceeds 1000 ng/mL or TS exceeds 50%

Inflammatory Bowel Disease: 2

• Ferritin <30 μg/L indicates iron deficiency
• Ferritin >100 μg/L with low TS suggests anemia of chronic disease

β-Thalassemia Major: 1

• Ferritin >2500 μg/L indicates increased risk of heart failure
• Risk increases even at levels >1000 μg/L