How should I evaluate and manage a patient with high ferritin levels?

Evaluation and Management of High Ferritin

When you encounter elevated ferritin, immediately measure transferrin saturation (TS) to determine whether this represents true iron overload (TS ≥45%) or secondary hyperferritinemia (TS <45%), because over 90% of elevated ferritin cases are NOT due to iron overload but rather inflammation, liver disease, metabolic syndrome, malignancy, or tissue injury. 1, 2

Initial Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Simultaneously

Never interpret ferritin alone—always check fasting transferrin saturation at the same time. 1, 2, 3

• If TS ≥45%: Suspect primary iron overload and proceed directly to HFE genetic testing for C282Y and H63D mutations 1, 2
• If TS <45%: Iron overload is extremely unlikely; focus on identifying secondary causes 1, 2, 3

This single test determines your entire diagnostic pathway because ferritin is an acute-phase reactant that rises with inflammation, infection, liver disease, malignancy, and tissue necrosis independent of actual iron stores. 1, 4, 5

Step 2: When TS <45% (Secondary Hyperferritinemia)

Systematically evaluate the most common causes, which account for >90% of cases: 1

Liver Disease Assessment

• Check ALT, AST, GGT, and albumin to assess hepatocellular injury 1, 2
• Order abdominal ultrasound to evaluate for fatty liver, chronic liver disease, or hepatomegaly 1
• NAFLD/metabolic syndrome is the most common cause in outpatients, where ferritin reflects hepatocellular injury and insulin resistance rather than iron overload 1, 2
• Assess for chronic alcohol consumption (increases iron absorption and causes hepatocellular injury) 1
• Screen for viral hepatitis B and C 1

Inflammatory/Infectious Causes

• Measure CRP and ESR to detect occult inflammation 1, 2
• Evaluate for active infection, as ferritin rises acutely during the inflammatory response 1
• Check CBC with differential to assess for hematologic malignancy or cytopenias 1, 2

Metabolic Syndrome Components

• Assess BMI, fasting glucose or HbA1c, lipid panel, and blood pressure 2
• Calculate HOMA-IR if insulin resistance is suspected 2

Malignancy Screening

• Evaluate for solid tumors, lymphomas, or hepatocellular carcinoma based on clinical context 1, 6, 4
• Consider CT imaging if B symptoms or lymphadenopathy present 1

Tissue Necrosis

• Check creatine kinase (CK) to evaluate for muscle injury or rhabdomyolysis 1, 2
• Consider myoglobin if exercise-induced muscle damage suspected 2

Step 3: When TS ≥45% (Suspect Primary Iron Overload)

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

• C282Y homozygosity confirms HFE-related hereditary hemochromatosis 1, 2
• C282Y/H63D compound heterozygosity also confirms HFE hemochromatosis 1, 2
• C282Y heterozygosity alone does NOT cause clinically significant iron overload without a second cofactor (alcohol, NAFLD, hepatitis C) 2

If genetic testing is negative but TS remains ≥45%, consider non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) and refer to hepatology. 1

Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L

• Low risk of organ damage with 94% negative predictive value for advanced liver fibrosis 1, 2
• In confirmed C282Y homozygotes with TS ≥45%, can initiate therapeutic phlebotomy without liver biopsy if age <40, normal liver enzymes, and no hepatomegaly 1

Ferritin 1,000–10,000 μg/L

• Higher risk of advanced fibrosis/cirrhosis if true iron overload present 1
• Consider liver biopsy or MRI if ferritin >1,000 μg/L with elevated liver enzymes, platelet count <200,000/μL, age >40, or hepatomegaly 1, 2
• The combination of ferritin >1,000 μg/L, elevated aminotransferases, and platelets <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes 1

Ferritin >10,000 μg/L

• Rarely represents simple iron overload—urgent specialist referral required 1
• Evaluate for life-threatening conditions: 6, 4
  • Adult-onset Still's disease (measure glycosylated ferritin; <20% is 93% specific for AOSD) 1, 2
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (look for persistent fever, cytopenias, splenomegaly, elevated triglycerides) 1, 2
  • Severe hepatocellular injury 4
  • Overwhelming infection or sepsis 4

Critical Pitfalls to Avoid

1. Never diagnose iron overload based on ferritin alone without confirming TS ≥45% 1, 2, 3

2. Do not initiate phlebotomy when TS <45%—the ferritin elevation is not from iron overload 2, 3

3. Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests, as this combination significantly increases cirrhosis risk 1

4. Do not assume C282Y heterozygosity alone causes iron overload—a second cofactor is required 2

5. Recognize that extremely high ferritin (>10,000 μg/L) almost never represents simple iron overload and demands urgent evaluation for inflammatory/rheumatologic emergencies 1, 6, 4

6. Do not order HFE genetic testing when TS <45%—it will not change management and wastes resources 2, 3

Management Strategy

For Secondary Hyperferritinemia (TS <45%)

Treat the underlying condition, not the elevated ferritin: 1, 2

• NAFLD/metabolic syndrome: Weight loss, exercise, glycemic control, lipid management 1, 2
• Inflammatory conditions: Disease-specific anti-inflammatory therapy 1
• Infection: Appropriate antimicrobial treatment 1
• Malignancy: Oncologic treatment 1
• Alcohol-related: Abstinence and hepatology referral 1

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

• Initiate therapeutic phlebotomy to target ferritin <50 μg/L and maintain TS <50% 1
• Screen first-degree relatives with ferritin and TS, followed by genetic testing if abnormal 1
• Monitor ferritin every 3 months during induction phlebotomy, then annually once target achieved 1

When to Refer to Hepatology

• Ferritin >1,000 μg/L with abnormal liver tests 1, 2
• TS ≥45% with negative C282Y/H63D testing (possible non-HFE hemochromatosis) 1
• Evidence of cirrhosis or advanced fibrosis 1
• Ferritin continues rising despite treatment of secondary causes 1

Special Populations

Chronic Kidney Disease

• Functional iron deficiency can occur with ferritin 100–700 ng/mL and TS <20% in patients on erythropoiesis-stimulating agents 1, 5
• Consider trial of IV iron (50–125 mg weekly for 8–10 doses) to distinguish functional deficiency from pure inflammatory block 1

Inflammatory Bowel Disease

• Ferritin <30 μg/L indicates true iron deficiency 1
• Ferritin >100 μg/L with low TS suggests anemia of chronic disease 1
• Consider IV iron when ferritin drops below 100 μg/L in known IBD patients 1