What causes elevated ferritin levels?

What Can Cause Elevated Ferritin

Elevated ferritin is most commonly caused by non-iron overload conditions—specifically chronic alcohol consumption, inflammation, metabolic syndrome/NAFLD, cell necrosis, and malignancy—which account for over 90% of cases in outpatients. 1, 2, 3

Understanding Ferritin as a Biomarker

Ferritin is not simply a marker of iron stores but functions as an acute phase reactant, tumor marker, and indicator of cellular damage. 4 This means ferritin rises during inflammation, infection, and tissue injury independent of actual iron levels. 1, 2

Primary Categories of Elevated Ferritin

Iron Overload Disorders (Minority of Cases)

• Hereditary hemochromatosis (HFE-related): C282Y homozygosity or C282Y/H63D compound heterozygosity 4, 1, 2
• Non-HFE hemochromatosis: Mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 2
• Secondary iron overload: Thalassemia syndromes, myelodysplastic syndrome, multiple blood transfusions, sideroblastic anemias 5, 6

Liver Disease (Very Common)

• Chronic alcohol consumption: Increases iron absorption and causes hepatocellular injury 4, 2, 3
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome: Ferritin reflects hepatocellular injury and insulin resistance rather than true iron overload 1, 7
• Viral hepatitis (B and C) 2
• Acute hepatitis and cirrhosis 4, 2

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease: Characterized by extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 2, 6
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Average ferritin ~14,242 μg/L 8
• Systemic inflammatory response syndrome 2
• Chronic rheumatologic diseases 4
• Active infections: Ferritin rises acutely as part of the acute phase response 1, 2

Malignancy

• Solid tumors 2, 8
• Lymphomas 2
• Hepatocellular carcinoma 1
• Malignancy was the most frequent cause in one large study of ferritin >1000 μg/L (153/627 cases) 8

Metabolic and Endocrine Conditions

• Metabolic syndrome/obesity/diabetes: Part of the inflammatory milieu 2, 3
• Chronic kidney disease: Can present with elevated ferritin despite functional iron deficiency 1, 2

Cellular Damage

• Cell necrosis: From muscle injury, hepatocellular necrosis, or tissue breakdown 4, 2
• Ferritin is released from necrotic or lysed cells 4

Critical Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Simultaneously

• If TS ≥45% with elevated ferritin: Suspect iron overload disorders; proceed to HFE genetic testing for C282Y and H63D mutations 1, 2, 7
• If TS <45% with elevated ferritin: Iron overload is unlikely; secondary causes predominate 1, 2, 7

Critical pitfall: Never use ferritin alone without transferrin saturation to diagnose iron overload. 1, 2, 7

Step 2: Risk Stratification by Ferritin Level

• Ferritin <1000 μg/L: Low risk of organ damage; negative predictive value of 94% for advanced liver fibrosis in hemochromatosis 1, 2
• Ferritin 1000-10,000 μg/L: Higher risk of cirrhosis if iron overload present (20-45% prevalence in C282Y homozygotes); consider liver biopsy if accompanied by elevated liver enzymes or platelets <200,000/μL 1, 9
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; suggests life-threatening conditions requiring urgent specialist referral (malignancy, Still's disease, hemophagocytic lymphohistiocytosis) 1, 2, 6

Step 3: Evaluate for Common Secondary Causes

• Check inflammatory markers: CRP, ESR to detect occult inflammation 1
• Assess liver enzymes: ALT, AST to evaluate hepatocellular injury 1, 2
• Screen for metabolic syndrome: Obesity, diabetes, hypertension, dyslipidemia 2, 3
• Evaluate for malignancy: Age-appropriate cancer screening, imaging if clinically indicated 8, 5
• Assess alcohol consumption: Detailed history 4, 3
• Rule out active infection: Clinical evaluation and appropriate cultures 1, 2

Special Clinical Contexts

Chronic Kidney Disease

• Elevated ferritin (500-1200 μg/L) with low transferrin saturation (<25%) may represent functional iron deficiency that still warrants IV iron therapy for anemia management 1, 2
• Distinguish functional iron deficiency from inflammatory iron block 1, 2

NAFLD Patients

• Elevated ferritin typically reflects hepatocellular injury and insulin resistance, not iron accumulation 7
• Do not automatically pursue iron overload evaluation unless TS is also elevated (>45%) 7
• Treatment should target underlying NAFLD (weight loss, lifestyle modifications) rather than the ferritin itself 7

When to Refer to Specialist

• Ferritin >1000 μg/L regardless of transferrin saturation: Refer to gastroenterologist, hematologist, or iron overload specialist 1, 3
• Ferritin >10,000 μg/L: Urgent specialist referral for life-threatening conditions 1, 2
• Evidence of organ damage: Cardiac evaluation if severe iron overload suspected 1
• Unclear etiology after initial workup 3