What are the possible causes of an elevated ferritin level?

Causes of Elevated Ferritin

Elevated ferritin is most commonly caused by inflammation, chronic liver disease, malignancy, and infection—not iron overload—accounting for over 90% of cases in clinical practice. 1

Primary Diagnostic Framework

Ferritin functions as an acute-phase reactant, tumor marker, and indicator of cellular damage, rising during inflammation, infection, and tissue injury completely independent of actual iron stores. 1, 2 This means that an elevated ferritin level requires systematic evaluation to distinguish true iron overload from the far more common secondary causes.

The Single Most Important Test: Transferrin Saturation

Measure transferrin saturation (TS) simultaneously with every ferritin level—this is the only way to determine if iron overload is present. 1, 3, 2 The algorithm is straightforward:

• If TS ≥45%: Suspect primary iron overload and proceed immediately to HFE genetic testing for C282Y and H63D mutations 1, 3, 2
• **If TS <45%**: Iron overload is excluded with >90% certainty; focus entirely on secondary causes 1, 3

Complete List of Causes by Category

Iron Overload Disorders (Only when TS ≥45%)

• Hereditary hemochromatosis (HFE-related): C282Y homozygosity or C282Y/H63D compound heterozygosity, most common in non-Hispanic white individuals (0.44% prevalence) 1, 2
• Non-HFE hemochromatosis: Mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 2

Liver Disease (Most common when TS <45%)

• Chronic alcohol consumption: Increases iron absorption and causes direct hepatocellular injury 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome: Ferritin reflects hepatocellular injury and insulin resistance, not iron overload 1, 2, 4
• Viral hepatitis (B and C): Approximately 50% of patients have abnormal iron studies 1, 3
• Acute hepatitis: Causes ferritin release from damaged hepatocytes 1

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease (AOSD): Extreme hyperferritinemia (4,000–30,000 ng/mL, occasionally up to 250,000 ng/mL); glycosylated ferritin fraction <20% is 93% specific 1, 2, 5
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Ferritin typically >5,000–10,000 ng/mL with cytopenias, fever, and multiorgan dysfunction 1, 6
• Chronic rheumatologic diseases: Rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus 1, 2
• Systemic inflammatory response syndrome: Any severe acute inflammation 1

Malignancy

• Solid tumors: Most frequent cause in one large series (153/627 patients with ferritin >1,000 μg/L) 7
• Lymphomas: Ferritin acts as a tumor marker 1, 7
• Hepatocellular carcinoma: Associated with very high ferritin levels 1

Infection

• Acute and chronic infections: Ferritin rises as part of the acute-phase response; second most common cause of ferritin >2,000 ng/mL in hospitalized patients (96/333 cases) 1, 6
• Respiratory infections and malaria: Can drive hepcidin blockade of iron absorption in children 8

Cellular Damage and Necrosis

• Hepatocellular necrosis: Most prevalent diagnosis in hospitalized patients with ferritin >2,000 ng/mL (126/333 cases) 1, 6
• Muscle injury: Rhabdomyolysis or severe trauma 1, 2
• Tissue breakdown: Any cause of massive cell lysis 1, 2

Metabolic and Renal Conditions

• Metabolic syndrome: Strongly associated with NAFLD-related ferritin elevation 1, 2
• Chronic kidney disease: Especially in dialysis patients; ferritin 500–1,200 ng/mL with TS <25% may represent functional iron deficiency despite elevated ferritin 1, 2
• Diabetes mellitus: Part of metabolic syndrome spectrum 1

Risk Stratification by Ferritin Level

Understanding the ferritin level helps prioritize the differential diagnosis:

• <1,000 μg/L: Low risk of organ damage; 94% negative predictive value for advanced fibrosis in hemochromatosis 1, 2
• 1,000–10,000 μg/L: In confirmed iron overload (TS ≥45%), 20–45% prevalence of cirrhosis in C282Y homozygotes; in secondary causes, suggests severe inflammation or malignancy 1, 2
• >10,000 μg/L: Rarely represents simple iron overload; strongly suggests life-threatening conditions such as HLH/MAS, AOSD, or severe hepatocellular injury requiring urgent specialist referral 1, 2, 7, 6

Critical Pitfalls to Avoid

Never diagnose iron overload based on ferritin alone without confirming TS ≥45%—this is the most common error in clinical practice. 1, 3, 2 Ferritin is an acute-phase reactant that rises in inflammation, liver disease, malignancy, and tissue necrosis completely independent of iron stores. 8, 1, 2

Do not assume that elevated ferritin means the patient needs iron restriction or phlebotomy—over 90% of elevated ferritin cases are due to secondary causes where iron depletion would be harmful. 1, 2

Recognize that extremely high ferritin (>5,000 ng/mL) in the setting of fever, cytopenias, and multiorgan dysfunction is a medical emergency—consider HLH/MAS or AOSD and refer urgently. 1, 2, 6, 5