What are the causes of an elevated ferritin level?

Causes of Elevated Ferritin

Elevated ferritin is most commonly caused by inflammation, chronic liver disease, malignancy, and infection—accounting for over 90% of cases—rather than true iron overload. 1, 2

Primary Categories of Elevated Ferritin

Iron Overload Disorders (Rare)

• Hereditary hemochromatosis (HFE-related) is characterized by C282Y homozygosity or C282Y/H63D compound heterozygosity, occurring in approximately 3–5 per 1,000 individuals in the general population, with highest prevalence (0.44%) among non-Hispanic white persons 1, 2
• Non-HFE hemochromatosis results from mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 2

Liver Disease (Very Common)

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury, leading to ferritin elevation 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation reflecting hepatocellular injury and insulin resistance rather than true iron overload 1, 2
• Viral hepatitis (B and C) causes abnormal serum iron studies in approximately 50% of patients 3, 2
• Acute hepatitis and cirrhosis release ferritin from damaged hepatocytes 2

Inflammatory and Rheumatologic Conditions

• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute-phase reactant 2, 4
• Adult-onset Still's disease produces extreme hyperferritinemia (4,000–30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% (93% specific for AOSD when combined with 5-fold ferritin elevation) 3, 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome causes ferritin >5,000 ng/mL with cytopenias, fever, and multiorgan dysfunction 3
• Systemic inflammatory response syndrome elevates ferritin as part of the acute-phase response 2

Malignancy

• Solid tumors, lymphomas, and hepatocellular carcinoma were the most frequent cause of markedly elevated ferritin (>1,000 μg/L) in one large academic center study, accounting for 153 of 627 cases 2, 5
• Acute myeloid leukemia is associated with increased ferritin levels both at diagnosis and during treatment, with high levels predicting decreased long-term survival 6

Cellular Damage and Necrosis

• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown releases ferritin from lysed cells independent of iron stores 2
• Tissue injury and inflammation cause ferritin to rise as both an acute-phase reactant and through direct cellular release 1, 7

Infection

• Active infection causes ferritin to rise acutely as part of the inflammatory response; this association is bidirectional—infection causes elevated ferritin, not vice versa 3
• Severe SARS-CoV-2 infection produces extremely elevated ferritin and IL-6 levels in individuals with high mortality 8

Metabolic and Endocrine

• Diabetes mellitus and metabolic syndrome are associated with ferritin elevation reflecting insulin resistance and hepatic inflammation 2

Chronic Kidney Disease

• CKD patients on erythropoiesis-stimulating agents may have ferritin 500–1,200 ng/mL with transferrin saturation <25%, representing functional iron deficiency despite elevated ferritin 3, 1

Critical Diagnostic Principle

Ferritin functions as an acute-phase reactant, tumor marker, and indicator of cellular damage, rising during inflammation, infection, and tissue injury independent of actual iron levels. 1, 2, 7 This means ferritin has high sensitivity but poor specificity for iron overload—it can be elevated in many inflammatory conditions without any true iron excess 2, 7

Risk Stratification by Ferritin Level

• Ferritin <1,000 μg/L indicates low risk of organ damage, with a 94% negative predictive value for advanced liver fibrosis in hemochromatosis 3, 1
• Ferritin 1,000–10,000 μg/L suggests higher risk of advanced fibrosis/cirrhosis if iron overload is present; in C282Y homozygotes, the combination of ferritin >1,000 μg/L, elevated aminotransferases, and platelet count <200,000/μL predicts cirrhosis in ~80% of cases 3, 1
• Ferritin >10,000 μg/L rarely represents simple iron overload and mandates urgent specialist referral to evaluate for life-threatening conditions such as hemophagocytic lymphohistiocytosis, adult-onset Still's disease, or severe infection 3, 1

Essential Diagnostic Algorithm

Never interpret ferritin alone—always measure transferrin saturation (TS) simultaneously to distinguish true iron overload from secondary causes. 3, 1, 2

• If TS ≥45% with elevated ferritin, suspect primary iron overload and proceed immediately to HFE genetic testing for C282Y and H63D mutations 3, 1, 2
• **If TS <45%** with elevated ferritin, iron overload is excluded with >90% certainty; evaluate secondary causes including inflammation (check CRP, ESR), liver disease (check ALT, AST, consider ultrasound), malignancy, infection, and metabolic syndrome 3, 1, 2

Common Pitfalls to Avoid

• Do not diagnose iron overload based solely on elevated ferritin without confirming TS ≥45%, as over 90% of elevated ferritin cases are not due to iron overload 1, 2
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests, as this combination warrants histologic assessment for cirrhosis 3, 2
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin under these circumstances 1, 2