What are the causes of elevated ferritin levels?

Causes of Elevated Ferritin

Primary Diagnostic Framework

Elevated ferritin has over 90% likelihood of being caused by non-iron overload conditions including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD—not hereditary hemochromatosis. 1

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 This means that serum ferritin has high sensitivity but low specificity for iron overload, as it can be elevated in many inflammatory conditions. 1

Major Categories of Elevated Ferritin

Iron Overload Disorders (Primary Causes)

• Hereditary hemochromatosis (HFE-related) is characterized by C282Y homozygosity or C282Y/H63D compound heterozygosity. 1, 2
• Non-HFE hemochromatosis involves mutations in TFR2, SLC40A1, HAMP, or HJV genes. 1, 2
• Transfusional iron overload occurs in patients with serum ferritin levels exceeding 7,500 ng/mL. 2

Liver Disease (Most Common Secondary Cause)

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury, representing one of the most frequent causes of hyperferritinemia. 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation that reflects hepatocellular injury and insulin resistance rather than iron overload. 1, 2
• Viral hepatitis (B and C) is a common cause of hyperferritinemia. 1, 2
• Acute hepatitis and cirrhosis are associated with elevated ferritin levels. 1

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease (AOSD) is characterized by extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20%. 1
• Hemophagocytic lymphohistiocytosis and macrophage activation syndrome cause extremely elevated ferritin levels. 1
• Systemic inflammatory response syndrome is a cause of hyperferritinemia. 1
• Chronic rheumatologic diseases are associated with elevated ferritin levels. 1

Malignancy

• Solid tumors are a frequent cause of hyperferritinemia, representing the most common condition in one large series (153/627 patients). 1, 3
• Lymphomas are associated with elevated ferritin. 1
• Hepatocellular carcinoma is a potential cause of elevated ferritin. 1

Cellular Damage and Necrosis

• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown causes ferritin release from necrotic or lysed cells. 1

Other Conditions

• Infections cause ferritin to rise acutely as part of the inflammatory response—the association is bidirectional: infection causes elevated ferritin, not vice versa. 1, 2
• Chronic kidney disease is associated with elevated ferritin. 1
• Diabetes mellitus and metabolic syndrome contribute to hyperferritinemia. 1

Critical Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Simultaneously

Never use ferritin alone without transferrin saturation to diagnose iron overload. 1 The American Association for the Study of Liver Diseases recommends measuring both serum ferritin and transferrin saturation together to prevent diagnostic errors. 1, 4

• If TS ≥45%: Suspect primary iron overload and proceed with HFE genetic testing for C282Y and H63D mutations. 1, 4
• If TS <45%: Iron overload is unlikely and secondary causes predominate—evaluate for inflammation, liver disease, malignancy, and other non-iron overload conditions. 1

Step 2: Rule Out Common Secondary Causes

• Check inflammatory markers (CRP, ESR) to detect occult inflammation. 4
• Assess liver enzymes (ALT, AST) and complete metabolic panel to evaluate for hepatocellular injury. 1, 4
• Obtain detailed alcohol consumption history. 1
• Evaluate for metabolic syndrome, obesity, and diabetes. 1
• Consider malignancy screening based on clinical context. 3
• Assess for active infection. 1

Step 3: Risk Stratification by Ferritin Level

• Ferritin <1,000 μg/L: Low risk of organ damage with negative predictive value of 94% for advanced liver fibrosis in hemochromatosis. 1
• Ferritin 1,000-10,000 μg/L: Higher risk of advanced fibrosis/cirrhosis if iron overload is present; consider liver biopsy if accompanied by elevated liver enzymes or platelet count <200,000/μL. 1, 4
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; suggests adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome requiring urgent specialist referral. 1, 4

Important Clinical Pearls

• In the general population, iron overload is NOT the most common cause of elevated ferritin. 1
• Glycosylated ferritin ≤20% has 93% specificity for adult-onset Still's disease when combined with 5-fold ferritin elevation. 1
• In chronic kidney disease, elevated ferritin (500-1200 μg/L) with low transferrin saturation (<25%) may represent functional iron deficiency that responds to IV iron therapy. 1, 4
• The combination of ferritin >1,000 μg/L, elevated aminotransferases, and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes. 1

Critical Pitfalls to Avoid

• Do not assume iron overload when TS <45%—in this scenario, secondary causes are far more likely. 1
• 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. 1, 4
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed. 1
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload and requires evaluation for life-threatening inflammatory conditions. 1, 4