What are the causes of elevated ferritin levels?

Causes of Elevated Ferritin

Elevated ferritin is most commonly caused by inflammation, chronic liver disease (including alcoholic and non-alcoholic fatty liver disease), metabolic syndrome, malignancy, and infection—accounting for over 90% of cases—rather than true iron overload. 1, 2

Primary Iron Overload Causes

Hereditary Hemochromatosis (HFE-related)

• C282Y homozygosity is the most common genetic cause, present in >80% of patients with clinically overt hemochromatosis 3
• C282Y/H63D compound heterozygosity can also cause iron overload, though less commonly 1, 2
• These patients typically present with elevated transferrin saturation (>45% in women, >50% in men) along with elevated ferritin 3

Non-HFE Hemochromatosis

• Mutations in TFR2, SLC40A1 (ferroportin disease), HAMP, or HJV genes cause rarer forms of hereditary iron overload 1, 2
• Ferroportin disease characteristically shows increased spleen iron overload on MRI, unlike HFE hemochromatosis 3

Transfusional Iron Overload

• Occurs in patients requiring chronic transfusions (thalassemia, myelodysplastic syndromes, sickle cell disease) 1, 4
• Ferritin levels can exceed 7,500 ng/mL with associated organ damage 1, 5

Secondary Causes (Non-Iron Overload)

Chronic Liver Disease

• Alcoholic liver disease: Alcohol increases iron absorption and causes liver injury, elevating ferritin through multiple mechanisms 3, 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/Metabolic syndrome: Very common cause of hyperferritinemia without true iron overload 3, 1, 2
• Viral hepatitis (B and C): Causes elevated ferritin through hepatocellular injury 1, 2
• Acute hepatitis: Can cause marked ferritin elevation from cell necrosis 2

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease: Can cause extremely elevated ferritin (often >10,000 ng/mL), with glycosylated ferritin ≤20% being a diagnostic marker 6, 2, 7
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Life-threatening condition with average ferritin ~14,000 μg/L 7
• Chronic inflammatory conditions: Rheumatologic diseases, systemic inflammatory response syndrome 6, 2

Malignancy

• Solid tumors and lymphomas: Most frequent cause in one large study (153/627 patients) 7
• Ferritin acts as a tumor marker and indicator of increased angiogenesis 3

Other Causes

• Infections: Ferritin is an acute phase reactant; infection causes increased ferritin rather than iron overload causing infection risk 1
• Cell necrosis: Release of ferritin from necrotic or lysed cells 3, 2
• Chronic kidney disease: Particularly in hemodialysis patients 6

Critical Diagnostic Approach

Initial Assessment

• Measure both transferrin saturation and ferritin together—never interpret ferritin alone 6, 2
• Obtain morning blood samples for transferrin saturation (fasting not required) 3, 1
• If TS ≥45% with elevated ferritin, proceed to HFE genetic testing for C282Y and H63D mutations 3, 2

Rule Out Common Secondary Causes First

• Assess for inflammation (CRP, ESR), liver disease (ALT, AST), alcohol consumption, metabolic syndrome, malignancy, and infection 6, 2
• Remember: In the general population, iron overload is NOT the most common cause of elevated ferritin 2

When to Pursue Iron Overload Workup

• If TS <45% and ferritin elevated, secondary causes are much more likely 6
• If HFE testing is negative but iron overload suspected, consider non-HFE hemochromatosis genes 2, 4
• Use MRI (R2 sequences) to quantify hepatic iron concentration* in unclear cases or when multiple risk factors present 3, 8

Critical Thresholds and Red Flags

Ferritin >1,000 μg/L

• Warrants referral to gastroenterologist, hematologist, or iron overload specialist 6, 9
• In hemochromatosis, consider liver biopsy if accompanied by elevated liver enzymes or platelets <200,000/μL to assess for cirrhosis 6, 2
• Below 1,000 μg/L with normal transaminases, risk of advanced liver fibrosis is very low (94% negative predictive value) 6

Ferritin >10,000 ng/mL

• Suggests life-threatening conditions: adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 6
• Requires urgent specialist referral 6
• Average ferritin in these syndromes is ~14,000 μg/L 7

Common Pitfalls to Avoid

• Do not use ferritin alone without transferrin saturation to diagnose iron overload—ferritin has high sensitivity but low specificity 1, 6, 2
• Do not overlook multiple contributing factors: patients can have both hemochromatosis and fatty liver disease simultaneously 3
• Do not assume elevated ferritin always means iron overload: 90% of cases are due to non-iron overload conditions 2, 9
• Do not delay investigation of unexpected ferritin changes—significant fluctuations are never normal 1
• In hemodialysis patients with inflammation, ferritin typically normalizes within 4 months after resolving the inflammatory state 1