What causes elevated ferritin levels?

Why Ferritin is Elevated

Ferritin elevation is most commonly caused by non-iron overload conditions—specifically chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD—which account for over 90% of cases, not hereditary hemochromatosis. 1

Primary Mechanism: Acute Phase Reactant

• Ferritin is an acute phase reactant that rises during any inflammatory state, making it highly sensitive but poorly specific for actual iron overload. 1
• The elevation occurs independently of body iron stores in most clinical scenarios, particularly during infection, inflammation, and liver injury. 1, 2

Most Common Causes (>90% of Cases)

Liver-Related Causes

• Chronic alcohol consumption elevates ferritin through multiple mechanisms including increased iron absorption and direct hepatocellular injury. 1, 2
• Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome are among the most frequent causes in outpatient settings. 1, 2
• Viral hepatitis (B and C) and acute hepatitis cause ferritin elevation through hepatocellular damage. 1, 2

Inflammatory and Systemic Causes

• Active infection causes ferritin to rise acutely as part of the inflammatory response—the association is bidirectional, meaning infection causes elevated ferritin, not the reverse. 1
• Systemic inflammatory conditions including adult-onset Still's disease, hemophagocytic lymphohistiocytosis, and systemic inflammatory response syndrome. 1
• Cell necrosis from any source (muscle, liver, other tissues) releases intracellular ferritin. 1

Malignancy

• Solid tumors and lymphomas frequently cause hyperferritinemia through inflammatory cytokine production. 1
• Hematologic malignancies are associated with elevated ferritin, particularly in acute myeloid leukemia where it serves as both a marker and regulator of cellular iron metabolism. 3
• In one large series, malignancy was the single most common cause (153/627 cases) of ferritin >1000 μg/L. 4

Less Common Causes: True Iron Overload (<10% of Cases)

Hereditary Hemochromatosis

• HFE-related hemochromatosis (C282Y homozygosity or C282Y/H63D compound heterozygosity) is far less common than traditionally assumed. 1, 2
• Non-HFE hemochromatosis involves mutations in TFR2, SLC40A1, HAMP, or HJV genes. 1, 2
• Critical distinction: These conditions typically present with transferrin saturation ≥45%, whereas inflammatory causes show elevated ferritin with normal or low transferrin saturation. 1

Transfusional Iron Overload

• Chronic transfusion therapy is a major cause of true iron overload, particularly in patients with thalassemia or other chronic anemias requiring regular transfusions. 2, 5
• Ferritin levels exceeding 7,500 ng/mL with transferrin saturation >88% indicate documented organ damage risk. 2, 6

Diagnostic Algorithm: The Critical First Step

Always measure transferrin saturation (TS) simultaneously with ferritin—never interpret ferritin in isolation. 1, 2

If TS ≥45%

• Consider primary iron overload and proceed with HFE genetic testing for C282Y and H63D mutations. 1, 2
• Evaluate for non-HFE hemochromatosis if genetic testing is negative but iron overload is confirmed. 1

If TS <45%

• Iron overload is unlikely—focus on secondary causes. 1
• Investigate for: alcohol use, metabolic syndrome, liver disease, inflammatory conditions, malignancy, and infection. 1, 7

Ferritin Level-Based Risk Stratification

Ferritin <1,000 μg/L

• Low risk of organ damage with 94% negative predictive value for advanced liver fibrosis in hemochromatosis. 1, 6
• Most cases represent secondary causes requiring treatment of the underlying condition, not the ferritin itself. 1

Ferritin 1,000-10,000 μg/L

• Moderate to high risk requiring additional evaluation including liver enzymes and platelet count. 1, 6
• In C282Y homozygotes with ferritin >1,000 μg/L, elevated liver enzymes, and platelets <200,000/μL, cirrhosis risk reaches 80%. 1
• Specialist referral indicated to gastroenterology, hematology, or iron overload specialist. 6, 7

Ferritin >10,000 μg/L

• Rarely represents simple iron overload—requires urgent evaluation for life-threatening conditions. 1, 6
• In one series, the average ferritin in adult-onset Still's disease, systemic juvenile idiopathic arthritis, or hemophagocytic lymphohistiocytosis was 14,242 μg/L. 4
• However, even at these extreme levels, chronic transfusion (35%), liver disease (27%), and hematologic malignancy (16%) remain more common than HLH/macrophage activation syndrome. 5

Special Clinical Contexts

Chronic Kidney Disease

• Functional iron deficiency can occur despite elevated ferritin (500-1,200 μg/L) when erythropoiesis is pharmacologically stimulated. 1, 6
• In the DRIVE study, CKD patients with ferritin 500-1,200 μg/L and TS <25% showed significant hemoglobin improvement with IV iron (16 g/L vs 11 g/L, P=0.028). 1
• Distinguish from inflammatory iron block by trial of weekly IV iron (50-125 mg for 8-10 doses)—no response indicates inflammatory block. 1

Inflammatory Bowel Disease

• Ferritin <30 μg/L indicates true iron deficiency, while levels >100 μg/L with low TS suggest anemia of chronic disease. 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without checking transferrin saturation. 1, 2
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L, abnormal liver tests, and evidence suggesting hemochromatosis. 1
• Do not assume iron overload when TS <45%—secondary causes predominate in this scenario. 1
• Recognize that extremely high ferritin (>10,000 μg/L) has low positive predictive value for HLH—consider more common explanations first (malignancy, chronic transfusion, liver disease). 5
• Do not treat the ferritin number—treat the underlying condition causing the elevation. 6