What are the causes of elevated ferritin (iron storage protein) levels?

Causes of Elevated Ferritin

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

Understanding Ferritin as a Biomarker

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. 2 It is released from necrotic or lysed cells and serves as an indicator of increased angiogenesis. 2 While ferritin has high sensitivity for iron overload, it has poor specificity, making clinical context essential for interpretation. 1

Primary Categories of Elevated Ferritin

Iron Overload Disorders (Require Transferrin Saturation ≥45%)

• Hereditary hemochromatosis (HFE-related): C282Y homozygosity or C282Y/H63D compound heterozygosity 2, 1
• Non-HFE hemochromatosis: Mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 3
• Transfusional iron overload: Particularly in patients with chronic transfusion requirements 3, 4
• Hematologic disorders: Thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, pyruvate kinase deficiency 5

Liver Disease (Most Common Secondary Cause)

• Chronic alcohol consumption: Increases iron absorption and causes hepatocellular injury 2, 3
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome: Ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload 1, 3
• Viral hepatitis (B and C): Approximately 50% of patients have abnormal serum iron studies 1, 3
• Acute hepatitis and cirrhosis: Associated with hepatocellular necrosis 1
• Hepatocellular carcinoma 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) with glycosylated ferritin fraction <20% 1, 6
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Ferritin typically >5,000-10,000 ng/mL with cytopenias, fever, and multiorgan dysfunction 1, 6, 4
• Chronic rheumatologic diseases: Systemic inflammatory conditions 2
• Systemic inflammatory response syndrome 1

Malignancy

• Solid tumors: Most frequent cause in one large series (153/627 patients) 6
• Lymphomas 1, 6
• Hematologic malignancies: Comprised 16% of extreme hyperferritinemia cases 4

Infection and Cellular Damage

• Active infections: Ferritin rises acutely as part of the inflammatory response 1, 3
• Cell necrosis: From muscle injury, hepatocellular necrosis, or tissue breakdown 2, 1

Chronic Kidney Disease

• Functional iron deficiency: Ferritin 500-1200 ng/mL with transferrin saturation <25%, especially in patients receiving erythropoietin therapy 1, 3

Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Simultaneously

The single most important test is fasting transferrin saturation (morning sample preferred, fasting not required) to distinguish true iron overload from secondary causes. 2, 1 Ferritin alone cannot make this distinction. 1

Step 2: Interpret Based on Transferrin Saturation

If TS ≥45% with elevated ferritin:

• Suspect primary iron overload 1
• Proceed immediately to HFE genotype testing for C282Y and H63D mutations 2, 1
• C282Y homozygotes confirm HFE hemochromatosis 1

If TS <45% with elevated ferritin:

• Iron overload is unlikely; secondary causes predominate 1, 7
• Evaluate for inflammation, liver disease, malignancy, and infection 1

Step 3: Additional Laboratory Evaluation

• Complete metabolic panel: ALT, AST to assess hepatocellular injury 1
• Inflammatory markers: CRP, ESR to detect occult inflammation 1
• Complete blood count with differential: Assess for anemia, polycythemia, or hematologic malignancy 1
• Creatine kinase: Evaluate for muscle necrosis 1

Step 4: Risk Stratification by Ferritin Level

• Ferritin <1,000 μg/L: Low risk of organ damage (negative predictive value 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 ferritin >1,000 μg/L with elevated liver enzymes or platelet count <200,000/μL 2, 1
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; suggests life-threatening conditions (HLH, macrophage activation syndrome, AOSD) requiring urgent specialist referral 1, 6, 4

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload 1
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin 1
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests—this combination predicts cirrhosis in 80% of C282Y homozygotes 1
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload—consider AOSD (glycosylated ferritin <20%), HLH, or malignancy 1, 6, 4
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 2, 1

Special Clinical Contexts

Chronic Kidney Disease

In CKD patients on erythropoiesis-stimulating agents, ferritin 500-1,200 ng/mL with transferrin saturation <25% may represent functional iron deficiency that responds to IV iron therapy despite elevated ferritin. 1, 3

Adult-Onset Still's Disease

Consider AOSD if ferritin rises above 4,000-5,000 ng/mL with persistent fever; measure glycosylated ferritin fraction (<20% is 93% specific for AOSD). 1, 6

Metabolic Syndrome/NAFLD

Mildly elevated ferritin with elevated ALT and normal transferrin saturation strongly suggests NAFLD—treat the underlying liver disease, not the ferritin itself. 1