What causes elevated ferritin levels?

Causes of Elevated Ferritin Levels

Elevated ferritin is most commonly caused by inflammation, chronic alcohol consumption, non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome, cell necrosis, and malignancy—accounting for over 90% of cases—not iron overload. 1

Understanding Ferritin as a Biomarker

Ferritin is an acute-phase reactant that rises during inflammation, making it highly sensitive but poorly specific for iron overload. 1, 2 The key to diagnosis is measuring transferrin saturation (TS) simultaneously with ferritin to distinguish true iron overload from secondary causes. 1

Algorithmic Diagnostic Approach

Step 1: Check Transferrin Saturation

• If TS ≥45%: Consider primary iron overload disorders 1

  • Hereditary hemochromatosis (HFE gene mutations: C282Y homozygosity or C282Y/H63D compound heterozygosity) 1, 2
  • Non-HFE hemochromatosis (TFR2, SLC40A1, HAMP, HJV mutations) 1, 2
  • Proceed with HFE genetic testing for C282Y and H63D mutations 1

• If TS <45%: Iron overload is unlikely; focus on secondary causes 1

Step 2: Evaluate Secondary Causes (Most Common)

Liver-Related Causes:

• Chronic alcohol consumption (increases iron absorption and causes hepatocellular injury) 1, 2
• NAFLD/metabolic syndrome 1, 2
• Viral hepatitis B or C 1, 2
• Acute hepatitis 1

Inflammatory/Rheumatologic Conditions:

• Systemic inflammatory response syndrome 1
• Adult-onset Still's disease (typically ferritin >10,000 μg/L with glycosylated ferritin ≤20%) 1, 3
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 1, 3
• Infections (ferritin rises acutely as part of acute-phase response) 1

Malignancy:

• Solid tumors 1
• Lymphomas 1
• Hematologic malignancies 4

Other Causes:

• Cell necrosis (muscle, liver) 1
• Chronic kidney disease 1
• Chronic transfusion therapy 4, 5

Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L:

• Low risk of organ damage (94% negative predictive value for advanced liver fibrosis in hemochromatosis) 1
• Most likely secondary causes 1

Ferritin 1,000-10,000 μg/L:

• Higher risk of cirrhosis if iron overload present (20-45% in C282Y homozygotes with elevated liver enzymes and platelets <200) 1
• Still commonly due to secondary causes 6

Ferritin >10,000 μg/L:

• Rarely represents simple iron overload 1
• Most common causes: chronic transfusion (35%), liver disease (27%), hematologic malignancy (16%), followed by solid malignancies, infection, and macrophage activation syndrome/HLH (22%) 4
• Average ferritin in Still's disease/HLH: 14,242 μg/L 6

Special Clinical Contexts

Chronic Kidney Disease:

• Distinguish functional iron deficiency from inflammatory iron block 7
• Functional iron deficiency: serial ferritin decreases during erythropoietin therapy but remains >100 ng/mL 7
• Inflammatory block: abrupt ferritin increase with sudden TS drop 7
• Trial of weekly IV iron (50-125 mg for 8-10 doses) can differentiate—no response indicates inflammatory block 7

Absolute vs. Functional Iron Deficiency:

• Absolute iron deficiency in CKD: ferritin <100 ng/mL and TS <20% 7
• Functional iron deficiency: inadequate iron release despite adequate stores, occurs with pharmacologic erythropoiesis stimulation 7

Critical Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without checking transferrin saturation 1
• Do not assume iron overload when TS <45%—secondary causes predominate 1
• Do not overlook liver biopsy or MRI in patients with ferritin >1,000 μg/L and abnormal liver tests 1
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload—consider malignancy, infection, transfusional overload, or hyperferritinemic syndromes first 1, 4
• Screen first-degree relatives if HFE-related hemochromatosis is confirmed 1
• In hemodialysis patients, unexpected ferritin changes warrant investigation—significant fluctuations are not normal 2

Initial Laboratory Workup

Order simultaneously:

• Fasting transferrin saturation (morning sample preferred) 1
• Serum ferritin 1
• Complete blood count with differential 1
• Liver enzymes (ALT, AST) 1
• Inflammatory markers (CRP, ESR) 1