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

Causes of Elevated Ferritin

Primary Diagnostic Framework

Elevated ferritin is caused by non-iron overload conditions in over 90% of cases, with chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD being the most common culprits—not hereditary hemochromatosis. 1

The key to diagnosis is measuring transferrin saturation (TS) simultaneously with ferritin, as ferritin alone cannot distinguish between true iron overload and secondary causes. 2, 1

Complete List of Causes

Iron Overload Disorders (Rare - <10% of cases)

Primary Iron Overload:

• HFE-related hereditary hemochromatosis (C282Y homozygosity or C282Y/H63D compound heterozygosity) 2, 1
• Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, or HJV genes) 1

Secondary Iron Overload:

• Chronic transfusion therapy (most common cause of extreme hyperferritinemia >10,000 ng/mL) 3
• Thalassemia syndromes 4
• Myelodysplastic syndrome and myelofibrosis 4
• Sickle cell disease 4
• Sideroblastic anemias and pyruvate kinase deficiency 4

Liver Disease (Very Common)

• Alcoholic liver disease (increases iron absorption and causes hepatocellular injury) 2, 1
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome (ferritin reflects hepatocellular injury and insulin resistance, not actual iron accumulation) 2, 1, 5
• Viral hepatitis B and C 1
• Acute hepatitis (releases ferritin from necrotic hepatocytes) 1
• Cirrhosis 1
• Hepatocellular carcinoma 1

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease (ferritin 4,000-250,000 ng/mL with glycosylated ferritin <20%) 2, 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (life-threatening, requires urgent specialist referral) 2, 1
• Chronic rheumatologic diseases 2, 1
• Systemic inflammatory response syndrome 1
• Active infections (ferritin rises acutely as part of inflammatory response) 1

Malignancy

• Solid tumors 1, 6
• Lymphomas 1
• Hematologic malignancies (16% of extreme hyperferritinemia cases) 3

Cellular Damage and Necrosis

• Muscle necrosis (check creatine kinase) 1
• Hepatocellular necrosis (ferritin released from lysed cells) 1
• Tissue breakdown from any cause 1

Metabolic and Renal Conditions

• Metabolic syndrome/obesity/diabetes 1, 7
• Chronic kidney disease (functional iron deficiency can occur despite elevated ferritin) 2, 1

Algorithmic Diagnostic Approach

Step 1: Measure Transferrin Saturation

If TS ≥45%: Suspect primary iron overload

• Order HFE genetic testing for C282Y and H63D mutations 2, 1
• C282Y homozygotes confirm HFE hemochromatosis 1
• Consider liver MRI to quantify hepatic iron concentration 1

If TS <45%: Iron overload is unlikely; secondary causes predominate 2, 1

• Proceed to evaluate inflammatory, hepatic, and malignant causes 1

Step 2: Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L:

• Low risk of organ damage (94% negative predictive value for advanced liver fibrosis) 2, 1
• Evaluate common secondary causes 1

Ferritin 1,000-10,000 μg/L:

• Higher risk of advanced fibrosis/cirrhosis if iron overload present 1
• Check platelet count and liver enzymes 2
• Consider liver biopsy if ferritin >1,000 μg/L with elevated ALT/AST or platelets <200,000/μL 2, 1
• Refer to gastroenterologist, hematologist, or iron overload specialist 2, 7

Ferritin >10,000 μg/L:

• Rarely represents simple iron overload 1
• Most commonly due to chronic transfusion (35%), liver disease (27%), or hematologic malignancy (16%) 3
• Consider adult-onset Still's disease (glycosylated ferritin <20%), hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 2, 1
• Requires urgent specialist referral 2

Step 3: Evaluate Secondary Causes (when TS <45%)

Check inflammatory markers:

• CRP and ESR to detect occult inflammation 2, 1

Assess liver function:

• ALT, AST, albumin to evaluate hepatocellular injury 2, 1
• Detailed alcohol consumption history 1

Screen for metabolic syndrome:

• Evaluate for obesity, diabetes, NAFLD 1, 7

Evaluate for malignancy and infection:

• Age-appropriate cancer screening 6
• Assess for active infections 1

Check for cellular damage:

• Creatine kinase for muscle necrosis 1

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload (ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores) 2, 1
• Do not assume iron overload when TS <45% 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) 2, 1
• 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 urgent evaluation for life-threatening conditions 1, 3

Special Clinical Contexts

NAFLD patients:

• Elevated ferritin typically reflects hepatocellular injury and insulin resistance, not iron accumulation 5
• Do not automatically pursue iron overload evaluation unless TS is also elevated (>45%) 5
• Treat underlying NAFLD with weight loss and metabolic syndrome management 5

Chronic kidney disease:

• Functional iron deficiency can occur despite ferritin 500-1,200 μg/L if TS <25% 2, 1
• IV iron may still be beneficial in this context 2

Inflammatory bowel disease:

• Ferritin <30 μg/L indicates iron deficiency 1
• Ferritin >100 μg/L with low TS suggests anemia of chronic disease 1