What causes elevated ferritin levels?

Elevated Ferritin: Causes and Clinical Approach

Most Common Causes

Over 90% of elevated ferritin cases in outpatients are caused by chronic alcohol consumption, inflammation, cell necrosis, tumors, and non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome—NOT iron overload. 1

The key distinction is that ferritin is an acute phase reactant that rises during inflammation, infection, and tissue injury independent of actual iron stores. 1, 2 This means most patients with elevated ferritin do not have iron overload and should not undergo phlebotomy.

Primary Categories of Causes

Iron Overload Disorders (Minority of Cases)

• Hereditary hemochromatosis (HFE-related): C282Y homozygosity or C282Y/H63D compound heterozygosity 1, 3
• Non-HFE hemochromatosis: Mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 2
• Transfusional iron overload: Patients with ferritin exceeding 7,500 ng/mL from chronic transfusions 2

Liver Disease (Very Common)

• Chronic alcohol consumption: Increases iron absorption and causes hepatocellular injury 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome: Ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload 1, 4
• Viral hepatitis B and C 1, 2
• Acute hepatitis: Causes ferritin release from damaged hepatocytes 1

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease (AOSD): Characterized by extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Average ferritin level 14,242 μg/L 5
• Systemic inflammatory response syndrome 1
• Chronic rheumatologic diseases 6
• Infections: Active infection causes ferritin to rise acutely as part of the inflammatory response 1, 2

Malignancy

• Solid tumors 1
• Lymphomas 1
• Hepatocellular carcinoma 1
• Malignancy was the most frequent condition in one large series (153/627 patients with ferritin >1000 μg/L) 5

Cellular Damage and Necrosis

• Muscle injury 1
• Hepatocellular necrosis: Ferritin is released from necrotic or lysed cells 1
• Tissue breakdown from any cause 1

Metabolic Conditions

• Metabolic syndrome: Ferritin levels are significantly related to insulin C-peptide level and insulin resistance 1, 4
• Chronic kidney disease: Can cause elevated ferritin through chronic inflammation 6

Critical Diagnostic Algorithm

Step 1: Measure Transferrin Saturation (TS) Simultaneously

Never use ferritin alone to diagnose iron overload. 1, 6 The single most important test is measuring fasting transferrin saturation alongside ferritin. 1, 2

• If TS ≥45%: Suspect primary iron overload and proceed with HFE genetic testing for C282Y and H63D mutations 1, 6
• If TS <45%: Iron overload is unlikely; secondary causes predominate 1, 6

Step 2: Rule Out Common Secondary Causes

When TS <45%, systematically evaluate for: 1

• Alcohol consumption: Detailed history of alcohol intake
• Metabolic syndrome/NAFLD: Check BMI, blood pressure, fasting glucose, lipid panel
• Inflammation: Measure CRP and ESR
• Liver disease: Check ALT, AST, albumin
• Malignancy: Age-appropriate cancer screening
• Infection: Clinical assessment for active infection

Step 3: Risk Stratification by Ferritin Level

• Ferritin <1,000 μg/L: Low risk of organ damage; negative predictive value of 94% for advanced liver fibrosis in hemochromatosis 1, 6
• Ferritin 1,000-10,000 μg/L: Higher risk of advanced fibrosis/cirrhosis if iron overload is present; consider liver biopsy if accompanied by elevated liver enzymes or platelet count <200,000/μL 1, 6
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; consider adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome; requires urgent specialist referral 1, 6

Special Clinical Contexts

Metabolic Syndrome/NAFLD

The majority of patients referred for hyperferritinemia are overweight middle-aged individuals with markers of metabolic syndrome but without increased iron stores. 4 In these patients, ferritin elevation reflects hepatocellular injury and insulin resistance, not iron overload. 1, 4

Chronic Kidney Disease

In CKD patients with anemia, elevated ferritin (500-1,200 μg/L) with low transferrin saturation (<25%) may represent functional iron deficiency that responds to IV iron therapy. 1, 6

Adult-Onset Still's Disease

Glycosylated ferritin fraction <20% combined with 5-fold ferritin elevation is 93% specific for AOSD. 1 Ferritin correlates with disease activity and often normalizes with remission. 1

Critical Pitfalls to Avoid

• 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 use ferritin alone without transferrin saturation: Ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 6
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests: This combination warrants histologic assessment for cirrhosis 1, 6
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1
• Do not delay specialist referral when ferritin >10,000 μg/L: This rarely represents simple iron overload and may indicate life-threatening conditions 1, 6

When to Refer to Specialist

Referral to a gastroenterologist, hematologist, or specialist in iron overload is appropriate if: 7

• Serum ferritin is >1,000 μg/L
• The cause of elevated serum ferritin remains unclear after initial evaluation
• Evidence of organ damage is present
• Ferritin >10,000 μg/L (urgent referral) 6