What are the causes and management of elevated ferritin levels?

Causes of High Ferritin

Primary Causes of Elevated Ferritin

Elevated ferritin is caused by chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD in over 90% of outpatient cases—not iron overload. 1

Iron Overload Disorders (Minority of Cases)

• Hereditary hemochromatosis (HFE-related) occurs with C282Y homozygosity or C282Y/H63D compound heterozygosity 2, 1
• Non-HFE hemochromatosis results from mutations in TFR2, SLC40A1, HAMP, or HJV genes 1
• These represent the minority of elevated ferritin cases in clinical practice 1

Secondary Causes (Majority of Cases)

Liver Disease

• Alcoholic liver disease causes both increased iron absorption and hepatocellular injury 1
• Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome are extremely common causes 1
• Viral hepatitis B and C elevate ferritin, with approximately 50% of hepatitis patients showing abnormal iron studies 3
• Acute hepatitis and cirrhosis release ferritin from damaged hepatocytes 1

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease (AOSD) produces extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 1
• Hemophagocytic lymphohistiocytosis (HLH) causes ferritin levels typically >6,000 μg/L with significantly increased mortality 4
• Systemic inflammatory response syndrome elevates ferritin as an acute phase reactant 1
• Chronic rheumatologic diseases cause persistent ferritin elevation 1

Malignancy

• Solid tumors elevate ferritin as a tumor marker 1
• Lymphomas are among the most common causes in hospitalized patients with markedly elevated ferritin 5
• Hepatocellular carcinoma should be considered in patients with liver disease 1

Infections and Cell Damage

• Active infections cause ferritin to rise acutely as part of the inflammatory response 1
• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown releases stored ferritin 1

Other Conditions

• Chronic kidney disease causes functional iron deficiency despite elevated ferritin 1
• Metabolic syndrome elevates ferritin through insulin resistance and hepatocellular injury 1

Critical Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Simultaneously

Never use ferritin alone—always check fasting transferrin saturation (TS) to distinguish iron overload from secondary causes. 1, 3

• If TS ≥45%: Suspect primary iron overload and proceed to HFE genetic testing for C282Y and H63D mutations 1, 3
• If TS <45%: Iron overload is unlikely; focus on identifying secondary causes 1

Step 2: Rule Out Common Secondary Causes

When TS <45%, systematically evaluate for: 1

• Inflammatory markers: Check CRP and ESR for occult inflammation 1
• Liver disease: Measure ALT, AST, and complete metabolic panel 1
• Alcohol consumption: Obtain detailed history of intake 1
• Metabolic syndrome: Assess for obesity, diabetes, hypertension 1
• Malignancy: Screen based on clinical suspicion with imaging 1
• Infection: Evaluate for active infectious processes 1

Step 3: Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L

• Low risk of organ damage with negative predictive value of 94% for advanced liver fibrosis in hemochromatosis 1
• In C282Y homozygotes with normal liver enzymes and no hepatomegaly, fewer than 2% have cirrhosis or bridging fibrosis 2

Ferritin 1,000-10,000 μg/L

• Higher risk of advanced fibrosis/cirrhosis if iron overload is present 1
• In C282Y homozygotes, ferritin >1,000 μg/L indicates 20-45% prevalence of cirrhosis 2, 1
• Consider liver biopsy if ferritin >1,000 μg/L with elevated liver enzymes, hepatomegaly, or platelet count <200,000/μL 2, 1

Ferritin >10,000 μg/L

• Rarely represents simple iron overload—requires urgent specialist referral 1
• Consider adult-onset Still's disease (measure glycosylated ferritin fraction), HLH, or macrophage activation syndrome 1

Important Clinical Pearls

Understanding Ferritin as a Biomarker

• Ferritin is an acute phase reactant that rises during inflammation, infection, and tissue injury independent of actual iron stores 1
• High sensitivity but low specificity for iron overload—elevated in many inflammatory conditions 1
• In the general population, iron overload is NOT the most common cause of elevated ferritin 1

Common Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without checking transferrin saturation 1, 3
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests 1, 3
• Do not assume iron overload when TS <45%—focus on secondary causes 1
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 2

Special Clinical Contexts

Chronic Kidney Disease

• Functional iron deficiency can occur with ferritin 500-1,200 μg/L and TS <25%, which may respond to IV iron therapy despite elevated ferritin 1, 3

NAFLD Patients

• Elevated ferritin reflects hepatocellular injury and insulin resistance rather than iron overload 1
• Do not automatically pursue iron overload evaluation unless TS is also elevated (>45%) 1

Inflammatory Bowel Disease

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