Why is serum ferritin elevated?

Why Ferritin Is Elevated

Ferritin is elevated in over 90% of cases due to inflammation, liver disease, chronic alcohol consumption, metabolic syndrome/NAFLD, cell necrosis, or malignancy—not iron overload. 1

Understanding Ferritin as a Biomarker

Ferritin functions simultaneously as an iron storage marker and an acute-phase reactant, rising during inflammation, infection, hepatocellular injury, and tissue necrosis completely independent of actual iron stores. 1 This dual nature makes ferritin highly sensitive but poorly specific for iron overload, requiring careful interpretation in clinical context. 2

The single most important principle: Never interpret ferritin alone—always measure transferrin saturation (TS) simultaneously to distinguish true iron overload from secondary causes. 1, 2

Primary Categories of Elevated Ferritin

Iron Overload Disorders (When TS ≥45%)

• Hereditary hemochromatosis (HFE-related) occurs in C282Y homozygotes or C282Y/H63D compound heterozygotes, with prevalence of 0.44% in non-Hispanic white populations. 1
• Non-HFE hemochromatosis results from mutations in TFR2, SLC40A1, HAMP, or HJV genes. 1
• Iron overload should only be suspected when TS ≥45% accompanies elevated ferritin—this combination triggers HFE genetic testing. 1, 2

Liver Disease (Most Common Cause)

• Chronic alcohol consumption increases intestinal iron absorption and causes hepatocellular injury, releasing ferritin from damaged cells. 1
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation reflecting hepatocellular injury and insulin resistance rather than true iron overload. 1, 3
• Viral hepatitis (B and C) produces abnormal iron studies in approximately 50% of patients. 1, 2
• Acute hepatitis releases ferritin from necrotic hepatocytes independent of iron stores. 1

Inflammatory and Rheumatologic Conditions

• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute-phase reactant. 1
• Adult-onset Still's disease produces extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20%. 1
• Systemic inflammatory response syndrome and hemophagocytic lymphohistiocytosis cause marked ferritin elevation. 1

Malignancy

• Solid tumors, lymphomas, and hepatocellular carcinoma elevate ferritin through inflammatory cytokine production and tumor cell ferritin secretion. 1
• Malignancy was the most frequent cause (153/627 patients) in one large series of markedly elevated ferritin (>1000 μg/L). 4

Cellular Damage and Necrosis

• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown releases ferritin from lysed cells independent of iron stores. 1
• The serum ferritin-transaminase ratio correlates with liver iron concentration, reflecting both hepatocellular injury and iron stores. 5

Metabolic and Obesity-Related

• Obesity and metabolic syndrome cause inflammatory hyperferritinemia through adipose tissue inflammation and insulin resistance. 3
• When TS <45% in obese patients, elevated ferritin reflects inflammation from obesity-related metabolic dysfunction rather than iron overload. 3

Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Simultaneously

Order fasting transferrin saturation alongside ferritin—this single test determines the entire diagnostic pathway. 1, 2

Step 2: Interpret Based on Transferrin Saturation

TS Result	Interpretation	Next Step
TS ≥45%	Suspect primary iron overload	Order HFE genetic testing (C282Y, H63D) [1,2]
TS <45%	Iron overload excluded with >90% certainty	Evaluate secondary causes [1,2]

Step 3: If TS ≥45%, Confirm Hereditary Hemochromatosis

• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE-related hereditary hemochromatosis. 1, 2
• If genetic testing is negative but TS remains ≥45%, consider non-HFE hemochromatosis (TFR2, SLC40A1, HAMP, HJV mutations). 1

Step 4: If TS <45%, Evaluate Secondary Causes

Order the following tests to identify the underlying cause: 1, 2

• Inflammatory markers: CRP and ESR to detect occult inflammation 1
• Liver enzymes: ALT, AST, alkaline phosphatase to assess hepatocellular injury 1
• Complete metabolic panel: Including bilirubin to evaluate liver function 2
• Creatine kinase (CK): To evaluate for muscle necrosis 1
• Abdominal ultrasound: To detect fatty liver, hepatomegaly, or cirrhotic features 2
• Alcohol history: Detailed assessment of consumption patterns 1
• Medication review: Many drugs cause hepatotoxicity 1

Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L

• Low risk of organ damage with 94% negative predictive value for advanced liver fibrosis in hemochromatosis. 1, 2
• If C282Y homozygote with TS ≥45%, age <40 years, and normal liver enzymes, proceed directly to therapeutic phlebotomy without liver biopsy. 1, 2

Ferritin 1,000-10,000 μg/L

• Increased risk of advanced fibrosis/cirrhosis if iron overload is present. 1, 2
• In C282Y homozygotes, the combination of ferritin >1,000 μg/L, elevated aminotransferases, and platelet count <200,000/μL predicts cirrhosis in ~80% of cases. 1, 2
• Consider liver biopsy if ferritin >1,000 μg/L with elevated liver enzymes or thrombocytopenia. 1, 2

Ferritin >10,000 μg/L

• Rarely represents simple iron overload—mandates urgent specialist referral to evaluate for life-threatening conditions. 1, 2
• Consider adult-onset Still's disease (measure glycosylated ferritin fraction; <20% is 93% specific for AOSD). 1
• Consider hemophagocytic lymphohistiocytosis/macrophage activation syndrome if accompanied by cytopenias, fever, and multiorgan dysfunction. 1, 2

Special Clinical Contexts

Chronic Kidney Disease

• Functional iron deficiency can occur despite ferritin 500-1,200 μg/L when TS <25% in patients on erythropoiesis-stimulating agents. 1, 2, 3
• IV iron may still be beneficial in this setting, as iron is sequestered and unavailable for erythropoiesis despite seemingly adequate ferritin. 1, 2

Inflammatory Bowel Disease

• Ferritin <30 μg/L indicates absolute iron deficiency. 1
• Ferritin 30-100 μg/L with TS <16% suggests combined iron deficiency and anemia of chronic disease. 2
• Ferritin >100 μg/L with TS <16% indicates predominant anemia of chronic disease. 2

Obesity and Metabolic Syndrome

• When TS <45%, elevated ferritin reflects inflammation from obesity-related metabolic dysfunction rather than iron overload. 3
• Treat the underlying metabolic condition, not the ferritin number itself—weight loss, glycemic control, and NAFLD management address the root cause. 3

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. 1, 2

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 warrants histologic assessment for cirrhosis. 1, 2

Do not order HFE genetic testing when TS <45%—over 90% of elevated ferritin cases with normal TS are due to secondary causes. 1

Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload—urgent evaluation for inflammatory syndromes, malignancy, or hemophagocytic disorders is required. 1, 4