What are the causes of elevated ferritin (iron storage protein) 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 understanding elevated ferritin is recognizing that ferritin is an acute phase reactant that rises during inflammation, infection, and tissue injury independent of actual iron stores. 1 This means you cannot use ferritin alone to diagnose iron overload—you must always check transferrin saturation (TS) simultaneously. 1

Algorithmic Approach Based on Transferrin Saturation

When TS ≥45%: Consider Primary Iron Overload

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

If TS ≥45%, proceed with HFE genetic testing for C282Y and H63D mutations. 1 If C282Y homozygosity is confirmed, you can initiate therapeutic phlebotomy without liver biopsy (unless ferritin >1000 μg/L with abnormal liver enzymes). 1

When TS <45%: Secondary Causes Predominate

When TS <45%, iron overload is unlikely and you should focus on identifying secondary causes. 1 This is the most common scenario in clinical practice.

Complete Differential Diagnosis

Liver Disease (Most 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, 3, 2
• Viral hepatitis B or C 1, 2
• Acute hepatitis: Can cause markedly elevated ferritin from hepatocellular necrosis 1
• Cirrhosis 1

Inflammatory/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 ~14,242 μg/L 4
• Systemic inflammatory response syndrome 1
• Chronic rheumatologic diseases 1
• Anemia of chronic disease: Typically presents with ferritin >100 μg/L and TS <16% 3

Malignancy (Second Most Common in Hospitalized Patients)

• Solid tumors: Including hepatocellular carcinoma 1
• Lymphomas 1
• Acute leukemia 5
• Pancreatic cancer 5

In one large study of 627 patients with ferritin >1000 μg/L, malignancy was the most frequent cause (153/627 cases), followed by iron-overload syndromes (136/627). 4

Infections

• Active infection causes ferritin to rise acutely as part of the acute phase response—the association is bidirectional, meaning infection causes elevated ferritin, not the other way around. 1, 2

Cellular Damage/Necrosis

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

Other Conditions

• Chronic kidney disease: Can present with elevated ferritin and functional iron deficiency 1
• Diabetes mellitus/metabolic syndrome 1

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 elevated TS, therapeutic phlebotomy can begin without liver biopsy if liver enzymes are normal and age <40 1

Ferritin 1,000-10,000 μg/L

• Higher risk of advanced fibrosis/cirrhosis if iron overload is present 1
• The combination of ferritin >1,000 μg/L, elevated aminotransferases, and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 1
• Liver biopsy should be considered in patients with ferritin >1,000 μg/L and abnormal liver tests 1

Ferritin >10,000 μg/L

• Rarely represents simple iron overload—requires urgent specialist referral to evaluate for life-threatening conditions 1
• Consider AOSD (average ferritin ~14,242 μg/L), hemophagocytic lymphohistiocytosis, or severe malignancy 1, 4

Critical Diagnostic 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
• 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
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1
• Recognize that extremely high ferritin (>10,000 μg/L) can occur in patients with seemingly indolent disease or chronic inflammation, not just acute life-threatening conditions 4

Initial Workup

Measure fasting transferrin saturation (morning sample preferred, fasting not required) alongside ferritin to distinguish between true iron overload and secondary causes. 1, 2 This is the single most important test. 1

Additional initial tests should include:

• Complete blood count with differential 1
• Liver enzymes (ALT, AST) 1, 3
• Inflammatory markers (CRP, ESR) to detect occult inflammation 1, 3
• Complete metabolic panel 1

Management Approach

Treat the underlying condition, not the elevated ferritin itself, in patients with secondary hyperferritinemia. 1 For example:

• NAFLD patients: Weight loss and metabolic syndrome management 1
• Inflammatory conditions: Disease-specific anti-inflammatory therapy 1
• Malignancy: Oncologic treatment 1

If hereditary hemochromatosis is confirmed (C282Y homozygote with TS ≥45%), initiate therapeutic phlebotomy and screen first-degree relatives. 1