What are the causes and treatments of elevated ferritin levels?

Causes of Elevated Ferritin

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

Primary Diagnostic Framework

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, 2 This means the ferritin level alone cannot distinguish between true iron overload and secondary causes.

Most Common Causes (>90% of cases)

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury, leading to elevated ferritin 1, 2
• Inflammation from any source (infections, rheumatologic diseases, inflammatory bowel disease) triggers ferritin release as an acute-phase reactant 1
• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown releases stored ferritin 1
• Malignancy (solid tumors, lymphomas, hepatocellular carcinoma) is the most frequent condition in patients with markedly elevated ferritin (>1000 μg/L), accounting for 24% of cases 1, 3
• Metabolic syndrome/NAFLD causes ferritin elevation through hepatocellular injury and insulin resistance rather than true iron overload 1

Secondary Liver Disease Causes

• Viral hepatitis (B and C) elevates ferritin through hepatocellular inflammation 1, 2
• Acute hepatitis causes rapid ferritin release from damaged liver cells 1
• Cirrhosis of any etiology is associated with elevated ferritin 2

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease (AOSD) causes extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 1
• Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome cause very high ferritin levels (average 14,242 μg/L in one series) 3
• Systemic inflammatory response syndrome elevates ferritin as part of the acute-phase response 1
• Chronic rheumatologic diseases cause persistent ferritin elevation 2

True Iron Overload Disorders (Minority of Cases)

• Hereditary hemochromatosis (HFE-related) with C282Y homozygosity or C282Y/H63D compound heterozygosity 1, 2
• Non-HFE hemochromatosis with mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 2
• Transfusional iron overload in patients receiving chronic transfusions (accounts for 35% of extreme hyperferritinemia >10,000 ng/mL) 2, 4

Other Important Causes

• Chronic kidney disease with anemia can show elevated ferritin with functional iron deficiency 1
• Hematologic malignancies account for 16% of extreme hyperferritinemia cases 4
• Infections cause ferritin to rise acutely as part of the inflammatory response 1, 2

Algorithmic Diagnostic Approach

Step 1: Measure Transferrin Saturation Simultaneously

Always check transferrin saturation (TS) alongside ferritin—never interpret ferritin alone. 5, 1, 6 This single step distinguishes true iron overload from secondary causes:

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

Step 2: Evaluate for Common Secondary Causes

When TS <45%, systematically assess for:

• Inflammatory markers (CRP, ESR) to detect occult inflammation 6
• Liver enzymes (ALT, AST) to assess hepatocellular injury 1, 6
• Alcohol consumption history (detailed quantification) 1, 2
• Metabolic syndrome components (obesity, diabetes, hypertension, dyslipidemia) 1
• Active infection through clinical evaluation and appropriate cultures 1
• Malignancy screening appropriate for age and risk factors 1, 3

Step 3: Risk Stratification by Ferritin Level

The absolute ferritin level guides urgency and specialist referral:

• <1,000 μg/L: Low risk of organ damage; outpatient evaluation appropriate 1, 6
• 1,000-10,000 μg/L: Higher risk if true iron overload present; consider gastroenterology/hematology referral if TS elevated or cause unclear 6, 7
• >10,000 μg/L: Rarely represents simple iron overload; urgent specialist referral needed to evaluate for life-threatening conditions (HLH, severe infection, malignancy) 1, 6, 4

Critical Clinical Pearls

Ferritin has high sensitivity but low specificity for iron overload—it can be elevated in many inflammatory conditions without true iron excess. 1, 2 In the general population, iron overload is NOT the most common cause of elevated ferritin. 1

In inflammatory states, ferritin rises while transferrin saturation often drops, creating a pattern of elevated ferritin with low TS that indicates functional iron deficiency or inflammatory iron block, not iron overload. 1

Extremely high ferritin levels (>10,000 μg/L) have a low positive predictive value for HLH—chronic transfusion (35%), liver disease (27%), and hematologic malignancy (16%) are more common causes. 4 However, AOSD and HLH should always be considered in this range, especially with glycosylated ferritin <20%. 1

Common Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload 1, 6
• Do not assume iron overload when TS <45%—focus on secondary causes instead 6
• Do not overlook liver biopsy or MRI in patients with ferritin >1,000 μg/L and elevated TS or abnormal liver tests 1, 6
• Do not delay evaluation of extreme hyperferritinemia (>10,000 μg/L)—this requires urgent assessment for life-threatening conditions 6, 4
• Recognize that ferritin can remain elevated for months after resolving inflammation in certain populations (e.g., hemodialysis patients may take 4 months to normalize) 2