Differential Diagnosis of Elevated Ferritin
Primary Diagnostic Framework
The vast majority (>90%) of elevated ferritin cases are caused by non-iron overload conditions including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD—not hereditary hemochromatosis. 1
The key to evaluating elevated ferritin is always measuring transferrin saturation (TS) simultaneously to distinguish true iron overload from secondary causes. 1
Complete Differential Diagnosis by Category
Iron Overload Disorders (TS ≥45%)
- HFE-related hereditary hemochromatosis - C282Y homozygosity or C282Y/H63D compound heterozygosity 1
- Non-HFE hemochromatosis - mutations in TFR2, SLC40A1, HAMP, or HJV genes 1
- Transfusional iron overload - chronic blood transfusions (≥100 mL/kg packed RBCs) 2
Liver Disease (Most Common Secondary Cause)
- Chronic alcohol consumption - one of the top causes accounting for >90% of cases 1
- Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome - extremely common cause 1
- Viral hepatitis - hepatitis B and C 1
- Acute hepatitis - can cause marked elevation 1
- Hepatocellular carcinoma 1
Inflammatory/Rheumatologic Conditions
- Adult-onset Still's disease (AOSD) - typically presents with extremely high ferritin (>10,000 μg/L), with glycosylated ferritin ≤20% being diagnostic 1
- Hemophagocytic lymphohistiocytosis (HLH) - ferritin >6,000 μg/L significantly associated with HLH diagnosis 3
- Systemic inflammatory response syndrome 1
- Chronic inflammatory conditions - any active inflammatory state 1
Malignancy
- Solid tumors - second most common cause in hospitalized patients 4
- Lymphomas 1
- Hematological malignancies - most prevalent diagnosis in patients with ferritin >2,000 μg/L 3
Infection
- Active infections - ferritin rises as an acute phase reactant 1
- Severe infections - second most common cause after hematologic malignancy in extreme hyperferritinemia 3
Other Conditions
- Chronic kidney disease - particularly with anemia 1
- Cell necrosis - muscle or liver tissue damage 1
- Diabetes mellitus/metabolic syndrome 1
Algorithmic Approach Based on Transferrin Saturation
Step 1: Measure TS and Ferritin Together
- If TS ≥45%: Suspect primary iron overload → proceed to HFE genetic testing for C282Y and H63D mutations 1
- If TS <45%: Iron overload unlikely → investigate secondary causes 1
Step 2: Risk Stratification by Ferritin Level
- Ferritin <1,000 μg/L: Low risk of organ damage (94% negative predictive value for advanced fibrosis) 5
- Ferritin 1,000-10,000 μg/L: Higher risk if iron overload present; evaluate for liver disease with liver enzymes and platelet count 1
- Ferritin >10,000 μg/L: Rarely represents simple iron overload; consider AOSD, HLH, or macrophage activation syndrome requiring urgent specialist referral 1, 5
Step 3: Distinguish Functional Iron Deficiency from Inflammatory Block
This distinction is crucial in chronic kidney disease patients. 6
- Functional iron deficiency: Serial ferritin levels decrease during erythropoietin therapy but remain >100 ng/mL; responds to IV iron 6
- Inflammatory iron block: Abrupt increase in ferritin with sudden drop in TS; does not respond to IV iron trial 6
- Trial approach: Give weekly IV iron (50-125 mg) for 8-10 doses; if no erythropoietic response occurs, inflammatory block is likely 6
Critical Pitfalls to Avoid
- Never use ferritin alone without transferrin saturation to diagnose iron overload 1
- Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests 1
- Do not assume iron overload when TS <45% - secondary causes predominate 1
- Recognize that ferritin is an acute phase reactant - it rises with inflammation, infection, and liver disease independent of iron stores 6
- Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1
- Extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload - consider life-threatening conditions like HLH 5
Special Clinical Contexts
Chronic Kidney Disease with Anemia
- Elevated ferritin (500-1,200 μg/L) with low TS (<25%) may still warrant IV iron therapy 1
- Functional iron deficiency can occur despite elevated ferritin when erythropoiesis is pharmacologically stimulated 6
Cardiac Risk in Iron Overload
- Ferritin >2,500 μg/L indicates increased risk of heart failure in β-thalassemia major 5
- Iron deposition in myocardium can cause arrhythmias and cardiomyopathy 6