What are the differential diagnoses for elevated ferritin levels?

Differential Diagnosis of Elevated Ferritin

Primary Diagnostic Framework

Elevated ferritin has over 90% likelihood of being caused by non-iron overload conditions including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD—not hereditary hemochromatosis. 1, 2

The critical first step is measuring transferrin saturation (TS) alongside ferritin to distinguish true iron overload from inflammatory/secondary causes. 3, 4, 2

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Algorithmic Approach Based on Transferrin Saturation

If TS ≥ 45% with elevated ferritin:

Consider iron overload disorders first:

• 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
• Secondary iron overload from hematologic disorders: Thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, pyruvate kinase deficiency 5
• Iatrogenic iron overload: Chronic transfusions, excessive iron supplementation 5

Action: Proceed directly to HFE genetic testing for C282Y and H63D mutations. 1, 3, 4

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If TS < 45% with elevated ferritin:

Iron overload is unlikely—focus on secondary causes: 4, 2, 6

Inflammatory/Infectious Causes:

• Acute or chronic infections (ferritin rises as acute phase reactant) 2, 7
• Systemic inflammatory response syndrome 2
• Rheumatologic conditions: Adult-onset Still's disease (especially if ferritin >10,000 μg/L with glycosylated ferritin ≤20%), hemophagocytic lymphohistiocytosis/macrophage activation syndrome 3, 2, 7

Liver Disease:

• Alcoholic liver disease 1, 2, 8
• Viral hepatitis (B and C) 2, 5
• Non-alcoholic fatty liver disease (NAFLD) 1, 2
• Acute hepatitis with cell necrosis 2

Malignancy:

• Solid tumors 2, 7
• Lymphomas 2, 7
• Hepatocellular carcinoma 1

Metabolic Conditions:

• Metabolic syndrome (check blood pressure, BMI, cholesterol, triglycerides, glucose) 1, 2, 8
• Diabetes mellitus 1
• Obesity 8

Other Causes:

• Chronic kidney disease/renal failure 2, 5
• Cell necrosis (check AST, ALT, CK) 1, 2

Action: Check inflammatory markers (CRP, ESR), liver enzymes (ALT, AST), and assess for underlying conditions listed above. 1, 3

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Risk Stratification by Ferritin Level

Ferritin < 1000 μg/L:

• Low risk of organ damage (negative predictive value 94% for advanced liver fibrosis in hemochromatosis) 3, 4, 2
• Focus on identifying and treating underlying secondary causes 3, 4

Ferritin 1000-10,000 μg/L:

• Higher risk of advanced fibrosis/cirrhosis if iron overload present (20-45% prevalence of cirrhosis in C282Y homozygotes) 3, 4
• Mandatory specialist referral to gastroenterologist, hematologist, or iron overload specialist 3
• Consider liver biopsy if ferritin >1000 μg/L with elevated liver enzymes, hepatomegaly, age >40 years, or platelet count <200,000/μL 1, 3, 4

Ferritin > 10,000 μg/L:

• Life-threatening conditions requiring urgent specialist referral: Adult-onset Still's disease (average ferritin 14,242 μg/L), hemophagocytic lymphohistiocytosis, macrophage activation syndrome 3, 2, 7
• Also consider severe malignancy or overwhelming infection 7

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Complete Differential Diagnosis List

Primary Iron Overload:

• HFE hemochromatosis (C282Y homozygosity, C282Y/H63D compound heterozygosity) 1, 2
• Non-HFE hemochromatosis (TFR2, SLC40A1, HAMP, HJV mutations) 1, 2, 5
• Thalassemia major/intermedia 3, 5
• Myelodysplastic syndrome 5
• Sideroblastic anemia 5

Liver Disease:

• Chronic alcohol consumption 1, 2
• NAFLD/metabolic syndrome 1, 2
• Viral hepatitis B or C 2, 5
• Acute hepatitis 2
• Cirrhosis from any cause 1, 4

Inflammatory/Rheumatologic:

• Adult-onset Still's disease 3, 2, 7
• Hemophagocytic lymphohistiocytosis 3, 2, 7
• Systemic inflammatory response syndrome 2
• Chronic inflammatory conditions 1

Malignancy:

• Solid tumors 2, 7
• Lymphomas 2, 7
• Hepatocellular carcinoma 1

Other:

• Chronic kidney disease 2, 5
• Diabetes mellitus 1, 8
• Infections (acute or chronic) 2, 7
• Cell necrosis (muscle, liver) 1, 2

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Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload—ferritin is highly sensitive but poorly specific. 1, 4
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests—this identifies cirrhosis with 100% sensitivity. 3, 4
• Do not assume iron overload when TS <45%—this pattern indicates inflammatory/secondary causes requiring different management. 4, 2, 6
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed. 1, 4
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload—think life-threatening inflammatory conditions first. 3, 7

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