What are the differential diagnoses and diagnostic tests for a patient with elevated ferritin (iron) levels?

Elevated Ferritin: Differential Diagnosis and Diagnostic Testing

Initial Diagnostic Framework

Measure both serum ferritin AND transferrin saturation (TS) simultaneously—never interpret ferritin in isolation. 1, 2 This single principle prevents the most common diagnostic error in evaluating hyperferritinemia.

Step 1: Obtain Initial Laboratory Tests

• Fasting transferrin saturation (morning sample preferred, though fasting not strictly required) 1, 3
• Serum ferritin 1, 2
• Complete blood count with differential 1
• Liver enzymes (ALT, AST) 1, 2
• Inflammatory markers (CRP, ESR) 1, 2

Step 2: Interpret Based on Transferrin Saturation

If TS <45%: Iron overload is unlikely—secondary causes predominate. 2, 4 Proceed directly to evaluating non-iron overload etiologies below. 1, 2

If TS ≥45%: Iron overload is possible—proceed to HFE genetic testing for C282Y and H63D mutations. 1, 2

Differential Diagnosis by Category

Primary Iron Overload (TS typically ≥45%)

• 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, 3
• Transfusional iron overload: Particularly when ferritin >7,500 μg/L 3

Secondary Causes (TS typically <45%)

These account for over 90% of hyperferritinemia cases in outpatients: 1, 2

Liver Disease:

• Chronic alcohol consumption 1, 2, 3
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome 1, 2, 3
• Viral hepatitis B or C 2, 3
• Acute hepatitis 2

Inflammatory/Rheumatologic Conditions:

• Adult-onset Still's disease (ferritin often >10,000 μg/L with glycosylated ferritin ≤20%) 2, 5
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 2, 5
• Systemic inflammatory response syndrome 2
• Chronic inflammatory diseases 3, 6

Malignancy:

• Solid tumors 1, 2, 5
• Lymphomas 2, 5
• Hepatocellular carcinoma 2

Other Conditions:

• Cell necrosis (hepatic, muscular—check CK) 1, 2
• Chronic kidney disease 2, 4
• Diabetes mellitus 2
• Infections (ferritin rises as acute phase reactant) 2, 3

Diagnostic Algorithm by Ferritin Level

Ferritin <1,000 μg/L

• Low risk of organ damage (negative predictive value 94% for advanced fibrosis in hemochromatosis) 2, 4
• If C282Y homozygote with elevated TS: Diagnose HFE-hemochromatosis and initiate therapeutic phlebotomy 1
• If TS <45%: Focus on secondary causes listed above 1, 2

Ferritin 1,000-10,000 μg/L

This is the critical threshold requiring additional evaluation: 1, 4

• Check platelet count and liver enzymes 1, 4
• If ferritin >1,000 μg/L with elevated AST/ALT and platelets <200,000/μL: 80% risk of cirrhosis in C282Y homozygotes—strongly consider liver biopsy 1, 4
• If C282Y homozygote: Liver biopsy recommended for patients >40 years, hepatomegaly, or elevated transaminases 1
• Consider non-invasive fibrosis assessment (MRI for hepatic iron concentration) 7
• Refer to gastroenterologist or hematologist 4

Ferritin >10,000 μg/L

Extremely high levels rarely represent simple iron overload: 2, 4

• Urgent specialist referral required 4
• Strongly consider adult-onset Still's disease (average ferritin 14,242 μg/L in one series) 5
• Evaluate for hemophagocytic lymphohistiocytosis/macrophage activation syndrome 2, 5
• Rule out severe infection, malignancy, or massive tissue necrosis 5, 6

Specific Diagnostic Tests to Order

When TS ≥45% or Suspected Iron Overload

1. HFE genetic testing for C282Y and H63D mutations 1, 2
2. If C282Y homozygote confirmed: Diagnosis established—no liver biopsy needed unless ferritin >1,000 μg/L with abnormal liver tests 1
3. If non-C282Y genotype with documented iron overload: Consider testing for non-HFE genes (TFR2, SLC40A1, HAMP, HJV) only after confirming iron excess by MRI or liver biopsy 1

When TS <45% (Secondary Causes)

1. Metabolic panel: Blood pressure, BMI, lipids, glucose for metabolic syndrome 1
2. Hepatitis B and C serologies 3
3. Alcohol use assessment 1, 3
4. Creatine kinase (CK) if muscle necrosis suspected 1
5. Age-appropriate cancer screening 1, 5
6. If ferritin >10,000 μg/L: Glycosylated ferritin (≤20% suggests Still's disease) 2

Advanced Imaging When Indicated

• Liver MRI with T2/T2 relaxometry:* Non-invasive standard for quantifying hepatic iron concentration 7
• Cardiac MRI with T2 mapping:* If severe iron overload suspected with cardiac symptoms 4, 7
• Liver biopsy: Reserved for C282Y homozygotes with ferritin >1,000 μg/L and abnormal liver tests, or when diagnosis remains unclear after non-invasive testing 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without checking transferrin saturation 2, 4
• Do not assume iron overload when TS <45%—this pattern indicates secondary hyperferritinemia 1, 2
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L, elevated liver enzymes, and low platelets 1, 4
• Do not fail to screen first-degree relatives if HFE-hemochromatosis confirmed (25% chance siblings are C282Y homozygotes) 1
• Recognize that ferritin is an acute phase reactant—inflammation, infection, and tissue damage elevate levels independent of iron stores 2, 3, 6, 8
• Do not delay specialist referral when ferritin >10,000 μg/L—these cases require urgent evaluation for life-threatening conditions 4, 5

Special Population Considerations

Inflammatory Bowel Disease

• In patients without active inflammation: Ferritin <30 μg/L indicates iron deficiency 1
• In patients with active inflammation: Ferritin up to 100 μg/L may still represent iron deficiency 1
• Ferritin >100 μg/L with TS <20% suggests anemia of chronic disease 1
• Ferritin 30-100 μg/L indicates mixed iron deficiency and anemia of chronic disease 1

Chronic Kidney Disease

• Elevated ferritin (500-1,200 μg/L) with low TS (<25%) may still warrant IV iron therapy for anemia management 4
• Ferritin >7,500 μg/L with TS >88% documented liver cell damage in dialysis patients 4, 3