What does a high ferritin level indicate?

What Does a High Ferritin Level Indicate?

A high ferritin level most commonly indicates inflammation, liver disease, or malignancy rather than true iron overload, but when accompanied by elevated transferrin saturation (≥45%), it suggests iron overload disorders such as hereditary hemochromatosis. 1

Primary Interpretation Framework

Ferritin is a highly sensitive but poorly specific marker that requires interpretation in clinical context:

• Ferritin suffers from low specificity as elevated values result from inflammatory conditions, metabolic disorders (diabetes mellitus), alcohol consumption, hepatocellular necrosis, and malignancies 1
• In a large tertiary care analysis of 627 patients with ferritin >1000 μg/L, malignancy was the most frequent cause (153/627), followed by iron-overload syndromes (136/627), with only 6 cases of inflammatory rheumatologic diseases 2
• Normal ferritin levels essentially rule out iron overload in hemochromatosis, making it an excellent negative predictor 1

Algorithmic Approach to Elevated Ferritin

Step 1: Measure Transferrin Saturation Simultaneously

• Always measure fasting transferrin saturation (TS) alongside ferritin to distinguish true iron overload from secondary causes 1, 3, 4
• If TS ≥45% with elevated ferritin, suspect iron overload disorders and proceed to HFE genotype testing for C282Y and H63D mutations 1, 3
• If TS <45% with elevated ferritin, consider inflammatory conditions, anemia of chronic disease, liver disease, or malignancy 3, 4, 5

Step 2: Risk Stratification by Ferritin Level

Ferritin <1000 μg/L:

• Low risk of significant organ damage even if iron overload is present 3, 4
• In C282Y homozygotes with ferritin <1000 μg/L, normal transaminases, and age <40 years, therapeutic phlebotomy can proceed without liver biopsy 1

Ferritin >1000 μg/L:

• Critical threshold indicating 20-45% prevalence of cirrhosis in C282Y homozygotes 1, 4
• Strongly consider liver biopsy if accompanied by elevated liver enzymes or platelet count <200,000/μL to assess for cirrhosis 1, 3, 4
• Negative predictive value of 94% for advanced fibrosis when ferritin <1000 μg/L with normal transaminases 4

Ferritin >10,000 μg/L:

• Suggests life-threatening conditions including adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome requiring urgent specialist referral 3, 2
• Average ferritin in these rheumatologic syndromes was 14,242 μg/L 2

Common Causes by Category

Iron Overload Disorders (True Iron Excess)

• Hereditary hemochromatosis (HFE-related): C282Y homozygosity present in >80% of clinically overt cases 1
• Penetrance varies significantly: 28.4% of male C282Y homozygotes develop iron-overload-related disease versus only 1.2% of female homozygotes 6
• Secondary iron overload: thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, pyruvate kinase deficiency, or transfusion-dependent disorders 7, 8

Non-Iron Overload Causes (Ferritin as Acute Phase Reactant)

• Chronic liver disease: alcoholic liver disease, viral hepatitis, non-alcoholic fatty liver disease (NAFLD) 1, 3, 7
• Inflammatory conditions: rheumatologic diseases, chronic kidney disease 1, 3, 5
• Malignancy: most common cause in patients with ferritin >1000 μg/L in tertiary care settings 2
• Infections and metabolic syndrome: diabetes mellitus, obesity 1, 5

Genotyping Considerations

• C282Y homozygosity prevalence varies by ethnicity: 0.44% in non-Hispanic whites, 0.11% in Native Americans, 0.027% in Hispanics, 0.014% in blacks, and near-zero in Asians 9
• 84% of male and 73% of female C282Y homozygotes have elevated transferrin saturation, while 88% of males and 57% of females have elevated ferritin 1, 9
• First-degree relatives of C282Y homozygotes should undergo genotyping as penetrance is higher in family members than the general population 1, 4
• H63D compound heterozygosity (C282Y/H63D) alone appears insufficient to cause significant iron overload without additional acquired risk factors 1

Critical Pitfalls to Avoid

• Never interpret ferritin in isolation without transferrin saturation 3, 4, 5
• Do not assume C282Y heterozygosity alone causes clinically relevant iron overload—a second cofactor (alcohol, NAFLD, hepatitis C) is required 5
• Avoid overlooking liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests, as this combination has 100% sensitivity for identifying cirrhosis 4
• Do not use serum iron concentration or transferrin saturation as surrogate markers of tissue iron stores—they do not quantitatively reflect body iron burden 1
• Recognize that extremely high ferritin can occur in seemingly indolent disease with chronic low-grade inflammation 2

When to Pursue Advanced Imaging

• MRI with T2/T2 relaxometry is the standard non-invasive method* to quantify hepatic iron concentration and monitor iron chelation therapy effectiveness 8
• MRI shows excellent correlation with biochemical hepatic iron concentration (correlation coefficient 0.74-0.98) with 84-91% sensitivity and 80-100% specificity 1
• Cardiac T2 mapping assesses cardiac iron* in transfusion-dependent disorders like β-thalassemia major, where ferritin >2500 μg/L indicates increased heart failure risk 3