What are the causes of elevated ferritin levels?

Causes of High Ferritin Levels

Elevated ferritin levels can be caused by various conditions including iron overload disorders, inflammatory conditions, liver disease, and malignancy, with 90% of cases due to non-iron overload conditions. 1, 2

Primary Categories of Hyperferritinemia

1. Iron Overload Disorders

• Hereditary Hemochromatosis
  • HFE gene mutations (p.C282Y homozygosity most common) 3
  • Non-HFE hemochromatosis variants 3
• Secondary Iron Overload
  • Hematologic disorders (thalassemia, myelodysplastic syndrome, sideroblastic anemia) 4
  • Multiple blood transfusions 5
  • Excessive iron supplementation 1

2. Inflammatory Conditions

• Acute and chronic infections 1
• Autoimmune disorders 1
• Adult-onset Still's disease (can cause extremely high levels >10,000 μg/L) 6, 5
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 6
• Rheumatic conditions 4

3. Liver Disease

• Alcoholic liver disease 3
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome 3, 1
• Viral hepatitis 1
• Cirrhosis 1

4. Malignancy

• Most common cause of markedly elevated ferritin (>1000 μg/L) in tertiary care settings 6
• Various cancer types 5

5. Other Causes

• Kidney failure 4
• Anemia of chronic disease 6
• Obesity 1, 2
• Diabetes 1
• Excessive alcohol consumption 3, 1

Diagnostic Approach to Hyperferritinemia

Step 1: Assess Transferrin Saturation (TSAT)

• TSAT >45% suggests true iron overload disorders 1
• TSAT <45% suggests non-iron overload causes 1

Step 2: Evaluate for Common Non-Iron Overload Causes

• Check liver function tests and hepatitis serology 1
• Screen for inflammatory markers (CRP, ESR) 1
• Assess for metabolic syndrome, obesity, diabetes 1
• Review alcohol consumption history 3

Step 3: Consider Genetic Testing if Iron Overload Suspected

• HFE genotyping for p.C282Y and H63D mutations 3, 4
• Diagnostic thresholds for hemochromatosis: 1
  • Males: TSAT >50% and ferritin >300 μg/L
  • Females: TSAT >45% and ferritin >200 μg/L

Step 4: Advanced Testing When Needed

• MRI to quantify hepatic iron concentration 1
• Liver biopsy if ferritin >1,000 μg/L to assess for cirrhosis or if cause remains unclear 1

Important Clinical Pearls

• Ferritin is an acute phase reactant and can be elevated in many inflammatory conditions without true iron overload 3
• Extremely elevated ferritin levels (>10,000 μg/L) are rare (0.08% of ferritin requests) and most commonly associated with malignancy, multiple blood transfusions, liver disease, and Still's disease 5
• Ferritin >1,000 μg/L carries a 20-45% risk of cirrhosis and warrants specialist referral 1, 2
• Serum ferritin shows significant variability when measured serially, which limits its usefulness as a standalone marker 3
• Ferritin levels can be elevated despite low tissue iron in some conditions, and conversely, cardiac iron deposition can occur despite relatively low serum ferritin levels 3

Common Pitfalls

• Assuming elevated ferritin always indicates iron overload (90% of cases are due to non-iron overload conditions) 2
• Failing to check transferrin saturation alongside ferritin 1
• Overlooking alcohol consumption as a cause of elevated ferritin 3
• Not considering malignancy in cases of markedly elevated ferritin 6
• Initiating phlebotomy therapy without confirming iron overload 2

When ferritin is >1,000 μg/L or the cause remains unclear after initial evaluation, referral to a gastroenterologist, hepatologist, or hematologist is recommended 1, 2.