What does elevated ferritin (iron storage protein) level mean?

What Does Elevated Ferritin Mean?

Elevated serum ferritin is most commonly caused by inflammatory conditions, liver disease, or metabolic disorders, rather than true iron overload. 1 In the general population, iron overload is not the most common cause of an elevated ferritin level.

Causes of Elevated Ferritin

Elevated ferritin can be categorized into several major causes:

1. Inflammatory Conditions

Ferritin is an acute phase reactant that increases in:

• Chronic inflammatory diseases
• Infections
• Malignancies
• Rheumatologic conditions (including adult-onset Still's disease, systemic juvenile idiopathic arthritis)
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 2

2. Liver Disease

• Alcoholic liver disease
• Chronic hepatitis B and C
• Nonalcoholic fatty liver disease (NAFLD) 1, 3
  • In NAFLD, ferritin >1.5× upper limit of normal is independently associated with advanced hepatic fibrosis and increased NAFLD Activity Score 3

3. Iron Overload Conditions

• Hereditary hemochromatosis (HFE gene mutations)
• Transfusional iron overload
• Other genetic iron loading disorders

4. Other Causes

• Metabolic syndrome
• Diabetes
• Obesity
• Alcohol consumption 4
• Malignancy (particularly hematologic)

Diagnostic Approach to Elevated Ferritin

Step 1: Assess Ferritin Level and Transferrin Saturation

• Measure both serum ferritin and transferrin saturation (TS)
• If TS ≥45% and ferritin is elevated, consider iron overload disorders 1
• If TS <45% with elevated ferritin, non-iron overload causes are more likely

Step 2: Evaluate for Common Non-Iron Overload Causes

• Check liver enzymes (ALT, AST)
• Screen for inflammatory markers (CRP, ESR)
• Assess for metabolic syndrome features
• Review alcohol consumption history

Step 3: Further Testing Based on Initial Findings

• For suspected iron overload (TS ≥45% and elevated ferritin):
  • Consider HFE gene testing for C282Y and H63D mutations 1
  • Consider MRI for liver iron concentration assessment 5
• For suspected inflammatory cause:
  • Identify and treat underlying inflammatory condition

Clinical Significance of Ferritin Levels

Mild to Moderate Elevation (200-1000 μg/L)

• Most commonly due to inflammation, liver disease, or metabolic disorders
• In this range, ferritin/AST ratio can help distinguish between iron overload and other causes 6

Marked Elevation (>1000 μg/L)

• Warrants referral to specialist (gastroenterologist, hematologist) 4
• May indicate:
  • Advanced iron overload
  • Significant inflammation
  • Malignancy
  • Severe liver disease

Extreme Elevation (>10,000 μg/L)

• Strongly associated with conditions like adult-onset Still's disease or hemophagocytic lymphohistiocytosis 2
• Requires urgent evaluation

Important Caveats

1. False Positives: Ferritin has significant false positive rate for iron overload due to its role as an acute phase reactant 1

2. Discordance with Iron Stores: In some cases, patients may have iron overload despite normal ferritin levels, particularly in non-HFE related iron overload 1

3. Predictor of Fibrosis: In hemochromatosis, ferritin >1000 μg/L with elevated liver enzymes and low platelets predicts cirrhosis in 80% of C282Y homozygotes 1

4. Monitoring Treatment: In patients receiving iron chelation therapy, ferritin is used to monitor response, with target levels typically <500-1000 μg/L 7

Remember that 90% of elevated ferritin cases are due to non-iron overload conditions 4, so a systematic approach to diagnosis is essential to avoid unnecessary treatments like therapeutic phlebotomy in patients who would not benefit.