What is the diagnosis and treatment approach for elevated ferritin levels?

Diagnosis and Management of Elevated Ferritin Levels

Elevated ferritin levels require a systematic diagnostic approach to determine if they represent true iron overload or are due to inflammatory conditions, with treatment directed at the underlying cause. 1

Diagnostic Evaluation

Initial Assessment

• Serum ferritin and transferrin saturation (TSAT) are the first-line tests
  • TSAT >45% suggests true iron overload disorders 1
  • TSAT >60% with ferritin >963 μg/L identifies 95% of patients with severe iron overload 2

Secondary Testing

• Review alcohol consumption history as alcohol is a common cause of hyperferritinemia 1
• HFE genotyping for p.C282Y and H63D mutations to identify hereditary hemochromatosis 1
• Inflammatory markers (CRP, ESR) to identify inflammatory causes 1
• Liver function tests including hepatitis serology and autoimmune markers 1

Advanced Testing

• MRI for liver iron concentration is the non-invasive standard for quantifying iron overload 1, 3
  • T2 and T2* relaxometry are considered standard techniques 3
  • Reduces need for liver biopsy, which should be reserved for selected cases 3

Common Causes of Elevated Ferritin

Iron Overload Conditions

• Hereditary hemochromatosis (HFE gene mutations)
• Non-HFE hemochromatosis variants
• Transfusional iron overload

Non-Iron Overload Conditions (90% of cases) 1

• Alcoholic liver disease
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome
• Inflammatory conditions (acute and chronic)
• Malignancies (most common cause in some studies) 4
• Renal failure
• Infections

Interpretation of Ferritin Levels

• <500 μg/L: Normal or mild elevation
• 500-1000 μg/L: Moderate elevation, commonly due to inflammation, liver disease, or early iron overload
• >1000 μg/L: High risk of cirrhosis (20-45%) if due to iron overload 1
• >10,000 μg/L: Severe elevation, often seen in hemophagocytic syndromes, Still's disease, or multiple underlying conditions 4, 5

Treatment Approach

For Non-Iron Overload Causes

• Treat the underlying condition (inflammation, infection, malignancy) 1
• Lifestyle modifications:
  • Weight loss if overweight/obese
  • Limited alcohol intake or abstinence
  • Avoidance of iron supplements
  • Regular physical activity
  • Reduced consumption of processed foods and sugar 1

For True Iron Overload

• Phlebotomy therapy for hereditary hemochromatosis and other iron overload conditions 1

  • Target maintenance ferritin levels: 50-100 μg/L
  • Target TSAT: <45%
  • Monitor every 1-3 months during treatment

• Iron chelation therapy (e.g., deferasirox) for transfusional iron overload 1, 6

  • Indicated when:
    • Ferritin >1000 μg/L with evidence of iron overload
    • TSAT >45%
    • In transfusion-dependent patients 6
  • Starting dose: 14 mg/kg/day (for patients with eGFR >60 ml/min/1.73m²) 6
  • Adjust dose every 3-6 months based on serum ferritin trends 6
  • Monitor serum ferritin monthly 6

Monitoring and Follow-up

• Regular monitoring of ferritin levels every 3 months until normalized 1
• Monitor liver enzymes regularly to detect liver damage 1
• Screen for complications such as diabetes, arthropathy, and cardiac dysfunction 1
• For patients on chelation therapy: Monitor blood counts, liver function, renal function monthly 6

When to Refer

• Ferritin >1,000 μg/L or unclear cause after initial evaluation 1
• Elevated TSAT >45% with suspected iron overload 1
• Elevated liver enzymes 1
• Primary referral should be to a gastroenterologist for initial evaluation 1

Common Pitfalls

• Assuming elevated ferritin always indicates iron overload - 90% of cases are due to non-iron overload conditions 1
• Overlooking alcohol consumption as a cause of elevated ferritin 1
• Continuing chelation therapy when ferritin falls below 500 μg/L (therapy should be interrupted) 6
• Using high doses of chelation when iron burden is approaching normal range (can lead to life-threatening adverse events) 6