What is the evaluation and management approach for patients with hyperferritinemia?

Evaluation and Management of Hyperferritinemia

The evaluation of hyperferritinemia requires a systematic approach that includes iron studies, transferrin saturation assessment, and targeted investigations for underlying causes, with treatment directed at the specific etiology. 1

Initial Diagnostic Approach

Step 1: Complete Iron Panel Assessment

• Obtain comprehensive iron studies:
  • Serum ferritin
  • Transferrin saturation (TSAT) = serum iron/TIBC × 100%
  • Complete blood count with reticulocytes
  • Liver function tests

Step 2: Interpret Iron Studies Based on Transferrin Saturation

• High TSAT (>45%) with elevated ferritin:

  • Suggests true iron overload
  • Proceed with HFE gene testing for hereditary hemochromatosis 2
  • For non-European patients, consider direct sequencing of HFE and non-HFE genes (HJV, TFR2, CP, SLC40A1) 2

• Normal/Low TSAT with elevated ferritin:

  • Suggests inflammation, liver disease, or other non-iron overload conditions 3
  • Evaluate for:
    • Inflammatory conditions (rheumatologic disorders, infections)
    • Liver diseases (hepatitis, alcoholic liver disease, NAFLD)
    • Malignancy (particularly hematologic)
    • Hemolytic anemia
    • Metabolic syndrome 4

Step 3: Risk Stratification Based on Ferritin Level

• Ferritin >1,000 μg/L:

  • Higher risk of cirrhosis (20-45%) 1
  • Consider liver biopsy or non-invasive fibrosis assessment
  • Evaluate for organ damage

• Ferritin >6,000 μg/L:

  • Consider hemophagocytic lymphohistiocytosis (HLH) 5
  • Calculate H-score to assess HLH probability
  • Associated with higher mortality

Management Based on Etiology

1. True Iron Overload (High TSAT)

• Therapeutic phlebotomy:

  • Primary treatment for iron overload
  • Remove 400-500 mL blood (200-250 mg iron) weekly or biweekly
  • Target ferritin: 50-100 μg/L 1
  • Can be performed even in patients with advanced fibrosis/cirrhosis

• Chelation therapy:

  • Indicated when ferritin >1,000 μg/L and phlebotomy is contraindicated
  • Options include deferasirox, deferoxamine, deferiprone
  • Requires careful monitoring for adverse effects:
    • Renal toxicity (contraindicated if eGFR <40 mL/min/1.73m²) 6
    • Hepatic toxicity
    • Gastrointestinal ulceration
    • Bone marrow suppression
    • Auditory and ocular abnormalities 6

2. Inflammatory/Metabolic Hyperferritinemia (Normal/Low TSAT)

• Focus on treating underlying condition:
  • Do not initiate phlebotomy (not recommended) 1
  • Implement lifestyle modifications:
    • Weight loss
    • Regular physical activity
    • Dietary modifications (reduce red meat)
    • Limit alcohol intake
    • Avoid iron supplements 1

Monitoring and Follow-up

• During active treatment:

  • Monitor ferritin and TSAT every 3 months
  • Assess for organ damage:
    • Liver: Transaminases, bilirubin, fibrosis assessment
    • Heart: ECG, echocardiography (if severe iron overload) 2
    • Joints: Evaluate for arthropathy (particularly 2nd/3rd MCP joints, ankles) 2

• After stabilization:

  • Annual monitoring of iron studies
  • Regular assessment of potentially affected organs

Special Considerations

• Cardiac evaluation:

  • ECG and echocardiography for severe iron overload
  • Consider cardiac MRI for iron quantification in severe cases 2

• Joint disease:

  • Common in hemochromatosis (particularly MCP joints, ankles)
  • Often does not respond to phlebotomy 1
  • May require specific treatment

• Extreme hyperferritinemia (>6,000 μg/L):

  • Higher mortality risk
  • Consider rare conditions like HLH, adult-onset Still's disease 7, 5
  • More aggressive evaluation and management needed

Indications for Specialist Referral

• Ferritin >1,000 μg/L with unclear etiology
• Evidence of organ damage
• Suspected hereditary hemochromatosis
• Need for chelation therapy 1

By following this systematic approach to hyperferritinemia, clinicians can identify the underlying cause and implement appropriate management strategies to reduce morbidity and mortality associated with iron overload or other conditions causing elevated ferritin.