What is the appropriate work-up and management for elevated ferritin levels?

Appropriate Work-up and Management for Elevated Ferritin Levels

The initial evaluation of elevated ferritin should include both serum ferritin and transferrin saturation (TS) measurements, as this combination provides the most accurate assessment of iron status. 1

Initial Diagnostic Approach

• Measure both serum ferritin and transferrin saturation (TS) simultaneously rather than relying on a single test 2, 1
• Interpret results based on the following algorithm:
  • If TS < 45% and normal ferritin: No further evaluation needed 2, 1
  • If TS ≥ 45% and/or elevated ferritin: Proceed with HFE gene mutation analysis 2, 1

Common Causes of Elevated Ferritin

• With normal transferrin saturation (non-iron overload causes):

  • Inflammatory conditions (most common): alcoholic liver disease, viral hepatitis, NAFLD 1, 3
  • Chronic inflammatory diseases: rheumatologic conditions 1
  • Malignancy (most frequent cause of markedly elevated ferritin >1000 μg/L) 4
  • Metabolic syndrome 3
  • Cell necrosis 3

• With elevated transferrin saturation (iron overload causes):

  • Hereditary hemochromatosis (HFE gene mutations) 2, 3
  • Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 3

Detailed Evaluation Based on Initial Findings

If TS < 45% (Normal):

• Evaluate for inflammatory conditions with CRP, ESR 1
• Check liver enzymes (ALT, AST) 1
• Consider metabolic syndrome markers 3
• Rule out malignancy if clinically indicated 4

If TS ≥ 45% (Elevated):

• Perform HFE genetic testing for C282Y and H63D mutations 2, 3
• Assess for potential organ damage:
  • Liver: hepatomegaly, liver enzymes 2
  • Joints: arthritis, joint swelling 2, 5
  • Heart: signs of cardiomyopathy 2
  • Skin: increased pigmentation 2
  • Endocrine: testicular atrophy, hypothyroidism 2

Management Based on Ferritin Level and Cause

For Hereditary Hemochromatosis:

• If ferritin < 1000 μg/L: Therapeutic phlebotomy to achieve ferritin < 50 μg/L 1
• If ferritin > 1000 μg/L: Consider liver biopsy, especially with elevated liver enzymes and platelets < 200,000/μL 2, 1

For Secondary Causes:

• Treat the underlying condition rather than focusing on the elevated ferritin 1
• For alcoholic liver disease: alcohol cessation 3
• For NAFLD: weight loss, management of metabolic syndrome 3
• For inflammatory conditions: appropriate anti-inflammatory therapy 1

Referral Guidelines

• Consider specialist referral if:
  • Ferritin > 1000 μg/L 6
  • Evidence of organ damage 1
  • Cause remains unclear despite initial evaluation 6
  • Extremely high ferritin (>10,000 μg/L) suggesting conditions like adult-onset Still's disease or hemophagocytic lymphohistiocytosis 1, 4

Common Pitfalls to Avoid

• Using ferritin alone without transferrin saturation to diagnose iron overload 1, 7
• Overlooking the need for liver biopsy in patients with ferritin > 1000 μg/L and abnormal liver tests 1
• Failing to recognize that 90% of elevated ferritin cases are due to non-iron overload conditions 6
• Initiating therapeutic phlebotomy without confirming iron overload 1, 6
• Neglecting family screening in confirmed cases of hereditary hemochromatosis 2