What are the implications and management of hyperferritinemia?

Management of Hyperferritinemia

Hyperferritinemia requires a systematic diagnostic approach with measurement of both serum ferritin and transferrin saturation (TS) to properly evaluate iron status and determine appropriate management. 1, 2

Diagnostic Approach

• Initial evaluation should include both serum ferritin and transferrin saturation (TS) measurements to distinguish between true iron overload and inflammatory conditions 3, 1
• Interpret ferritin levels based on the following algorithm:
  • TS ≥ 45% with elevated ferritin: Consider iron overload disorders (hemochromatosis) 3, 2
  • TS < 45% with elevated ferritin: Consider inflammatory conditions, liver disease, or other non-iron overload causes 1, 2

Risk Stratification Based on Ferritin Level

• Ferritin < 1000 μg/L: Lower risk of significant organ damage 3, 2
• Ferritin > 1000 μg/L: Higher risk of advanced fibrosis/cirrhosis in iron overload conditions; consider liver biopsy 3
• Extremely high ferritin levels (>10,000 μg/L): Consider adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 3, 4

Common Causes of Hyperferritinemia

Iron Overload Conditions

• Hereditary hemochromatosis (HFE gene mutations, particularly C282Y homozygotes) 3, 1
• Transfusional iron overload 4

Non-Iron Overload Conditions

• Inflammatory disorders (rheumatologic diseases, adult-onset Still's disease) 3, 1
• Liver diseases (alcoholic liver disease, viral hepatitis, NAFLD) 1, 2
• Infections 1, 5
• Malignancies (hematologic and solid) 4, 5

Management Based on Cause

For Hereditary Hemochromatosis

• If ferritin < 1000 μg/L and normal liver enzymes: Therapeutic phlebotomy without liver biopsy 3
• If ferritin > 1000 μg/L or abnormal liver enzymes: Consider liver biopsy to assess for fibrosis/cirrhosis 3
• Therapeutic phlebotomy goal: Achieve ferritin < 50-100 μg/L 1, 2

For Secondary Causes

• Treat the underlying condition rather than focusing on the elevated ferritin 1
• Monitor ferritin levels as a marker of disease activity in inflammatory conditions 1

For Iron Chelation (in transfusional iron overload)

• Consider deferasirox in transfusion-dependent patients with chronic iron overload 6
• Monitor for potential adverse effects including:
  • Renal toxicity (acute kidney injury, Fanconi syndrome) 6
  • Hepatic toxicity 6
  • Gastrointestinal ulceration 6
  • Bone marrow suppression 6

Monitoring Recommendations

• For patients with iron overload on phlebotomy: Check hemoglobin before each procedure and ferritin every 10-12 phlebotomies 2
• For patients with secondary causes: Monitor based on the underlying condition 1
• For patients with ferritin > 1000 μg/L: Regular monitoring of liver function tests 3, 1

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 3, 1
• Failing to screen first-degree relatives of patients with HFE-related hemochromatosis 3, 2
• Administering iron supplements to patients with elevated ferritin 2
• Overlooking rare but serious causes of extreme hyperferritinemia (>10,000 μg/L) such as hemophagocytic lymphohistiocytosis 4, 5