What is the next step in managing a patient with normal iron levels but elevated ferritin?

Management of Normal Iron Levels with Elevated Ferritin

In patients with normal iron levels but elevated ferritin, the next step should be to assess transferrin saturation (TSAT) and inflammatory markers to determine the underlying cause, followed by targeted evaluation based on these results. 1

Diagnostic Algorithm

1. Initial Assessment

   • Confirm complete iron studies: serum iron, TIBC, TSAT, and ferritin
   • Evaluate TSAT to guide further workup:
     • TSAT >45%: Suggests true iron overload
     • TSAT <20%: Suggests functional iron deficiency with inflammation
     • Normal TSAT with elevated ferritin: Consider inflammatory conditions

2. Additional Laboratory Testing

   • Inflammatory markers (CRP, ESR)
   • Liver function tests
   • Hepatitis B and C serology
   • Complete blood count
   • Metabolic panel (glucose, lipid profile)
   • Consider ceruloplasmin and copper levels if rare disorders are suspected

Common Causes of Elevated Ferritin with Normal Iron

Inflammatory Conditions (Most Common)

• Chronic infections
• Autoimmune disorders
• Malignancy (most frequent cause of markedly elevated ferritin >1000 μg/L) 2
• Adult-onset Still's disease (extremely high ferritin levels, often >10,000 μg/L)

Metabolic Disorders

• Non-alcoholic fatty liver disease (NAFLD)
• Metabolic syndrome
• Alcohol use disorder

Other Causes

• Chronic liver disease
• Renal disease
• Hemophagocytic lymphohistiocytosis (HLH) - rare but serious

Management Based on Underlying Cause

For Inflammatory Causes

• Treat the underlying inflammatory condition
• Monitor ferritin levels every 3 months
• Avoid iron supplementation or phlebotomy

For Metabolic Syndrome/NAFLD

• Lifestyle modifications:
  • Weight loss
  • Regular physical activity
  • Reduced red meat consumption
  • Limited alcohol intake
  • Avoidance of iron supplements 1

For Suspected Iron Overload

• If TSAT >45% with elevated ferritin: Consider genetic testing for hereditary hemochromatosis
• Consider liver biopsy if ferritin >1000 μg/L (20-45% risk of cirrhosis) 1

When to Refer to Specialists

• Ferritin >1000 μg/L: Refer to gastroenterologist or hematologist
• Elevated TSAT >45%: Refer to gastroenterologist
• Extremely high ferritin (>10,000 μg/L) with cytopenias: Urgent hematology referral to rule out HLH 1
• Persistent unexplained hyperferritinemia: Consider hematology consultation

Important Caveats

• Ferritin is an acute phase reactant that increases with inflammation, complicating diagnosis 3
• Standard thresholds for iron deficiency (<30 μg/L) do not apply in inflammatory conditions 3
• In patients with inflammatory conditions, iron deficiency may be present despite normal or elevated ferritin levels
• Serum ferritin to iron ratio may be elevated in malignancy and can help differentiate from non-malignant causes 4
• Avoid therapeutic phlebotomy when hyperferritinemia is related to inflammation rather than true iron overload 1

Monitoring Recommendations

• Patients with confirmed iron overload: Monitor every 3 months during treatment
• Stable patients without iron overload: Annual monitoring
• Monitor complete blood count, liver function, and renal function monthly during treatment