To whom should a patient with elevated ferritin levels be referred?

Referral Pathway for Patients with Elevated Ferritin

Patients with elevated ferritin levels should be referred based on the degree of elevation, associated symptoms, and suspected underlying cause, with levels >1000 μg/L warranting specialist referral to a gastroenterologist, hematologist, or physician with expertise in iron disorders.

Initial Assessment and Classification

When evaluating elevated ferritin levels, first determine the degree of elevation and check additional iron studies:

• Mild-Moderate Elevation (above normal but <1000 μg/L)

  • Check transferrin saturation (TS) to differentiate true iron overload from inflammatory causes 1
  • TS ≥45% suggests iron overload
  • TS <45% suggests inflammatory/reactive cause

• Marked Elevation (>1000 μg/L)

  • Requires specialist referral regardless of other findings 2
  • Urgent referral if >10,000 μg/L (90% sensitive, 96% specific for hemophagocytic lymphohistiocytosis) 3

Referral Algorithm Based on Clinical Context

1. Suspected Iron Overload (TS ≥45%)

• Refer to Hematologist or Gastroenterologist
  • Order HFE gene testing before referral if hereditary hemochromatosis suspected 1
  • Patients with C282Y homozygosity or compound heterozygosity (C282Y/H63D) with elevated ferritin should be referred for therapeutic phlebotomy evaluation 1
  • Patients with ferritin >1000 μg/L and elevated liver enzymes require urgent referral due to high risk of cirrhosis 1

2. Suspected Iron Deficiency (Low Ferritin)

• Refer to Gastroenterologist
  • Men and postmenopausal women with iron deficiency anemia require bidirectional endoscopy 1
  • Premenopausal women with GI symptoms should have endoscopy and small bowel biopsy 4

3. Inflammatory/Reactive Causes (Normal or Elevated Ferritin with TS <45%)

• Refer based on suspected underlying condition:
  • Rheumatologist: For suspected adult-onset Still's disease, systemic juvenile idiopathic arthritis, or other rheumatologic conditions 5
  • Hematologist: For suspected hematologic malignancy, especially if accompanied by cytopenias, splenomegaly 6
  • Hepatologist: For suspected liver disease, especially with elevated liver enzymes 5
  • Infectious Disease: For suspected chronic infections with persistent hyperferritinemia 6

4. Extremely Elevated Ferritin (>10,000 μg/L)

• Emergency Referral to Hematologist
  • Highly suspicious for hemophagocytic lymphohistiocytosis/macrophage activation syndrome 3
  • May also indicate advanced malignancy or severe liver disease 7
  • Requires immediate evaluation and treatment

Additional Testing Before Referral

• Complete blood count
• Comprehensive metabolic panel (liver and kidney function)
• Transferrin saturation
• HFE gene testing if hereditary hemochromatosis suspected
• Inflammatory markers (CRP, ESR) if inflammatory condition suspected
• Consider tissue transglutaminase antibodies if celiac disease suspected 1

Common Causes of Elevated Ferritin

1. Non-Iron Overload Conditions (90% of cases) 2

   • Inflammatory states (infection, autoimmune disease)
   • Liver disease (alcoholic, viral, NAFLD)
   • Malignancy
   • Metabolic syndrome
   • Renal failure

2. Iron Overload Conditions (10% of cases)

   • Hereditary hemochromatosis
   • Multiple blood transfusions
   • Ineffective erythropoiesis

Pitfalls to Avoid

• Do not assume elevated ferritin always indicates iron overload; it's an acute phase reactant 1
• Do not refer all patients with mildly elevated ferritin if other causes are evident
• Do not overlook the need for GI evaluation in men and postmenopausal women with iron deficiency 1
• Do not miss extremely elevated ferritin (>10,000 μg/L) as this requires urgent evaluation 3
• Do not interpret ferritin in isolation; always check transferrin saturation 1

By following this structured approach, primary care physicians can ensure appropriate and timely referral of patients with elevated ferritin levels to the most suitable specialist.