What is the protocol for managing patients with elevated ferritin (iron storage protein) levels and normal iron serum levels?

Management Protocol for Elevated Ferritin with Normal Iron Serum Levels

Patients with elevated ferritin levels and normal serum iron should be evaluated using a systematic approach that prioritizes identifying the underlying cause, as hyperferritinemia often reflects inflammatory conditions rather than true iron overload. 1

Diagnostic Approach

Initial Assessment

• Evaluate transferrin saturation (TSAT) alongside ferritin:
  • TSAT >45%: Suggests true iron overload
  • TSAT <20%: Suggests functional iron deficiency with inflammation 1
  • Normal TSAT with elevated ferritin: Consider non-iron overload causes

Common Causes of Elevated Ferritin with Normal Iron

1. Inflammatory conditions (most common):

   • Chronic infections
   • Autoimmune disorders
   • Malignancies (most frequent cause of markedly elevated ferritin >1000 μg/L) 2
   • Liver disease (especially non-alcoholic fatty liver disease)

2. Metabolic conditions:

   • Metabolic syndrome
   • Obesity
   • Diabetes mellitus

3. Rare but serious conditions:

   • Hemophagocytic lymphohistiocytosis (HLH) - ferritin often >10,000 μg/L 1
   • Adult-onset Still's disease
   • Macrophage activation syndrome

Diagnostic Testing Algorithm

1. First-line tests:

   • Complete blood count
   • Comprehensive metabolic panel (liver function tests)
   • Iron studies (serum iron, TIBC, TSAT, ferritin)
   • C-reactive protein and ESR (to assess inflammation)

2. Second-line tests (based on clinical suspicion):

   • Calculate ferritin/AST ratio:
     • High ratio (>20) suggests iron overload
     • Low ratio suggests inflammation as cause 3
   • HFE gene testing for C282Y and H63D mutations if TSAT >45% 1
   • Liver ultrasound if liver enzymes are elevated

3. Advanced testing (for selected cases):

   • Liver biopsy with hepatic iron concentration measurement if ferritin >1000 μg/L 1
   • Cardiac evaluation (ECG, echocardiography) for severe suspected iron overload 1

Management Protocol

For Inflammatory Causes (Normal TSAT, elevated ferritin)

• Identify and treat the underlying inflammatory condition
• Do not initiate phlebotomy as this may worsen anemia of chronic disease 1
• Monitor ferritin levels every 3 months during treatment of underlying condition 1

For True Iron Overload (Elevated TSAT >45%, elevated ferritin)

• Therapeutic phlebotomy (400-500 mL weekly or biweekly) until ferritin reaches 50-100 μg/L 1
• Genetic counseling for patients with confirmed hereditary hemochromatosis
• Monitor ferritin and TSAT every 3 months during active treatment 1

For Metabolic Syndrome/NAFLD

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

Referral Criteria

• Refer to gastroenterology or hematology when:
  • Ferritin >1000 μg/L
  • TSAT >45% with elevated ferritin
  • Persistently elevated liver enzymes
  • Suspected hematologic malignancy 1

Important Considerations and Pitfalls

• Pitfall #1: Relying solely on ferritin levels without TSAT can lead to misdiagnosis of iron overload 4

• Pitfall #2: Using standard ferritin thresholds (<30 μg/L) for iron deficiency in inflammatory states can miss true iron deficiency 4

• Pitfall #3: Initiating phlebotomy based on ferritin alone without confirming iron overload can worsen anemia 1

• In inflammatory conditions, a higher ferritin threshold (<100 μg/L) or TSAT <20% should be used to diagnose iron deficiency 4

• Extremely high ferritin levels (>10,000 μg/L) should prompt urgent evaluation for HLH or malignancy 1, 2

Monitoring

• Patients with confirmed non-iron overload hyperferritinemia: Monitor every 3-6 months
• Patients undergoing treatment for iron overload: Monitor every 3 months
• Stable patients without iron overload: Annual monitoring 1