What is the initial step in managing a patient with elevated ferritin (iron storage protein) and neutropenia (low neutrophil count)?

Initial Evaluation and Management of Elevated Ferritin and Neutropenia

The initial step in managing a patient with elevated ferritin and neutropenia should be to determine the underlying cause through targeted laboratory testing, including complete blood count with differential, comprehensive metabolic panel, iron studies, and genetic testing for hemochromatosis.

Diagnostic Approach

Step 1: Initial Laboratory Evaluation

• Complete blood count with differential to confirm neutropenia (<1500 neutrophils/μL)
• Comprehensive metabolic panel to assess liver and kidney function
• Iron studies:
  • Transferrin saturation (TS)
  • Serum ferritin
  • Total iron binding capacity (TIBC)
  • Serum iron
• Inflammatory markers: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)

Step 2: Interpret Iron Studies

• If TS ≥45% and elevated ferritin: Consider iron overload disorders 1
• If TS <45% with elevated ferritin: Consider inflammatory conditions, malignancy, or liver disease 1

Step 3: Further Testing Based on Initial Results

• If iron overload suspected (TS ≥45% and elevated ferritin):

  • HFE genetic testing for C282Y and H63D mutations 1
  • If ferritin >1000 μg/L: Consider liver biopsy to assess hepatic iron concentration and fibrosis 1

• If inflammatory condition suspected (normal/low TS with elevated ferritin):

  • Evaluate for infections, autoimmune disorders, and malignancies 2
  • Consider bone marrow examination to assess neutropenia etiology 3, 4

Differential Diagnosis

Iron Overload with Neutropenia

• Hemochromatosis (HFE-related or non-HFE variants)
• Transfusional iron overload
• Ferroportin disease (rare)

Inflammatory Conditions with Elevated Ferritin

• Adult-onset Still's disease
• Hemophagocytic lymphohistiocytosis
• Macrophage activation syndrome
• Malignancy (most common cause of markedly elevated ferritin) 2

Neutropenia Etiologies

• Congenital neutropenia syndromes 4
• Acquired neutropenia (drug-induced, autoimmune)
• Iron deficiency (paradoxically can cause neutropenia) 5
• Bone marrow infiltration (malignancy)

Management Algorithm

1. For confirmed hemochromatosis with neutropenia:

   • Therapeutic phlebotomy if ferritin >1000 μg/L 1
   • Monitor neutrophil counts during treatment
   • Screen first-degree relatives for HFE mutations 1

2. For inflammatory conditions with elevated ferritin:

   • Treat underlying inflammatory condition
   • Consider G-CSF for severe neutropenia (ANC <0.5 × 10^9/L) with recurrent infections 3, 4

3. For transfusional iron overload:

   • Consider iron chelation therapy with deferasirox if:
     • Evidence of chronic transfusional iron overload
     • Serum ferritin consistently >1000 μg/L 6
   • Monitor for bone marrow suppression during treatment, as deferasirox can worsen neutropenia 6

Monitoring and Follow-up

• Monitor serum ferritin monthly during treatment 1, 6
• For patients on phlebotomy: Target ferritin <1000 μg/L initially, then <500 μg/L for maintenance 1
• For patients on chelation therapy: Monitor CBC, liver function, renal function monthly 6
• For neutropenia: Follow neutrophil counts regularly; frequency depends on severity

Common Pitfalls to Avoid

1. Misinterpreting elevated ferritin: Remember that ferritin is an acute phase reactant and can be elevated in many inflammatory conditions unrelated to iron overload 1, 2

2. Overlooking non-HFE causes of iron overload: Not all iron overload is due to classic hemochromatosis; consider rare genetic disorders if HFE testing is negative 1

3. Focusing only on iron overload: Neutropenia requires its own diagnostic workup and may be unrelated to the elevated ferritin 3, 4

4. Initiating treatment before establishing diagnosis: Therapeutic phlebotomy or chelation therapy should not be started until iron overload is confirmed 1

5. Missing malignancy: Malignancy is the most common cause of markedly elevated ferritin levels (>1000 μg/L) and should always be considered 2