What is the appropriate management for a patient with hypoferritinemia and hyperferremia?

Management of Hypoferritinemia with Hyperferremia

A patient with low ferritin (24 ng/mL) and high serum iron (228 μg/dL) with elevated iron saturation (58%) requires evaluation for rare genetic disorders of iron metabolism and should undergo genetic testing for conditions like hypotransferrinemia or ferroportin disease.

Diagnostic Approach

This unusual pattern of laboratory values (low ferritin with high iron and high transferrin saturation) is atypical and suggests a rare disorder of iron metabolism rather than common conditions like hemochromatosis or iron deficiency.

Key Findings in This Case:

• Ferritin: 24 ng/mL (LOW) - below reference range of 30-400 ng/mL
• Serum Iron: 228 μg/dL (HIGH) - above reference range of 59-158 μg/dL
• Iron Saturation: 58% (HIGH) - above reference range of 20-55%
• TIBC: 396 μg/dL (NORMAL) - within reference range of 228-428 μg/dL

Differential Diagnosis:

1. Hypotransferrinemia due to TF gene defects:

   • The combination of low ferritin with high iron saturation is characteristic 1
   • This condition presents with hypochromic microcytic anemia, low iron binding capacity, and increased ferritin 1
   • However, this patient has normal TIBC, making this diagnosis less likely

2. Ferroportin disease (SLC40A1 mutations):

   • Can present with variable iron parameters
   • May have hyperferritinemia with normal transferrin saturation in classical form

3. Aceruloplasminemia (CP gene defects):

   • Presents with low serum iron, high ferritin, and low ceruloplasmin 1
   • Not consistent with this patient's high serum iron

4. Rare ferritin L-subunit variants:

   • Recently identified FTL gene mutations can cause severe hypoferritinemia without anemia 2
   • Can lead to iron overload despite low ferritin levels
   • Patients may develop severe iron overload with only modest increases in ferritin 2

Recommended Evaluation

1. Complete Blood Count:

   • Assess for anemia, microcytosis, or hypochromia

2. Genetic Testing:

   • Test for mutations in:
     • Transferrin (TF) gene 1
     • Ferritin light chain (FTL) gene 2
     • SLC40A1 gene (ferroportin)

3. Additional Laboratory Tests:

   • Ceruloplasmin level
   • Liver function tests
   • Inflammatory markers (CRP, ESR) to rule out inflammatory causes 3
   • Hepatitis serology to exclude liver disease as a cause 3

4. Imaging:

   • MRI for liver iron quantification is essential to assess for tissue iron overload 3, 4
   • This can differentiate between true iron overload and other causes of abnormal iron parameters 3

Treatment Approach

Treatment should be guided by the underlying diagnosis and evidence of tissue iron overload:

1. If FTL gene mutation is confirmed:

   • Avoid IV iron supplementation which can lead to severe iron overload 2
   • Consider phlebotomy if MRI shows evidence of tissue iron overload

2. If hypotransferrinemia is confirmed:

   • Transferrin supplementation by plasma transfusion or apotransferrin infusion is recommended 1
   • Monitor iron status to detect toxic iron loading early 1
   • Consider phlebotomies if systemic iron loading is present 1

3. If tissue iron overload is confirmed by MRI:

   • Initiate phlebotomy with careful monitoring of hemoglobin levels 3
   • Target ferritin level of 50-100 μg/L for maintenance 1, 3
   • Remove one unit of blood (450-500 mL) weekly or biweekly 3
   • Check hemoglobin before each phlebotomy 3

4. If no tissue iron overload is found:

   • Avoid iron supplementation 3
   • Monitor iron parameters every 3-6 months 3

Important Considerations

• Avoid empiric iron supplementation despite low ferritin, as this could worsen iron overload, especially in patients with FTL mutations 2
• Family screening may be necessary once a genetic diagnosis is established 1
• Lifestyle modifications:
  • Avoid vitamin C supplements as they can accelerate iron mobilization 3
  • Limit alcohol intake 3
  • Avoid iron-fortified foods 1
  • Limit red meat consumption 1

Follow-up

• Monitor iron parameters (ferritin, transferrin saturation) every 3 months 3
• Repeat MRI for liver iron concentration after 6-12 months of treatment 4
• Screen for complications of iron overload including diabetes, arthropathy, and cardiac dysfunction 3

This unusual presentation requires careful evaluation to establish the correct diagnosis and guide appropriate management, as standard approaches to either iron deficiency or iron overload may be harmful in this context.