What is the management approach for a patient with elevated ferritin and total iron-binding capacity (TIBC)?

Management Approach for Elevated Ferritin and Total Iron-Binding Capacity

Patients with elevated ferritin and total iron-binding capacity (TIBC) should be evaluated for hemochromatosis, even in the absence of symptoms, with genetic testing for HFE mutations as the next step in management. 1

Initial Diagnostic Approach

• Confirm elevated iron studies with repeat testing, preferably with fasting samples for transferrin saturation (TS) 1
• Calculate TS by dividing serum iron by TIBC; a TS ≥45% is considered elevated 1
• Evaluate for both primary and secondary causes of elevated ferritin 1, 2
• Check liver function tests (ALT, AST) as abnormal liver enzymes with ferritin >1000 μg/L may predict cirrhosis in hemochromatosis 1

Differential Diagnosis

Primary Iron Overload

• Hereditary hemochromatosis (HH) - most commonly due to C282Y homozygosity or C282Y/H63D compound heterozygosity 1
• Non-HFE hemochromatosis - consider when genetic testing is negative 1
• Ferroportin disease - can present with elevated ferritin but variable transferrin saturation 1

Secondary Causes

• Inflammatory conditions (ferritin acts as acute phase reactant) 1, 2
• Liver disease (alcoholic liver disease, viral hepatitis, NAFLD) 1
• Malignancy (most common cause of markedly elevated ferritin >1000 μg/L) 2
• Chronic inflammatory conditions 1
• Hematologic disorders (myelodysplastic syndromes, hemolytic anemias) 1

Diagnostic Algorithm

1. Initial iron studies interpretation:

   • If TS ≥45% AND elevated ferritin: Proceed with HFE genetic testing 1
   • If TS is in upper reference range (30-45% women, 35-50% men) with elevated ferritin: Still consider iron overload evaluation 3

2. HFE genetic testing results:

   • C282Y homozygote or C282Y/H63D compound heterozygote: Confirms hereditary hemochromatosis 1
   • Heterozygous or negative: Consider other causes of iron overload or secondary causes 1

3. Additional testing based on ferritin level:

   • Ferritin >1000 μg/L: Higher risk of hepatic fibrosis; consider liver assessment 1
   • Ferritin <1000 μg/L with normal liver enzymes: Lower risk of significant liver disease 1

Advanced Diagnostic Evaluation

• Liver assessment: Consider non-invasive methods first

  • MRI for liver iron concentration is the preferred non-invasive method to quantify iron overload 4
  • Liver biopsy may be necessary in selected cases with suspected advanced fibrosis or when diagnosis remains unclear 1, 4

• Exclude other causes of hyperferritinemia:

  • Complete blood count to assess for anemia or other hematologic abnormalities 1
  • Inflammatory markers (CRP) to identify inflammatory conditions 1, 2
  • Liver enzymes and function tests 1

Treatment Approach

For Confirmed Hemochromatosis or Iron Overload

• Therapeutic phlebotomy is the mainstay of treatment 1
  • Initial frequency: Weekly until ferritin normalizes
  • Maintenance: Typically every 2-4 months to maintain ferritin <50-100 μg/L

For Secondary Causes

• Treat the underlying condition causing elevated ferritin 1, 2
• Monitor iron parameters regularly (ferritin, TS) 1

For Iron Chelation (if phlebotomy contraindicated)

• Consider deferasirox in transfusion-dependent iron overload 5
• Dosing based on serum ferritin levels and body weight 5
• Monitor for adverse effects including renal dysfunction, hepatotoxicity, and cytopenias 5

Monitoring

• Check serum ferritin and TS every 3-6 months during initial treatment 1
• For patients on phlebotomy, adjust frequency based on ferritin trends 1
• If ferritin falls below 500 μg/L, interrupt therapy and continue monthly monitoring 5
• Monitor for complications of iron overload (diabetes, arthropathy, cardiac dysfunction) 1

Family Screening

• Screen first-degree relatives of patients with confirmed hereditary hemochromatosis 1
• Consider genetic counseling for patients with confirmed hereditary forms of iron overload 1

Common Pitfalls to Avoid

• Don't assume all elevated ferritin indicates iron overload - ferritin is an acute phase reactant and can be elevated in many inflammatory conditions 1, 2
• Don't miss non-HFE hemochromatosis - consider rare forms when HFE testing is negative but iron overload is present 1
• Don't delay treatment in symptomatic patients with confirmed iron overload 1
• Don't overlook cardiac and endocrine complications of iron overload 1