What is the appropriate workup for a patient with elevated ferritin (iron storage protein) levels?

Workup for Elevated Ferritin

The appropriate workup for elevated ferritin should begin with investigating common causes of hyperferritinemia including inflammation, liver disease, metabolic syndrome, and iron overload disorders, before considering more specialized testing for hereditary hemochromatosis or other rare conditions.

Initial Assessment

Step 1: Rule Out Common Causes of Hyperferritinemia

• Check for inflammatory conditions:

  • Measure C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 1, 2
  • Evaluate for acute or chronic infections
  • Screen for autoimmune disorders (rheumatoid factor, ANA)

• Assess for liver disease:

  • Liver function tests (ALT, AST, alkaline phosphatase, bilirubin) 1, 2
  • Evaluate for non-alcoholic fatty liver disease (NAFLD) 3
  • Check alcohol consumption history 4

• Screen for metabolic syndrome:

  • Check blood pressure, BMI, fasting glucose, lipid profile 1, 2
  • Evaluate for diabetes 4

• Consider malignancy:

  • Appropriate age-specific cancer screening 5

Step 2: Assess Iron Status

• Complete iron studies:
  • Serum iron
  • Total iron binding capacity (TIBC)
  • Transferrin saturation (TSAT) 2
  • Complete blood count with red cell indices 2

Interpretation and Further Workup

If Transferrin Saturation is Normal or Low (<45% in females, <50% in males)

• With inflammation (elevated CRP/ESR): Consider anemia of chronic disease 2
• Without inflammation: Consider non-iron related causes of hyperferritinemia 4

If Transferrin Saturation is High (>45% in females, >50% in males)

• Proceed with genetic testing for HFE mutations (C282Y and H63D) 1

Based on Genetic Testing Results:

• C282Y homozygote: Diagnosis of HFE-related hemochromatosis is established 1
• C282Y/H63D compound heterozygote or H63D homozygote: Further investigate other causes of hyperferritinemia 1
• Negative for common HFE mutations: Consider rare genetic disorders (TFR2, SLC40A1, HAMP, HJV) if iron overload is confirmed by other means 1

Additional Testing Based on Ferritin Level

Ferritin <1000 μg/L

• Monitor ferritin levels and continue evaluation of common causes 4

Ferritin >1000 μg/L

• Refer to gastroenterologist, hematologist, or physician with interest in iron overload 4
• Consider liver biopsy to assess hepatic iron content and fibrosis, especially in C282Y homozygotes with:
  • Serum ferritin >1000 μg/L
  • Elevated AST
  • Hepatomegaly
  • Age >40 years 1

Ferritin >1.5× Upper Limit of Normal

• Higher risk of advanced hepatic fibrosis in NAFLD patients 3
• Consider liver biopsy to assess for NASH and fibrosis

Special Considerations

• In patients with chronic kidney disease, ferritin may be elevated due to inflammation rather than iron overload 1
• In inflammatory conditions, a higher ferritin cutoff (up to 100 μg/L) should be used to diagnose iron deficiency 2
• Soluble transferrin receptor (sTfR) measurement can help differentiate between iron deficiency and anemia of chronic disease when inflammation is present 2
• Reticulocyte hemoglobin content can be useful for monitoring iron status 2

Pitfalls to Avoid

• Don't assume elevated ferritin always indicates iron overload; 90% of cases are due to non-iron overload conditions 4
• Don't initiate phlebotomy or chelation therapy without confirming iron overload and excluding other causes of hyperferritinemia
• Don't overlook the possibility of multiple concurrent causes of hyperferritinemia
• Avoid unnecessary genetic testing when inflammatory causes are evident
• Remember that ferritin is an acute phase reactant and can be elevated in any inflammatory condition 1, 2

By following this systematic approach, the underlying cause of elevated ferritin can be identified and appropriate management initiated to address the specific etiology.