What is the initial workup for suspected iron overload?

Initial Workup for Suspected Iron Overload

The initial workup for suspected iron overload should include fasting transferrin saturation and serum ferritin measurements as the first-line tests, followed by HFE genetic testing if these markers are elevated. 1, 2

Step 1: Initial Laboratory Testing

• Fasting transferrin saturation (TS): Primary screening test

  • Threshold: >45% in women, >50% in men 1
  • Must be drawn after overnight fast for accuracy 1

• Serum ferritin: Should be measured simultaneously

  • Threshold: >200 ng/mL in women, >300 ng/mL in males 1
  • Increases diagnostic accuracy when combined with TS 1

• Additional baseline tests:

  • Complete blood count (CBC)
  • Liver function tests (AST, ALT)
  • Inflammatory markers (CRP) to rule out non-iron related hyperferritinemia
  • Fasting glucose and HbA1c 2

Step 2: Genetic Testing

• HFE gene mutation analysis for C282Y and H63D mutations if iron markers are elevated 1, 2
  • C282Y homozygosity accounts for >90% of hereditary hemochromatosis cases
  • C282Y/H63D compound heterozygosity accounts for 3-5% of cases 2

Step 3: Confirmation of Iron Overload

For patients with elevated iron markers but unclear genetic results:

• MRI quantification of liver iron: Non-invasive method to confirm and quantify iron overload 1, 2

  • Particularly useful when genetic testing is negative or equivocal

• Liver biopsy: Consider in specific circumstances:

  • C282Y homozygotes with serum ferritin >1000 ng/mL
  • Elevated liver enzymes
  • Hepatomegaly
  • Age >40 years 1
  • When other causes of liver disease need to be excluded 1

Important Considerations

• False positives: Ferritin is an acute phase reactant and can be elevated in:

  • Inflammatory conditions
  • Liver disease (especially fatty liver)
  • Malignancy
  • Alcohol consumption 1, 2

• Cardiac evaluation: Consider cardiac MRI with T2* measurement if cardiac involvement is suspected, particularly in secondary iron overload 1

• Secondary causes: If HFE genetic testing is negative, evaluate for:

  • Hematologic disorders (thalassemia, myelodysplastic syndrome, sideroblastic anemia)
  • Chronic liver diseases
  • Excessive alcohol consumption 3

Pitfalls to Avoid

1. Don't rely solely on ferritin: Ferritin alone has poor specificity; always check transferrin saturation 1

2. Don't diagnose hemochromatosis based on C282Y homozygosity alone: Evidence of increased iron stores is required 1

3. Don't measure ferritin too soon after iron infusion: Wait 8-10 weeks as levels will be falsely elevated 1

4. Don't overlook other causes of hyperferritinemia: Particularly metabolic syndrome and fatty liver disease, which are common causes of elevated ferritin without true iron overload 2

5. Don't initiate treatment without confirming iron overload: Phlebotomy should not be started based solely on genetic testing without evidence of iron overload 2