What workup is indicated for a patient with elevated ferritin and transferrin saturation levels?

Workup for Elevated Ferritin and Transferrin Saturation

For a patient with elevated ferritin (272 μg/L) and transferrin saturation (61%), genetic testing for HFE mutations should be ordered as the first step to evaluate for hereditary hemochromatosis. 1, 2

Initial Diagnostic Approach

The laboratory values provided indicate potential iron overload:

• Total iron: 196
• Iron binding capacity: 323
• Transferrin saturation: 61% (elevated above the 45% threshold)
• Ferritin: 272 μg/L (elevated)
• Normal hemoglobin and RBC values

Step 1: Confirm Iron Overload

• Repeat transferrin saturation measurement (preferably fasting) to confirm elevation above 45% 1
• Elevated transferrin saturation >45% with ferritin >300 μg/L in males or >200 μg/L in females suggests iron overload requiring further workup 1

Step 2: Genetic Testing

• Order HFE gene testing for C282Y and H63D mutations (most common mutations in hereditary hemochromatosis) 2
• This is crucial as the American Association for the Study of Liver Diseases recommends genetic testing when transferrin saturation is elevated 1

Step 3: Imaging Studies

• MRI with quantitative assessment of liver iron content is recommended to:
  • Confirm tissue iron overload
  • Differentiate between true iron overload and other causes of hyperferritinemia 1, 3
• Recent evidence (2025) shows that transferrin saturation >60% (as in this case) is highly predictive of significant liver iron overload 3

Step 4: Additional Laboratory Tests

• Liver function tests (AST, ALT, ALP, GGT, bilirubin)
• Fasting glucose and HbA1c (to assess for diabetes, a complication of iron overload)
• Ceruloplasmin level (to rule out aceruloplasminemia) 1

Considerations for Differential Diagnosis

If HFE genetic testing is negative for the common mutations, consider secondary causes of iron overload:

1. Hematologic disorders:

   • Thalassemia syndromes
   • Myelodysplastic syndrome
   • Sideroblastic anemias 2

2. Liver disorders:

   • Alcoholic liver disease
   • Non-alcoholic fatty liver disease
   • Chronic hepatitis 2

3. Other causes of hyperferritinemia without true iron overload:

   • Inflammatory conditions
   • Malignancy
   • Metabolic syndrome 1, 2

Important Caveats and Pitfalls

• Pitfall #1: Relying solely on ferritin levels for diagnosis. Ferritin is an acute phase reactant and can be elevated in inflammatory conditions without true iron overload 1

• Pitfall #2: Failing to consider secondary causes of iron overload when HFE testing is negative. Always pursue further evaluation if genetic testing is negative but iron parameters remain elevated 2

• Pitfall #3: Missing cardiovascular risk assessment. Patients with iron overload have higher cardiovascular risk profiles with insulin resistance, dyslipidemia, and oxidative stress 4

• Pitfall #4: Delaying specialist referral. Consider referral to a gastroenterologist when ferritin is >1,000 μg/L or the cause remains unclear after initial evaluation 1

The most recent evidence (2025) suggests that using transferrin saturation and ferritin levels together can identify over 95% of patients with significant iron overload, potentially reducing the need for MRI in some cases 3. However, given this patient's transferrin saturation of 61%, which exceeds the 60% threshold identified in recent research, MRI assessment of liver iron content would be strongly indicated.