Laboratory Evaluation for Iron Overload
To evaluate iron overload, draw transferrin saturation (calculated from serum iron and either transferrin or TIBC), serum ferritin, and a complete blood count with reticulocytes. 1
Core Iron Panel
The essential initial laboratory tests are:
- Transferrin saturation (TSAT): Calculated from serum iron plus either transferrin or total iron-binding capacity (TIBC) 1
- Serum ferritin 1
- Complete blood count with reticulocytes: To exclude anemia and red cell disorders that could confound interpretation 1
Diagnostic Thresholds for Iron Overload
Transferrin saturation >45% combined with elevated ferritin (>200 μg/L in females, >300 μg/L in males) indicates biochemical iron overload requiring further evaluation. 1, 2
The specific cutoffs are:
- Transferrin saturation: >45% is the most sensitive threshold 1, 2
- Serum ferritin: >200 μg/L in females, >300 μg/L in males 1, 2
Additional Laboratory Tests for Risk Stratification
Once iron overload is confirmed, additional labs help assess disease severity and organ involvement:
Liver Assessment
- AST and ALT: Elevated transaminases with ferritin >1,000 μg/L suggest significant liver involvement 1
- Platelet count: Platelets <200,000 combined with ferritin >1,000 μg/L and elevated transaminases predict cirrhosis in approximately 80% of C282Y homozygotes 2
- Calculate FIB-4 score: Requires age, platelet count, AST, and ALT to assess for advanced fibrosis non-invasively 1
Complete Metabolic Panel
Draw a comprehensive metabolic panel to evaluate for:
- Liver synthetic function (albumin, bilirubin) 1
- Glucose (diabetes is a common manifestation) 2
- General organ function assessment 1
Important Caveats About Interpretation
Ferritin as an Acute Phase Reactant
Serum ferritin can be falsely elevated by inflammation, infection, malignancy, or liver disease independent of iron stores. 1, 3, 4 When ferritin is elevated but transferrin saturation is normal or low, consider these alternative causes before attributing it to iron overload 5, 3.
Pattern Recognition
The classic pattern of hemochromatosis is elevated transferrin saturation (typically the earliest abnormality) followed by rising ferritin. 2 Elevated ferritin with normal transferrin saturation is atypical for HFE-related hemochromatosis and should prompt investigation for other causes of hyperferritinemia 2, 5.
Severity Stratification by Ferritin Level
- Ferritin <1,000 μg/L with normal transaminases and no hepatomegaly: Risk of advanced liver fibrosis is very low 1
- Ferritin >1,000 μg/L: Consider liver biopsy or advanced imaging, especially if transaminases are elevated, patient is >40 years old, or hepatomegaly is present 1, 2
Predictive Value for Severe Iron Overload
Transferrin saturation >60% or transferrin saturation <60% with ferritin >963 μg/L correctly identifies >95% of patients with severe hepatic iron overload (>7 mg/g dry weight). 6 This can guide decisions about advanced imaging with MRI.
What NOT to Order
Do not measure hepcidin levels—this is not recommended for clinical diagnosis or management of iron overload. 1 While hepcidin plays a pathophysiologic role, it lacks clinical utility for diagnosis 4.
Subsequent Genetic Testing
After confirming biochemical iron overload with the above labs, proceed to HFE gene mutation analysis (C282Y and H63D variants) in patients of European origin. 1, 2 This genetic testing should follow, not precede, the biochemical confirmation, as this strategy is more cost-effective than universal genetic screening 2.