Screening for Hereditary Hemochromatosis
Order transferrin saturation and serum ferritin as the first-line screening tests for hereditary hemochromatosis. 1
Initial Biochemical Screening
The 2022 EASL guidelines, with 100% consensus, establish that the first step in testing for haemochromatosis is the assessment of serum iron parameters, which should include transferrin saturation and serum ferritin 1. This represents the most authoritative and recent guidance available.
Key Thresholds for Abnormal Results:
- Males: Transferrin saturation >50% and ferritin >300 μg/L
- Females: Transferrin saturation >45% and ferritin >200 μg/L 1
These thresholds indicate biochemical evidence of iron overload and warrant further investigation.
Additional Iron Parameters (Optional)
While transferrin saturation and ferritin are essential, serum iron and transferrin (or total iron binding capacity) can provide additional information for differential diagnosis, though this received only 87% consensus 1. These are supplementary, not primary screening tests.
What NOT to Order
Do not measure hepcidin - this received 100% consensus against its use in screening 1. Despite its pathophysiologic role in hemochromatosis, hepcidin measurement has no clinical utility in diagnosis.
When to Proceed to Genetic Testing
After abnormal biochemical screening, genotyping for p.C282Y in HFE should be carried out in individuals of European origin with the biochemical thresholds noted above 1. This represents the second step, not the initial screening approach.
Special Screening Populations:
First-degree relatives of patients with confirmed p.C282Y homozygous hemochromatosis should proceed directly to genetic testing (after informed consent) rather than biochemical screening first 1. This is the one exception where genetic testing precedes biochemical assessment.
Clinical Context
The approach differs significantly from population-based screening. These guidelines apply to:
- Patients with clinical signs/symptoms suggestive of hemochromatosis
- Unexplained persistently elevated liver enzymes 2
- Patients with specific high-risk presentations (diabetes, chronic fatigue with arthralgia, unexplained liver disease) 3
- Family members of known cases
Common Pitfall to Avoid:
Do not order genetic testing as the initial screening test in the general population or symptomatic patients without first documenting biochemical iron overload. The penetrance of C282Y homozygosity is incomplete - approximately 75% show elevated serum iron measures, but only about 10% develop significant liver disease 4. Starting with biochemical tests prevents unnecessary genetic testing and its associated implications.
The algorithmic approach is straightforward: transferrin saturation + ferritin first → if elevated above thresholds → then genetic testing (except for first-degree relatives who go straight to genetics).