What is the recommended screening protocol for family members if one member is diagnosed with hemochromatosis?

Screening Family Members for Hemochromatosis

All adult first-degree relatives (siblings, parents, children over 18 years) of a patient diagnosed with hemochromatosis should undergo both HFE genetic testing for the C282Y mutation AND simultaneous phenotypic screening with transferrin saturation and serum ferritin. 1, 2

Recommended Screening Protocol

Initial Testing for First-Degree Relatives

• Perform both genetic and phenotypic testing simultaneously rather than one or the other 1, 2, 3

  • HFE genotyping for C282Y (and H63D) mutations 1, 2
  • Transferrin saturation (diagnostic threshold ≥45%) 2, 3
  • Serum ferritin (>300 μg/L in men, >200 μg/L in women indicates elevation) 2, 3

• The yield is particularly high in siblings, with 33% showing C282Y homozygosity compared to 23% of all first-degree relatives 1

Why Both Tests Are Necessary

The European Association for the Study of the Liver (EASL) 2022 guidelines emphasize that genotyping should be combined with biochemical assessment because homozygosity for C282Y alone is neither necessary nor sufficient for the diagnosis of hemochromatosis 1. This dual approach is critical because:

• Penetrance in family members is higher than in the general population, making screening more cost-effective 1
• Some relatives may have iron overload despite different genotypes (compound heterozygotes) 2, 4
• Phenotypic testing helps determine disease severity and need for treatment 2

Pre-Test Genetic Counseling

Before ordering genetic tests, discuss with family members: 2, 3

• Available treatment (phlebotomy) and its efficacy
• Costs of testing and ongoing monitoring
• Implications for insurability and employment
• Psychological impact of disease labeling
• Possibility of uncertain or variant genotypes

Interpretation and Follow-Up

If C282Y Homozygous (C282Y/C282Y)

• Confirms genetic predisposition to HFE-related hemochromatosis 4
• Assess for iron overload with ferritin and transferrin saturation 2
• If ferritin >1,000 μg/L with elevated liver enzymes or age >40 years, consider liver biopsy to assess for cirrhosis 2, 3

If Compound Heterozygous (C282Y/H63D)

• Lower risk than C282Y homozygosity but still requires monitoring 4
• Annual monitoring of iron parameters if currently normal 4
• Investigate other contributing causes if iron overload is present 4

If Normal Genotype with Normal Iron Studies

• Reassure but consider periodic monitoring given family history 2

Important Caveats

Common Pitfalls to Avoid

• Do not rely on ferritin alone - it can be falsely elevated due to inflammation, liver disease, malignancy, or metabolic syndrome 2, 4
• Do not skip second-degree relatives entirely - testing only first-degree relatives carries a 2.5% chance of missing at-risk individuals 5
• Uptake is often poor - only 24-53% of relatives actually complete testing when recommended, leaving many with undiagnosed iron overload 6

Morbidity in Family Members

Research demonstrates that first-degree family members of C282Y homozygous probands have significantly higher morbidity (45.7%) compared to the general population (19.4%), though mortality rates are similar 7. This underscores the importance of active case-finding rather than passive recommendations.

Practical Implementation Strategy

To maximize screening uptake: 6

• Provide structured genetic information and counseling
• Actively contact relatives rather than relying on the proband to inform them
• Emphasize that early detection enables treatment before end-organ damage occurs
• Consider cascade screening to second-degree relatives in high-risk families 5