CLINICAL SIGNIFICANCE OF HFE C282Y AND H63D HETEROZYGOSITY: A REVIEW OF CURRENT GUIDELINES AND EVIDENCE

With the increasing availability of genetic testing, individuals heterozygous for the C282Y or H63D variant of the HFE gene are being identified more frequently. Although clinical management is better established for patients homozygous for C282Y, recommendations for those with heterozygous HFE genotypes remain less clearly defined. This narrative review included 29 sources identified through searches of PubMed and Google Scholar, and screening of the reference lists of relevant publications. It aimed to synthesise the available evidence on the clinical risk associated with HFE heterozygosity and to assess the appropriateness of diagnostic and therapeutic interventions in this population. The evidence base included professional society guidelines and position statements, observational studies, case reports, and review articles addressing genotype-phenotype relationships in HFE-related haemochromatosis. The available data indicate that heterozygosity for a single C282Y or H63D variant rarely results in clinically significant iron overload and do not support routine dietary restrictions or prophylactic phlebotomy in individuals with iron indices within normal limits. Similar conclusions apply to C282Y/H63D compound heterozygosity, although this genotype is associated with a slightly higher clinical risk. The review also highlights the limited guidance on family testing when the proband is a heterozygous carrier, as well as the clinical consequences of overinterpreting H63D. Overall, these findings support a phenotype-guided approach to the diagnostic and therapeutic management of individuals heterozygous for HFE variants.