Ferritin Normalization Is Not Disease Control in HFE-Related Hemochromatosis: Residual Risk, Transferrin Saturation,...

HFE-related hemochromatosis is conventionally managed as a disorder of iron excess, with therapeutic phlebotomy as effective, inexpensive, first-line therapy. Ferritin normalization, however, may not fully capture clinical burden. Delphi consensus data identify the lack of alternatives to phlebotomy, persistent symptoms, and uncertainty regarding the clinical role of transferrin saturation (TSAT) and non-transferrin-bound iron (NTBI) as principal unmet needs, while general-population studies link HFE p.Cys282Tyr (p.C282Y) homozygosity to diabetes, osteoarthritis, fractures, and liver disease even at apparently normal iron indices. At the same time, the randomized evidence base for iron reduction rests on a single sham-controlled trial of erythrocytapheresis rather than on any randomized comparison of phlebotomy itself, and epidemiologic estimates of penetrance remain genuinely uncertain. This critical review evaluates the shortcomings of therapeutic phlebotomy, the ongoing risk that remains following ferritin normalization, and the potential supportive role of tracking TSAT levels. It further explores novel hepcidin-ferroportin axis targeted treatments, including the hepcidin mimetic rusfertide, the oral ferroportin inhibitor vamifeport, and agents targeting TMPRSS6. Crucially, it highlights that these agents are still investigational and acknowledges that not all persistent morbidity in p.C282Y homozygotes stems from iron deposition. Nevertheless, the combination of high treatment burden, circulating iron toxicity unmeasured by ferritin, and continued tissue and organ risk post-ferritin normalization indicates that disease management in HFE-related hemochromatosis must look beyond ferritin alone, supporting the need for clinical trials to evaluate disease-targeted interventions rigorously.