Approach to a patient with an iron profile suggestive of overload

Abstract

A basic iron profile often provides a useful approach to ferropenic or iron-sequestered inflammatory conditions, but sometimes also to the primary suspicion of iron overloading pathologies, which may or may not, at last, harbor a real iron overload. Therefore, a thoughtful interpretation of the results is mandatory to avoid misdiagnosis. The serum iron concentration reflects the quantity of iron moving at one moment from ferroportin- to transferrin receptor-1-expressing cells, while the transferrin concentration reflects the organism avidity for iron. But serum ferritin concentration may reflect iron deposits as well as inflammatory conditions, hence being difficult the interpretation of its normal or high values. In this paper I distinguish, among abnormal iron profiles, those with evident iron overload from those with hiperferritinemia without (clear) evidence of iron overload, although there is a frequent overlap between these two conditions. Secondary reactive hiperferritinemia is, by far, much more common than hiperferritinemia related to iron overload, as it is also frequent to deal with patients with more than one cause for their hiperferritinemia. "Reactive hiperferritinemia of unknown origin" should be the temporary diagnosis for patients with (yet) no evident etiology for their hiperferritinemia. Some patients have clearly absence or presence of iron overload, but in many cases this condition is doubtful, incomplete or intermittent. Hence, it is difficult in some cases to decide the need for chelation therapy. Iron overload, if present, may be secondary (basically to ineffective erythropoiesis) or primary. Primary iron overload may be, in turn, classified as hemochromatosic (HFE or non HFE) or non hemochromatosic. Although very rare, the non hemochromatosic primary iron overloads have confounding iron profiles, but with an easy approach if suspected. One of them, the ferroportin disease, just the opposite of hemochromatosis, deserves some attention, for it is not very infrequent. Finally, the diagnosis of hemochromatosis must be supported by an unequivocal typical iron profile and by biallelic severe HFE mutations or, rarer, mutations in non-HFE genes. The last but not the least, mild HFE mutations, as H63D, either mono o biallelic, do not justify by themselves any typical iron overload. In presence of such a genetic diagnosis, other cause(s) of iron overload must be looked for: non-HFE hemochromatosis if the iron profile is typically hemochromatosic, non-hemochromatosic iron overload (primary o secondary) if not. The risk of considering a mild HFE mutation (even in the case of HFE C282Y/H63D double heterozygous) as responsible for an iron overload or a hiperferritinemia is to overlook other causes for these conditions that may deserve particular and, eventually, more imperative attention and treatment.