Hemochromatosis redefined

In this issue of Blood, Girelli et al propose a new classification for hemochromatosis (HC).¹ The new classification is intended to be of practical help, avoiding delays in diagnosis and treatment even if detailed molecular characterization is not readily available.

HC is a heterogeneous genetic disease marked by the abnormal accumulation of iron, resulting ultimately in damage to the heart, liver, endocrine glands, and other internal organs. Within a few years following the discovery in 1996 of the HC gene HFE by Feder et al,² it was shown that HC is caused by mutations in at least 5 genes, resulting in insufficient production or decreased response to the master regulator of iron homeostasis hepcidin.³ Paradoxically, progress in understanding the complex molecular mechanisms of iron homeostasis resulted in increased difficulties in the evaluation of subjects presenting with clinical findings suggestive of HC. Identification of the molecular defects causing rarer forms of HC is currently only offered by few laboratories worldwide, requiring patients to travel or DNA to be sent to referral centers, with inevitable discomfort, delays, and costs.

The current classification of HC is based on a series of discoveries on iron regulation made within a few years of the identification of the HFE HC gene. In addition to HFE, several non-HFE genes were described, including genes coding for a second receptor for transferrin (TFR2),^4,5 ferroportin (SLC40A1),⁶ hepcidin (HAMP),^3,7 and hemojuvelin (HJV).⁸ Some of the mutants of HAMP and HJV were responsible for a phenotype that is more severe than HFE, causing a juvenile form of HC with early onset of cardiac and endocrine disease. From a pathophysiological point of view, all HFE and non-HFE genes participate in the mechanism controlling hepcidin synthesis, and their mutants produce insufficient hepcidin, causing excessive iron accumulation.³ A notable exception is ferroportin (SLC40A1), in both its loss-of-function (type 4A) and gain-of-function (type 4B) forms, which, unlike all other genetic subgroups of HC, are autosomal dominant instead of autosomal recessive. Ferroportin does not cause insufficient hepcidin production but, in the case of type 4B, an inability of hepcidin to function by preventing its binding to ferroportin.

Several shortcomings exist within the current classification of HC. The most important among these is the limited availability of laboratory facilities for the identification of molecular defects other than HFE, responsible for rarer forms of HC. Such practical difficulties render the diagnostic process required to establish the existence of one or more of the known molecular defects uncomfortable, time-consuming, and expensive. Second, the current HC classification disregards the possibility of digenic inheritance with double-heterozygosity or double-homozygosity/heterozygosity for mutations in different genes involved in iron metabolism (HFE and/or non-HFE). Such patients have no designated place among the 6 types of HC. In addition, the current classification has no place allocated to patients in whom a complete diagnostic workup failed to show the existence of any of the 5 classical HC genes: HFE, HAMP, HJV, TFR2, and SLC40A1. It is further argued that type 4A, listed among the conditions included according to the current classification, has unique clinical, biochemical, and pathological features, which do not fit the definition of HC. Finally, the authors warn against the indiscriminate use of the term “juvenile” in relation to types 2A and 2B because of considerable overlap in clinical severity with some of the subjects in other HC subgroups.

The proposed new classification (see table) is much more than a rearrangement of HC subgroups. It is the unique contribution of a group of outstanding clinicians and basic scientists who were personally responsible for establishing new insights into the regulation of iron metabolism in health and disease. It was thought by these investigators that there is a current need to introduce a new nomenclature for classifying HC. The difference between the old and new classification is a reflection of the experience gained in HC research and clinical experience accumulated within the last 2 decades. It is patient oriented and clinically oriented, making it user-friendly for nonexpert clinicians and patients alike. Its essential elements are as follows: (1) Reliance on simple accessible clinical tools, such as the combination of increased serum ferritin, transferrin saturation, and increased liver iron concentrations. This by itself will eliminate unnecessary concerns in patients with a nonspecific increase in serum ferritin in conditions other than HC; (2) Use of first- and second-level genetic tests. In white patients negative for HFE-related HC and all other subjects with clinical indication of CH, second-level genetic workup based on next-generation sequencing gene panel should be recommended, but this should not delay optimal clinical management; (3) As long as a second-level genetic workup has not been completed and/or if complete workup failed to disclose one of the known genetic variants of HC, such patients will be designated “molecularly undefined”; (4) “Digenic inheritance,” deriving from the combination of heterozygous pathogenic variants in 2 different genes involved in iron metabolism, is recognized as a special entity.^9,10

The aim of the new classification is to offer practical help when a detailed molecular characterization of HC is not yet available. Although the principles guiding these recommendations are sound, a critical assessment of the benefits or limitations of the new classification would only be feasible following long-term monitoring of patient health and quality of life.