Phenotyping rare hepcidin deficiency

In this issue of Blood, Sandhu et al¹  comprehensively catalog the individual data from all reported cases of hepcidin-deficient hemochromatosis related to HAMP, HJV, and TFR2 mutations to determine their phenotype compared with HFE hemochromatosis. Sheldon’s Haemochromatosis textbook was a landmark in the field, thoroughly reviewing all reported cases of hemochromatosis in 1935.²  Similarly, this study describes the rare forms of hereditary hemochromatosis that will help interpret results through genotype-phenotype correlations and foster the search for genes involved in the still unexplained forms of non-HFE hemochromatosis.

Since the initial description of hemochromatosis, many studies have delineated the regulation of iron metabolism. Because there is no significant mechanism for iron excretion, absorption is tightly regulated; this is where the hepcidin-ferroportin axis plays a central role in iron metabolism. Hepcidin (coded by HAMP) is a hormone secreted by the liver, which interacts with the only known iron exporter, ferroportin, at the enterocyte membrane, inducing its degradation that eventually hampers iron egress into the bloodstream.³  Alteration in the hepatocyte’s iron detection platform disconnect hepcidin secretion from body iron stores leading to hepcidin deficiency and thus iron overload. Hepcidin-deficient hemochromatosis is the main type of hereditary hemochromatosis, with HFE hemochromatosis its most common.⁴  Research progressively identified other genes involved in the detection platform (HJV, TFR2, BMP6), allowing characterization of new subtypes of hepcidin-deficient hemochromatosis related to mutation in these genes.

Although the underlying mechanism is straightforward, description of HFE hemochromatosis has proven that the phenotype is highly variable because of the influence of many factors.⁵  Because of their rarity, cases of non-HFE hepcidin-deficient hemochromatosis have only been reported as small retrospective series or case reports. This prevents consistent phenotyping. As expected, because they share a common biological pathway with HFE hemochromatosis, there are phenotype similarities. The differences among the phenotype have not yet been defined.

To overcome this deficiency by defining the HAMP, HJV, and TFR2 hemochromatosis phenotypes, the authors conducted a systematic literature search to identify all published cases of hemochromatosis related to these genes. They extracted clinical, biological, and genetic data from all available journal articles. Then the authors used a large local database of “classical” HFE hemochromatosis patients as a reference population to perform univariate and multivariate analysis. Overall, 156 patients with non-HFE hepcidin-deficient hemochromatosis were identified and compared with 984 patients with HFE hemochromatosis.

The first finding is that there is significant variability of the clinical presentation. Although HAMP, HJV, and TFR2 hemochromatosis patients had overall more severe iron overload at diagnosis than HFE hemochromatosis patients, a significant number of patients in each group had milder disease. This suggests an underreporting bias resulting from the costs and restricted availability of targeted genetic testing that were only performed in severe patients. Similar to what was observed with the advent of HFE testing, the lower cost and greater availability of next-generation sequencing might uncover cases of mild HJV or TFR2-related hemochromatosis. Further, although patients with HAMP and HJV hemochromatosis that were referred to as having “juvenile” hemochromatosis are younger at diagnosis than HFE (and to a lesser extent TFR2) hemochromatosis patients, the mean age of 24 years reflects a disease that is not restricted to youth. Therefore, neither the severity of the iron burden nor age helps distinguish these rare forms.

Interestingly, despite limitations resulting from missing data, some phenotypical peculiarities were identified. Cardiac involvement and hypogonadism are strikingly more frequent in HJV and HAMP hemochromatosis, even after adjusting for age, sex, and iron burden at diagnosis. This suggests that the level of iron overload is not the only factor accounting for organ damage. Other mechanisms involving HAMP or HJV in different organs, or more probably the varying sensitivity of organs to iron overload may be involved. On the other hand, liver fibrosis, although more frequently seen in HAMP, HJV, and TFR2 hemochromatosis, is not significantly increased compared with HFE hemochromatosis once adjusted for age, sex, and iron burden at diagnosis. This supports the classical view of toxicity from iron with the severity of organ damage paralleling iron overload.

Besides raising clinical awareness of these rare forms of hemochromatosis, this work will have an important clinical implication for diagnosis. With the advent of next-generation sequencing, more genes are being tested in the setting of iron overload.⁶  Because interpretation of sequence variants is frequently difficult⁷  this meticulous work provides a reference phenotype for non-HFE hepcidin-deficient hemochromatosis.

Further work will be required to elucidate the complexity of non-HFE hemochromatosis. The availability of hepcidin assay did not solve the issue of the lack of a simple biological test to identify patients. There is still no rigorous prospective and comprehensive screening study of non-HFE hemochromatosis. Follow-up data regarding efficacy and complications of treatment are scarce. For all these issues, building a reference network and international database will be a crucial step to overcome the challenge of these rare disorders.