Hemochromatosis classification: update and recommendations by the BIOIRON Society

Abstract

Hemochromatosis (HC) is a genetically heterogeneous disorder in which uncontrolled intestinal iron absorption may lead to progressive iron overload responsible for disabling and life-threatening complications such as arthritis, diabetes, heart failure, hepatic cirrhosis, and hepatocellular carcinoma. The recent advances in the knowledge of pathophysiology and molecular basis of iron metabolism have highlighted that HC is caused by mutations in at least five genes, resulting in insufficient hepcidin production or, rarely, resistance to hepcidin action. This has led to an HC classification based on different molecular subtypes, mainly reflecting successive gene discovery. This scheme was difficult to adopt in clinical practice and therefore needs revision. Here we present recommendations for unambiguous HC classification developed by a working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) including both clinicians and basic scientists during a meeting in Heidelberg, Germany. We propose to deemphasize the use of the molecular subtype criteria in favor of a classification addressing both clinical issues and molecular complexity. Ferroportin Disease (former type 4a) has been excluded because of its distinct phenotype. The novel classification aims to be of practical help whenever a detailed molecular characterization of HC is not readily available.

Ferroptosis: A Potential Therapeutic Target in Acute Kidney Injury

“…In particular, iron overload is detrimental, affecting several parenchymal organs [ 38 ]. Common affected organs in this condition are endocrine glands, heart, and the liver [ 39 ]. The kidney can also be damaged by iron.…”

New Mutations in HFE2 and TFR2 Genes Causing Non HFE-Related Hereditary Hemochromatosis

“…Recently, a new classification for HH has been proposed, where the previously described types of HH have been reorganized into the “ HFE-related ” HH caused by mutations in the HFE gene, the “ non HFE-related ” due to mutations in the HFE2 , HAMP , TFR2 and gain-of-function mutations in the SLC40A1 gene, the “ Digenic ” caused by compound heterozygosity between mutations in iron-metabolism-related genes ( HFE and/or non-HFE genes) and lastly, the “ molecularly undefined ” group where the genetic origin is unknown. From this point forward, we will use this new recommended nomenclature [ 21 ].…”

PIGA mutations (can) cause juvenile hemochromatosis

“…In this issue of Blood, Muckenthaler et al 1 investigated 3 male children with neurologic symptoms, including seizures, who otherwise had typical iron overload and organ dysfunction consistent with severe juvenile hemochromatosis. Will we have to rewrite the classification and textbook discussions of hereditary hemochromatosis, 2 or is the novel finding of neurologic involvement just an add-on to the known mutations causing primary iron overload in humans?…”

“…Typically, hemochromatosis develops owing to mutations in the hemochromatosis gene, HFE (see figure B lower panel), HJV, TFR2, hepcidin, or ferroportin. 2 Either reduced hepcidin synthesis is caused by one of these mutations or a mutation in ferroportin leads to excessive iron accumulation. Mutations in HJV or hepcidin cause the most severe form of iron overload, juvenile hemochromatosis.…”

“…Soluble ceruloplasmin oxidizes Fe 21 to Fe 31 , which, in turn, is bound to transferrin and transported to the bone marrow for erythropoiesis. Typically, hemochromatosis develops owing to mutations in the hemochromatosis gene, HFE (B lower panel), HJV, TFR2, hepcidin, or ferroportin 2. Either reduced hepcidin synthesis is caused by one of these mutations or a mutation in ferroportin leads to excessive iron accumulation.…”