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 (IO) 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 5 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.

Figure 1

Hepcidin regulation by iron. Increase in transferrin saturation induces hepcidin transcription via the BMP/SMAD signaling pathway. Diferric transferrin binds to TfR2, while BMP6 and BMP2 secreted by liver sinusoidal endothelial cells (LSECs) bind to BMP receptors on hepatocytes. These events trigger phosphorylation of regulatory SMAD1/5/8, recruitment of SMAD4, and translocation of the SMAD complex to the nucleus for activating hepcidin transcription upon binding to BMP/SMAD responsive element in the HAMP promoter. BMPs can be trapped by ERFE, leading to hepcidin inhibition in iron-loading anemias. Efficient iron signaling requires the BMP coreceptor HJV and the protein HFE, and is negatively regulated by the transmembrane serine protease matriptase-2 (TMPRSS6). The complex molecular pathogenesis of HC reflects the numerous proteins involved in the regulation of the hepcidin-ferroportin axis.

Figure 2

Proposal of an algorithm for the diagnosis of HC, from clinical/biochemical and imaging studies to molecular confirmation. Important note: in Whites, HFE genotyping is indicated with the specific purpose of detecting p.Cys282YTyr homozygosity (homoz.) and, if confirmed, to recommend appropriate preventive treatment by phlebotomies. Asian, African, and Native American subjects with defined HC phenotype could be directly referred to second-level genetic testing. In populations with a frequent component of Northern European ancestry, such as African Americans and Hispanics, there may still be a role for HFE genetic testing.

Figure 3

Iron homeostasis in normal conditions (A) and mechanisms leading to iron accumulation in HC (B) and in iron-loading anemias that are nontransfusion-dependent (C) and transfusion-dependent (D). In HC, iron hyperabsorption through the portal vein leads to iron accumulation in liver parenchymal cells, initially with a typical portal-central gradient (see histology) and sparing of macrophages (Kupffer cells). In nontransfusion-dependent anemias with ineffective erythropoiesis, hepcidin insufficiency is also central to the pathogenesis of IO, but it is due to suppression by soluble factors (eg, ERFE) produced by ineffective/expanded erythroblasts rather than to a genetic defect in pathways regulating hepcidin synthesis. In transfusion-dependent anemias, regular red blood cells (RBCs) transfusions represent the major contributing factor to IO; in these conditions, hepcidin is relatively upregulated by iron but fluctuates in response to intermittent erythropoiesis suppression by transfusions.