During a meeting of clinicians and basic scientists in Heidelberg, Germany, a working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) developed new recommendations for the classification of hemochromatosis (HC) based on both clinical factors and molecular complexity. The recommendations were recently published in Blood.
In HC, a genetically heterogenous disorder, uncontrolled intestinal iron absorption may lead to progressive iron overload, in turn causing complications such as arthritis, diabetes, heart failure, hepatic cirrhosis, and hepatocellular carcinoma. Recent studies show that HC is caused by mutations in at least five genes that lead to insufficient hepcidin production or resistance to hepcidin action. A BIOIRON Society working group identified a need for revision to current HC classification based on molecular subtypes, which has been difficult to adopt in clinical practice.
To avoid any ambiguity and encourage clear communication around diagnosis and treatment of HC, the working group panelists recommend that “the term ‘hemochromatosis’ should be reserved for a unique genetic clinical-pathological condition characterized by increased transferrin saturation, inflow occlusion (IO) in the liver [but not the spleen], prevalent involvement of peri-portal hepatocytes with iron-spared Kupffer cells, and signs and/or symptoms associated with IO.” The panelists also suggest that to distinguish the disorder from other iron overload conditions, the definition of HC should include the absence of hematologic signs of a primary red blood cell disorder such as anemia or reticulocytosis.
This new classification of HC proposed by the working group panelists, shown in the TABLE, is based on a pathophysiological cornerstone of hepcidin deficiency and a distinct clinical/biochemical phenotype. “It recognizes the difficulties of a complete molecular characterization and has the potential of being easily shareable between practicing physicians and referral centers,” the panelists wrote.
By placing more emphasis on clinical features, the new classification prevents challenges represented by second-level genetic testing for rare variants in the HFE and non-HFE genes, therefore avoiding delayed diagnosis and treatment. Second-level genetic tests can be costly and time-consuming, may not be available in certain geographic regions, and their interpretation requires a high level of expertise. The panelists suggest that some cases could be reclassified into HFE-related, digenic, or non-HFE HC based on next-generation sequencing results. In the FIGURE, the panelists illustrated a potential process for the diagnosis of HC, from clinical, biochemical, and imaging studies to molecular confirmation.
Additionally, the working group panelists suggest abandoning the current terminology of type 4A and 4B HC, reclassifying type B as ferroportin-related HC and renaming type 4A as “ferroportin disease,” an inherited rare disorder of iron metabolism separate from HC.
Study authors report no relevant conflicts of interest.
Girelli D, Busti F, Brissot P, et al. Hemochromatosis classification: update and recommendations by the BIOIRON Society [published online ahead of print, 2021 Oct 3]. Blood. doi: 10.1182/blood.2021011338.