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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

TABLE . New Classification of HC Proposed by the Working Group

Non HFE – related Rare pathogenic variants in “ non-HFE ” genes :

• HJV-related

• HAMP-related

• TFR2-related

• SLC40A1 ( GOF ) -related

Digenic ** Double heterozygosity and / or double homozygosity / heterozygosity for mutations in two different genes involved in iron metabolism ( HFE and / or non-HFE )

Molecularly undefined

Molecular characterization ( still ) not available after sequencing of known genes ( provisional diagnosis )

FIGURE . Algorithm for Hemochromatosis Diagnosis

Low penetrance ; consider presence of host-related or environmental cofactors for IO

In subjects with other HFE genotypes ( e . g ., p . Cys282Tyr / His63Asp compound heterozygosity or p . His63Asp homozygosity ) consider second-line genetic testing for rarer variants .

Potentially , mutations in any hepcidin-regulatory gene may be causative ( the effects of novel mutations should be confirmed through functional and epidemiological studies ).

Molecular subtypes characterization only at specialized centers , but the diagnosis of non-HFE related HC is sufficient to start phlebotomies at non-specialized centers .*

More commonly , p . Cys282Tyr mutation in HFE gene might coexist with mutation in other genes ; rarely , both mutations involve non-HFE genes

Patients should be referred ( or DNA should be sent ) to specialized centers

* Providing that iron overload is confirmed by MRI . If this is not accessible , close monitoring of hemoglobin level is needed to avoid the occurrence of anemia . ** Caution is needed to interpret as digenic inheritance results from NGS outputs reporting several variants in gene panels . Whenever possible , strict criteria for defining pathogenic variants should be adopted , and corroborated by family segregation and / or functional studies . 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 ferroportinrelated 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 .

Reference 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 .

10 ASH Clinical News Bonus 2021 ASH Annual Meeting Preview Edition