Letter to the Editor
Hemochromatosis: The new Heidelberg classification of 2019
Hemocromatosis: nueva clasificación de Heidelberg de 2019
a Unidad de Ferropatología, Hospital Gregorio Marañón, Madrid, Spain
b Grupo de Investigación Trastornos del Metabolismo del Hierro, Instituto de Investigación Gregorio Marañón, Madrid, Spain
c Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
d Sociedad Internacional para el Estudio del Hierro en Biología y Medicina (BIOIRON)
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The term "haemochromatosis" should therefore be reserved for entities in which the iron overload (IO) is of genetic origin and due to hepcidin deficiency, recommending that the unnecessary use of adjectives such as "hereditary", "genetic" or "primary"<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> should be avoided.</p><p id="par0015" class="elsevierStylePara elsevierViewall">In clinical practice, the demonstration of the homozygous p.Cys282Tyr mutation (C282Y/C282Y) in the <span class="elsevierStyleItalic">HFE</span> gene, together with elevated ferritin and saturation index, is considered sufficient to make the diagnosis of HC. Liver biopsy may still be useful in HC patients with serum ferritin levels consistently > 1000 μg/L to detect fibrosis, subclinical cirrhosis, and monitor for hepatocellular carcinoma even after iron depletion, because, in other situations, magnetic resonance imaging (MRI) can be used to determine hepatic iron overload and transient elastography (Fibroscan) can detect liver fibrosis, so liver biopsy should be limited to undiagnosed cases, maintaining phlebotomies as first-line treatment.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The current HC classification,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> based on different subtypes, is very informative from a molecular point of view and is officially endorsed by OMIM (Online Mendelian Inheritance in Man) but is difficult to apply in clinical practice. Therefore, a classification is needed that addresses both clinical problems and genetic complexity and is a practical aid when molecular characterisation is not available.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The new classification (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) reorganizes HC types into four groups: 1) “related to HFE", caused by mutations in the <span class="elsevierStyleItalic">HFE</span> gene; 2) "unrelated to HFE", due to mutations in genes <span class="elsevierStyleItalic">HFE2, HAMP, TFR2</span> and <span class="elsevierStyleItalic">SLC40A1</span>; 3) “digenic”, caused by compound heterozygous mutations in two different genes (<span class="elsevierStyleItalic">HFE</span> and/or <span class="elsevierStyleItalic">HFE</span>), and 4) “molecularly undefined”, when the genetic origin is unknown (provisional diagnosis). In Caucasians with IO and a negative first-tier <span class="elsevierStyleItalic">HFE</span> test (no homozygous p.Cys282Tyr detected) and in non-Caucasians, a second-tier genetic testing [next-generation sequencing (NGS)] should be performed to identify rare variants.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Although molecular characterization is still important in these patients, especially for genetic counselling and first-degree relative screening, the treatment of patients with the HC phenotype should not be delayed, pending the result of the genetic test.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Genetic diagnosis of HC (C282Y/C282Y) can occur but without a phenotype of IO, this is called "potential" HC because the mutation has variable penetrance; however, the p. His63Asp(H63D) polymorphism is currently considered of no interest in the genotypic assessment of IO, even when homozygous (H63D/H63D) or heterozygous compound (C282Y/H63D) and is not diagnostic of HC.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">As for types 4A and 4B related to mutations that are responsible for loss or gain of ferroportin function, respectively, type 4A or ferroportin disease is excluded in the new classification as a rare inherited disorder of iron metabolism without the features of HC, while type 4B is included as HC unrelated to <span class="elsevierStyleItalic">HFE</span> although with special features such as autosomal dominant inheritance and hepcidin resistance.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In short, the new clinical-molecular classification makes it possible to better correlate the HC phenotype with the different genotypes that produce it, as well as its effect on hepcidin.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><elsevierMultimedia ident="202209020726444081"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">New classification proposed in 2019 by the working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON) in Heidelberg.</p>" ] ] 1 => array:5 [ "identificador" => "202209020726444081" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 1449 "Ancho" => 3333 "Tamanyo" => 441678 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemochromatosis classification: update and recommendations by the BIOIRON Society" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "D. 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