Scientific letter
Is H63D a ‘minor’ HFE polymorphism?
¿Es la H63D un polimorfismo “menor”?
Teresa Pinto-Pais
, Sónia Fernandes, Carlos Fernandes, Iolanda Ribeiro, Sónia Leite, Ana Paula Silva, Luís Alberto, José Fraga, João Carvalho
Corresponding author
Department of Gastroenterology and Hepatology, Centro Hospitalar de Gaia/Espinho, Gaia, Portugal
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"tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "588" "paginaFinal" => "589" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Teresa Pinto-Pais, Sónia Fernandes, Carlos Fernandes, Iolanda Ribeiro, Sónia Leite, Ana Paula Silva, Luís Alberto, José Fraga, João Carvalho" "autores" => array:9 [ 0 => array:4 [ "nombre" => "Teresa" "apellidos" => "Pinto-Pais" "email" => array:1 [ 0 => "teresapintopais@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Sónia" "apellidos" => "Fernandes" ] 2 => array:2 [ "nombre" => "Carlos" "apellidos" => "Fernandes" ] 3 => array:2 [ "nombre" => "Iolanda" "apellidos" => "Ribeiro" ] 4 => array:2 [ "nombre" => "Sónia" "apellidos" => "Leite" ] 5 => array:2 [ "nombre" => "Ana Paula" "apellidos" => "Silva" ] 6 => array:2 [ "nombre" => "Luís" "apellidos" => "Alberto" ] 7 => array:2 [ "nombre" => "José" "apellidos" => "Fraga" ] 8 => array:2 [ "nombre" => "João" "apellidos" => "Carvalho" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Gastroenterology and Hepatology, Centro Hospitalar de Gaia/Espinho, Gaia, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "¿Es la H63D un polimorfismo “menor”?" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Iron overload is associated with a variety of genetic and acquired conditions. Of these, HFE-hemochromatosis is by far the most frequent, well-defined inherited cause, and the majority of patients are homozygotes for the C282Y polymorphism. H63D is considered a ‘minor’ HFE polymorphism<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> but some clinical studies suggest an association between H63D homozygosity and iron overload. However, its role in the development of iron overload remains unclear.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We aimed to study the prevalence and phenotypic expression of H63D homozygotes in a cohort of patients referred to our hepatology clinic.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Method</span><p id="par0015" class="elsevierStylePara elsevierViewall">Patients with increased serum ferritin (1.5× upper limit of normal, >300<span class="elsevierStyleHsp" style=""></span>ng/mL in females, >450<span class="elsevierStyleHsp" style=""></span>ng/mL in males – values adopted from the <span class="elsevierStyleItalic">Hemochromatosis and Iron Overload Screening Study</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a>) and increased transferrin saturation (>45% in females, >50% in males) were enrolled in our study, for three consecutive years. Genetic testing for C282Y/H63D/S65C mutations of the HFE gene was performed by polymerase chain reaction. Standard biochemical markers of iron status, including serum ferritin and transferrin saturation, were obtained. Other laboratorial data included complete blood count, fasting glucose, liver function tests, lipid profile and serology for hepatitis B and C. Also, baseline demographic and clinical characteristics (with quantification of alcohol consumption) were recorded. Chronic renal disease, shunts, chronic haemolytic anemia, thalassemia major, sideroblastic or spur cell anemia, parenteral iron overload and <span class="elsevierStyleItalic">porphyria cutanea tarda</span> were excluded.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Results</span><p id="par0020" class="elsevierStylePara elsevierViewall">230 consecutive patients fulfilled the inclusion criteria, and were enrolled in our study. After HFE genetic analysis, the H63D homozygous mutation was identified in 6.96% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16) of the individuals. The mean age was 53.8 years (28–76), and ten (62.5%) were male. In this group, we found median value of serum ferritin of 550.3<span class="elsevierStyleHsp" style=""></span>ng/mL and transferrin saturation of 57.6%.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Other causes of liver disease were found in 15: Non-Alcoholic Fatty Liver (NAFLD) in 8 patients, chronic alcohol consumption (>60<span class="elsevierStyleHsp" style=""></span>g/day) in 3, chronic Hepatitis B in 3 and C in 1 patient. One patient with H63D homozygosity was negative for other hepatic diseases, viral infections, alcohol abuse and NAFLD.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Discussion</span><p id="par0030" class="elsevierStylePara elsevierViewall">It has been suggested that the H63D mutation contributes to iron overload, increasing serum iron and transferrin, and that its relationship with hemochromatosis is independent.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In our study, H63D+/+ mutation in the HFE gene was detected in 6.96% of our cohort of patients with iron overload. Underlying causes were found in 93.7% such as NAFLD, chronic alcohol consumption and chronic hepatitis B and C. These data confirm the association between hyperferritinemia and these conditions, especially fatty liver. However it does not clarify whether siderosis was related to the underlying disease, namely steatosis, rather than homozygosity for the H63D mutation. Therefore, co-morbid factors may complicate the interpretation of data in population studies of the expression of H63D homozygosity.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In one patient, however, the investigation for other causes was negative, and H63D homozygosity may have played a role. The causative role of H63D+/+ mutation in HH or iron overload has been demonstrated,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> but with less penetrance and a considerable variation of phenotypic expression.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> Environmental factors, variable gene penetrance or other gene mutations may explain the variable phenotypic expression of H63D homozygosity.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conflicts of interests</span><p id="par0045" class="elsevierStylePara elsevierViewall">None declared.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Grant support</span><p id="par0050" class="elsevierStylePara elsevierViewall">None declared.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Method" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Results" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of interests" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Grant support" ] 5 => array:2 [ "identificador" => "xack195010" "titulo" => "Acknowledgments" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "EASL clinical practice guidelines for HFE hemochromatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "European Association for the Study of the Liver" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2010.03.001" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2010" "volumen" => "53" "paginaInicial" => "3" "paginaFinal" => "22" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20471131" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemochromatosis and iron-overload screening in a racially diverse population" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.C. Adams" 1 => "D.M. Reboussin" 2 => "J.C. Barton" 3 => "C.E. McLaren" 4 => "J.H. Eckfeldt" 5 => "G.D. McLaren" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa041534" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2005" "volumen" => "352" "paginaInicial" => "1769" "paginaFinal" => "1778" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15858186" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0040" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "H63D homozygotes with hyperferritinaemia: is this genotype the primary cause of iron overload" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "C. De Diego" 1 => "S. Opazo" 2 => "M.J. Murga" 3 => "P. Martinez-Castro" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1600-0609.2006.00775.x" "Revista" => array:6 [ "tituloSerie" => "Eur J Haematol" "fecha" => "2006" "volumen" => "78" "paginaInicial" => "66" "paginaFinal" => "71" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17042772" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Aguilar-Martinez" 1 => "M. Bismuth" 2 => "M.C. Picot" 3 => "C. Thelcide" 4 => "G.P. Pageaux" 5 => "F. Blanc" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gut" "fecha" => "2001" "volumen" => "48" "paginaInicial" => "836" "paginaFinal" => "842" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11358905" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Iron overload is rare in patients homozygous for the H63D mutation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Kelley" 1 => "N. Joshi" 2 => "Y. Xie" 3 => "M. Borgaonkar" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Can J Gastroenterol Hepatol" "fecha" => "2014" "volumen" => "28" "paginaInicial" => "198" "paginaFinal" => "202" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24729993" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack195010" "titulo" => "Acknowledgments" "texto" => "<p id="par0055" class="elsevierStylePara elsevierViewall">None declared.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/02105705/0000003800000010/v1_201511140017/S0210570515000680/v1_201511140017/en/main.assets" "Apartado" => array:4 [ "identificador" => "45760" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Cartas cientítficas" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/02105705/0000003800000010/v1_201511140017/S0210570515000680/v1_201511140017/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210570515000680?idApp=UINPBA00004N" ]
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