Scientific Letter
Spectrum of Alpha-1 Antitripsin Deficiency Mutations Detected in Tenerife
Espectro de mutaciones deficitarias de alfa-1 antitripsina detectadas en Tenerife
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The synthesis of AAT depends on the SERPINA1 gene.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The most common deficiency alleles found in Spain are the PI*S and the PI*Z, and approximately 1/5 and 1/61 individuals in Spain, respectively, are carriers of this mutation.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3–5</span></a> These alleles have been associated with the development of pulmonary emphysema in early adulthood, liver diseases in children and adults, and other entities such as systemic vasculitis (especially Wegener's granulomatosis positive for c-ANCA) or necrotizing panniculitis.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">2,6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Few population genetic studies of AAT deficiency alleles have been conducted in the Canary Islands,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a> and none have identified rare deficiency alleles. For this reason, the aim of this study was to describe the spectrum of mutations found in the population of Tenerife seen at the Hospital Universitario Nuestra Señora de Candelaria (HUNSC).</p><p id="par0020" class="elsevierStylePara elsevierViewall">This was a cross-sectional, descriptive study of a series that includes index cases with AAT plasma levels below 100<span class="elsevierStyleHsp" style=""></span>mg/dl who were referred to the Clinical Laboratory department of the HUNSC on clinical suspicion of alpha-1 antitrypsin deficiency (AATD) between January 1, 2009 and August 31, 2016.</p><p id="par0025" class="elsevierStylePara elsevierViewall">AAT serum values were determined by nephelometry (BN ProSpec System, Siemens). Genomic DNA was purified from whole blood with EDTA (QIAamp DNA blood mini kit, Qiagen). The two most common deficiency alleles PI*S and Pi*Z were genotyped by real-time PCR using FRET probes (LightCycler 2.0). The genotypes obtained were correlated with previously determined plasma AAT values, following the routine protocol in our hospital.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> Patients with AAT plasma levels out of range of those expected for the genotypes S/Z obtained underwent complete sequencing of the coding exons and intronic sequences flanking the SERPINA1 gene (BigDye v3.1, Thermo Fisher), replacing conventional isoelectric focusing phenotyping. SERPINA1 sequencing was performed in a AB3500 capillary sequencer (Applied Biosystems), and results were compared with the NM_001127701.1 reference sequence (SeqScape 3.0).</p><p id="par0030" class="elsevierStylePara elsevierViewall">In total, 325 AATD patients with AAT plasma levels <100<span class="elsevierStyleHsp" style=""></span>mg/dl were included in the study. Studies directed at the PI*S and Pi*Z deficiency alleles were conducted in all patients. Genotypes are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Forty-six patients (14.2%) had a genotype associated with severe deficiency (AAT<50<span class="elsevierStyleHsp" style=""></span>mg/dl), of which 24 were PI*ZZ, 10 PI*SZ, 1 PI*SS, 2 PI*S/Mmalton, 1 PI*Z/Q0amersfoort, 1 PI*Z/Q0cardiff, 1 PI*Z/Mmalton, 2 PI*Mmalton/Mmalton, 1 PI*MZ, 2 PI*S/NoSnoZ and 1 PI*Z/NoSnoZ. In total, 279 patients (85.8%) were recorded as having mild-to-moderate deficiency (AAT between 50 and 100<span class="elsevierStyleHsp" style=""></span>mg/dl), distributed as follows: 119 PI*Z/NoSnoZ, 59 PI*SZ, 36 PI*S/NoSnoZ, 24 PI*SS, 8 PI*M/Mmalton, 4 PI*M/Mpalermo, 2 PI*S/Mmalton, 1 PI*S/Mpalermo, 1 PI*ZZ, 1 PI*MZ, 1 PI*MI, 3 PI*MM and 20 NoSnoZ/NoSnoZ.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The percentage of carriers of rare deficiency alleles was 7.7%, 80% of whom had the mutation F76del (PI*Mmalton and PI*Mpalermo).</p><p id="par0045" class="elsevierStylePara elsevierViewall">In this study, we performed an AATD diagnostic protocol based on the quantification of AAT plasma levels, followed by genotyping for deficiency alleles PI*S and PI*Z, as these are the most common in our population. In recent years, correlation of both results has been shown to be the most efficient technique, achieving an unequivocal diagnosis in approximately 96% of cases.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> In the remaining patients, SERPINA1 full-gene sequencing was performed, a technique that has been shown to improve the accuracy of AATD diagnosis.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> Most AATD study protocols use isoelectric focusing phenotyping as the gold standard. However, in our case, we decided to use SERPINA1 gene sequencing, due to the limitations of phenotyping in the identification of rare deficiency variants.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">An interesting finding in our study was the yield obtained from the combination of protein levels and PI*S and Pi*Z allele genotyping (84.9%), which was lower than reported in the literature.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> This low yield from the diagnostic protocol is due to the high prevalence of rare deficiency variants, particularly the mutation F76del (PI*Mmalton and PI*Mpalermo) that accounts for 81.5% of the rare variants encountered; this percentage is higher than described in similar studies conducted in Spain.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a> Moreover, in the 25 patients who underwent SERPINA1 gene sequencing, we found 20 with NoSnoZ/NoSnoZ, 4 with PI*S/NoSnoZ, and 1 with genotype PI*Z/NoSnoZ with AAT plasma levels discordant with genotyping for the S and Z alleles. Although they were candidates for SERPINA1 full-gene sequencing, this was not performed as the technique was not available in our hospital at the time of the study. We should add that in 3 patients with mild-to-moderate AAT deficiency, no mutations were detected, despite SERPINA1 full-gene sequencing. This may be due to mutations in gene regulatory regions that were not studied,<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> or mutations that are undetectable by sequencing that require alternative techniques for diagnosis.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">AATD is one of the most prevalent hereditary diseases in our population, and the mutation F76del, like the PI*Z allele, has been associated with the development of pulmonary emphysema and liver disease,<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">14,15</span></a> so we believe it is appropriate to detect these mutations in all patients in whom it is impossible to obtain an unequivocal diagnosis with the standard genetic protocols combining serum AAT levels, genotyping for deficiency alleles PI*S and Pi*Z, and phenotyping.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Martínez Bugallo F, Figueira Gonçalves JM, Martín Martínez MD, Díaz Pérez D. Espectro de mutaciones deficitarias de alfa-1 antitripsina detectadas en Tenerife. Arch Bronconeumol. 2017;53:595–596.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">AAT: alpha-1 antitrypsin deficiency; SD: standard deviation; rare: rare deficiency variants.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genotype \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AAT \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SD \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">SS</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">SZ</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">59.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">ZZ</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">M/M</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">88.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">NoSnoZ/NoSnoZ</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">80.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">NoSnoZ/S</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">NoSnoZ/Z</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">122 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">37.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">S/Rare</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>S/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>S/Mpalermo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Z/Rare</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Z/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Z/Q0cardiff \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Z/Q0amersfoort \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">M/Rare</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>M/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">77.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>M/Mpalermo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">74.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>M/<span class="elsevierStyleSmallCaps">I</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">84.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Rare/Rare</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mmalton/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Total</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">325 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1526389.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Genotypes and AAT Levels Obtained in the Study.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnóstico y tratamiento del déficit de alfa-1-antitripsina" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 36 | 19 | 55 |
| 2024 September | 77 | 23 | 100 |
| 2024 August | 105 | 51 | 156 |
| 2024 July | 70 | 22 | 92 |
| 2024 June | 108 | 43 | 151 |
| 2024 May | 94 | 34 | 128 |
| 2024 April | 66 | 34 | 100 |
| 2024 March | 68 | 25 | 93 |
| 2024 February | 39 | 18 | 57 |
| 2023 December | 1 | 2 | 3 |
| 2023 November | 1 | 0 | 1 |
| 2023 March | 24 | 2 | 26 |
| 2023 February | 117 | 20 | 137 |
| 2023 January | 53 | 52 | 105 |
| 2022 December | 85 | 49 | 134 |
| 2022 November | 57 | 24 | 81 |
| 2022 October | 86 | 38 | 124 |
| 2022 September | 44 | 31 | 75 |
| 2022 August | 42 | 54 | 96 |
| 2022 July | 39 | 51 | 90 |
| 2022 June | 40 | 41 | 81 |
| 2022 May | 47 | 35 | 82 |
| 2022 April | 40 | 33 | 73 |
| 2022 March | 39 | 42 | 81 |
| 2022 February | 39 | 31 | 70 |
| 2022 January | 80 | 31 | 111 |
| 2021 December | 45 | 41 | 86 |
| 2021 November | 38 | 41 | 79 |
| 2021 October | 59 | 56 | 115 |
| 2021 September | 31 | 51 | 82 |
| 2021 August | 47 | 38 | 85 |
| 2021 July | 30 | 23 | 53 |
| 2021 June | 60 | 41 | 101 |
| 2021 May | 52 | 50 | 102 |
| 2021 April | 163 | 109 | 272 |
| 2021 March | 77 | 26 | 103 |
| 2021 February | 69 | 38 | 107 |
| 2021 January | 78 | 21 | 99 |
| 2020 December | 49 | 17 | 66 |
| 2020 November | 48 | 17 | 65 |
| 2020 October | 58 | 23 | 81 |
| 2020 September | 41 | 18 | 59 |
| 2020 August | 37 | 20 | 57 |
| 2020 July | 49 | 30 | 79 |
| 2020 June | 41 | 8 | 49 |
| 2020 May | 38 | 10 | 48 |
| 2020 April | 59 | 22 | 81 |
| 2020 March | 40 | 11 | 51 |
| 2020 February | 35 | 19 | 54 |
| 2020 January | 59 | 27 | 86 |
| 2019 December | 62 | 25 | 87 |
| 2019 November | 49 | 27 | 76 |
| 2019 October | 27 | 23 | 50 |
| 2019 September | 37 | 12 | 49 |
| 2019 August | 41 | 24 | 65 |
| 2019 July | 37 | 18 | 55 |
| 2019 June | 42 | 20 | 62 |
| 2019 May | 57 | 21 | 78 |
| 2019 April | 63 | 45 | 108 |
| 2019 March | 45 | 25 | 70 |
| 2019 February | 38 | 17 | 55 |
| 2019 January | 39 | 35 | 74 |
| 2018 December | 34 | 31 | 65 |
| 2018 November | 117 | 24 | 141 |
| 2018 October | 170 | 24 | 194 |
| 2018 September | 56 | 62 | 118 |
| 2018 May | 32 | 3 | 35 |
| 2018 April | 62 | 11 | 73 |
| 2018 March | 28 | 11 | 39 |
| 2018 February | 32 | 8 | 40 |
| 2018 January | 76 | 21 | 97 |
| 2017 September | 0 | 1 | 1 |
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