The Expression of PNPLA3 Polymorphism could be the Key for Severe Liver Disease in NAFLD in Hispanic Population
Leonardo A. Martínez*, Elena Larrieta*, Juan J. Calva**, David Kershenobich***, Aldo Torre
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* Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City
** Department of Infectology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City
*** Institutional Director, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City
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Diagnosis is performed by ultrasonography (hepatic steatosis) and/or hepatic biopsy.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">1</span></a> It is the third worldwide leading cause of liver disease; however, in the west, conditioned by obesogenic environment, ranks the first place.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">2</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">The NAFLD spectrum includes: steatosis (SS), steato-hepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma; hepatic steatosis represents the first evidence of organ damage.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">3</span></a> Those who develop NASH; in high contrast to those with steatosis, are more likely to progress to more severe states; this differentiation is conditioned by different factors ongoing research.</p><p id="p0020" class="elsevierStylePara elsevierViewall">In 2008, a Single Nucleotide Polymorphism (SNP) in the gene for phospholipase A3: PNPLA3 was identified and strongly associated with increased triglycerides in the hepatic content.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">1,4</span></a> The variant is due to the substitution of methionine by isoleucine at residue 148 of PNPLA3, which results in an increased lipogenesis (SNP rs738409 C/G, M148I). It is predominantly expressed in liver and adipose tissue, it has lipolytic and lipogenic activity <span class="elsevierStyleItalic">in vitro</span> and it is stimulated by glucose and insulin. Speliotes, <span class="elsevierStyleItalic">et al</span>. demonstrated that G allele of rs738409 PNPLA3 confers increased risk of NAFLD, histologically confirmed (odds ratio [OR] = 3.26, 95% [CI] = 2.11-7.21; P = 3.6 3 x 10<span class="elsevierStyleSup">-43</span>).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">5</span></a> There was no observed association with IMC, triglycerides, HDL or diabetes, so it can be concluded that PNPLA3 genetic variations have no visible effects on metabolic syndrome components.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">2,6</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">It is, nowadays known, that PNPLA3 contributes to ethnic and differences regarding hepatic fat content and progression susceptibility in the spectrum, but not in metabolic syndrome components.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">7,8</span></a> This SNP is common in Hispanic population and it has been demonstrated to be associated to NAFLD in Mexican population with allele frequency of 59%.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">9,10</span></a> We aimed to analyze the association between SNP PNPLA3 and NAFLD in adult Mexican patients.</p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Objective</span><p id="p0030" class="elsevierStylePara elsevierViewall">Determine association; in Mexican adults, of SNP PNPLA3 with NAFLD and its spectrum related; fatty liver, steatohepatitis and fibrosis.</p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Material and Methods</span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Ethnicity and ethics</span><p id="p0035" class="elsevierStylePara elsevierViewall">Participants were Mexicans, recruited in a consecutively fashion, half-caste, with more than 2 family generations living in Mexico City, between 18 and 70 years old and they all signed informed consent prior to participation. The study was approved by the Institutional Ethics Committee and was conducted according to WMA Declaration of Helsinki. The study was evaluated in conferences and research seminars by outside researchers.</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Design</span><p id="p0040" class="elsevierStylePara elsevierViewall">Transversal and observational case-control study was implemented. Comparison of NAFLD patients based on the presence (cases) or absence(controls) of risk allele (G) of PNPLA3. All patients belonging to Instituto Na-cional de Ciencias Médicas y Nutrición Salvador Zubirán from December 2013 to January 2015.</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Study population</span><p id="p0045" class="elsevierStylePara elsevierViewall">NAFLD patients according to 2012<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">1</span></a> Guides diagnose criteria. Patients with secondary causes of steatosis, such as those related to alcohol consumption were excluded. Fatty liver ultrasound diagnosis was performed by two standardized radiologists; equipment with 3.5-MHz transducer (Adama Siemens, Erlangen, Germany) was used. Liver biopsy was used in cases where both; the treating physician indicated it for diagnosis approach and, where the patient consented. The doctors who performed the imaging studies were blinded to patients’ diagnosis. It had previously been documented interobserv-er agreement kappa of 0.83 among radiologists who performed and interpreted studies. Two pathologists blinded to diagnosis and comorbidities performed biopsy interpretation according to Brunt and Kleiner classifi-cation.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">11,12</span></a></p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Clinical and demographic factors</span><p id="p0050" class="elsevierStylePara elsevierViewall">All patients received medical assessment; nutritional, anthropometrical, abdominal ultrasound and laboratory studies. The criteria for metabolic syndrome were consistent to the agreed definition published in Circulation 2009.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">13</span></a> The figures for abdominal circumference validated in Mexican population: > 90 cm in men and> 80 cm in women. Alcohol consumption – related liver disease was according to if in a 2 years period prior to the date of inclusion or liver biopsy; the patient had a higher intake of 21 cups for men and 17 cups for women, within a week.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">12</span></a> Five basal samples of peripheral venous blood were obtained at intervals of one minute. Total cholesterol, triglycerides, low-density lipoprotein cholesterol (HDL) and non-HDL; liver function tests, fasting glucose and insulin for calculating insulin resistance index (HOMA) was analyzed. Glucose alterations and diabetes were diagnosed according to the International Diabetes Federation.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">14</span></a></p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Ultrasound as diagnostic method for NAFLD</span><p id="p0055" class="elsevierStylePara elsevierViewall">Ultrasound is the most common image method to assess the diagnosis for fatty liver due to its low cost, wide availability and noninvasive nature.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">15,16</span></a> The sonographic criteria for steatosis diagnosis include: liver hyperecho-genicity, far field attenuation and limited diaphragm visualization. They are rated from 1 to 3 (1 Mild, 2 Moderate and 3 Serious). Sensitivity goes from 85% to 95% and specificity from 90 to 100%.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">17-19</span></a></p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">SNP selection and genotyping</span><p id="p0060" class="elsevierStylePara elsevierViewall">Genomic DNA was isolated from peripheral blood leukocytes by salt fractionation method (96 QIAmp DNA Blood Kit, Quiagen). Samples were genotyped for SNP rs738409 PNPLA3 using TaqMan probes for allelic discrimination (LightCycler 480 Real-Time PCR System, Roche). Genotyping quality was examined by a quality control procedure with a success rate of 95%, positive internal controls samples and Hardy-Weinberg balance test. Laboratory personnel was blinded to the source of samples and their diagnoses.</p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Statistics analysis</span><p id="p0065" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">•</span><p id="p0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Calculation of sample size.</span> Based on N. Méndez, <span class="elsevierStyleItalic">et al</span>.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">9</span></a> the allele frequency was 59% and the variant effect on the odds ratio for having fatty liver was in the range of 1.8 to 2.3 (OR 1.8 reported for NAFLD). The number of participants required for a case-control study by additive or dominant model is 53 for GG, 53 for GC, 53 for CC, with 80% of statistical power, using QUANTO® software.</p></li></ul></p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Variables analysis</span><p id="p0075" class="elsevierStylePara elsevierViewall">Descriptive statistics was used; average ± standard deviation or median and interquartile ranges as appropriate to distribution type. We use T-Student for continuous variables and χ<span class="elsevierStyleSup">2</span> for categorical ones. For allele frequency associations, χ<span class="elsevierStyleSup">2</span> or Fisher exact test was used. Performance of correlation analysis between grade of steatosis determined by biopsy and that by ultrasound and also fibrosis determined by NAFLD fibrosis score and that by Spearman Rho biopsy. Clinical variables and genetic markers were analyzed with Pearson χ<span class="elsevierStyleSup">2</span> test and trend. Regression analyses were performed to control for the effect of age, AST, ALT, BMI, and GenotipoPNPLA3 additive and dominant. We consider statistically significant at p < 0.05. Statistical SPSS v.20 (Illinois USA) and SDS 2.2 softwares were used.</p></span></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">Results</span><p id="p0080" class="elsevierStylePara elsevierViewall">Samples from 211 patients, between 18 and 67 years old; 136 (64.5%) were women, 80 (40%) had diabetes mellitus type 2. One hundred percent had ultrasound: 78 patients (37%) had steatosis grade 1, 72 (34.1%) steatosis grade 2 and 61 patients (28.9%) steatosis grade 3. In 95 patients (45%) liver biopsy was done, from those 61/95 (64.2%) had NASH and 41/95 (43.1%) some grade of liver fibrosis. The correlation between the grade of steatosis determined by biopsy and that determined by ultrasound was r = 0.76 (p < 0.001). The correlation between fibrosis determined by NAFLD fibrosis score that by biopsy (presence or absence of fibrosis) was r = 0.83 (p < 0.001). Demographic characteristics and main variables are detailed in <a class="elsevierStyleCrossRef" href="#t0010">table 1</a>.</p><elsevierMultimedia ident="t0010"></elsevierMultimedia><p id="p0085" class="elsevierStylePara elsevierViewall">According to genotyping: 23 patients (11%) were CC, 73 (34.5%) were GC and 115 (54.5%) were GG. By dominant analysis, 188 patients (89.5%) carried the risk allele (G), (p 0.039, OR 4.34, CI 95% 1.43 - 5.2). The overall al-lele frequency was 77%. The allelic frequency as variant was: 80.47% for SS, 71.87% for NASH and 73.1% for fibro-sis. The observed frequencies were in balance to those expected.</p><p id="p0090" class="elsevierStylePara elsevierViewall">The effect of I148M PNLAP3 variant on the expression of seriousness of hepatic steatosis determined by ultra-sonography and liver biopsy was progressive depending on the number of copies present of the risk allele (<a class="elsevierStyleCrossRef" href="#f0010">Figure 1</a>).</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0095" class="elsevierStylePara elsevierViewall">The homozygous risk allele G had 3.81 times more risk of having NASH (p < 0.05, IC 95%: 3.03-4.79) and 2.32 times more the risk of fibrosis (p < 0.05, 95% CI 1.77 ~ 3.23). The probability of having NASH was higher in homozygous and heterozygous carrying the risk allele (<a class="elsevierStyleCrossRef" href="#f0015">Figure 2</a>).</p><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0100" class="elsevierStylePara elsevierViewall">To greater number of copies of the risk allele, the more likelihood of having scores of NAFLD fibrosis score predictors of presence of significant fibrosis (> 0.675) and increased severity of liver fibrosis confirmed by biopsy (<a class="elsevierStyleCrossRef" href="#f0020">Figure 3</a>).</p><elsevierMultimedia ident="f0020"></elsevierMultimedia><p id="p0105" class="elsevierStylePara elsevierViewall">Homozygous and heterozygous patients with the risk allele had higher percentages of severe steatosis <span class="elsevierStyleItalic">vs.</span> the ho-mozygous wild-type allele. The highest percentages of severe steatosis occurred in nondiabetic homo and heterozygous with the risk allele.</p><p id="p0110" class="elsevierStylePara elsevierViewall">After controlling for ALT, AST, age, BMI, PNPLA3 genotype dominant in our multivariate models, fibrosis remains significantly associated with ALT (Odds Ratio [OR]: -0.2767, 95% Confidence Interval [CI]: -0.5518 to -0.0016, p = 0.049), AST (0.5542, 95% CI: 0.1257-9827, p = 0.012), IMC (-0.0124, 95% CI: -0.0048 to 0.0200, p = 0.001), and PNPLA3 genotype dominant (0.1918, 95% CI: 0.0117-0.3719, p = 0.037) but no longer for age. Steatosis remains significantly associated with PNPLA3 genotype dominant (-0.2255, 95% CI: -4194 to -0.0315, p = 0.023), but no longer for IMC, AST, ALT, or age.</p></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0100">Discussion</span><p id="p0115" class="elsevierStylePara elsevierViewall">Although etiology and pathogenic mechanisms of NAFLD are not entirely known, all series are consistent in clinical situations called “risk factors”: women (65-83%), obesity (47-100%), diabetes mellitus type 2 (34-55%) and dyslipidemia (20-81%).<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">19,20</span></a> The sum of risk factors seems to have an additive role in risk or severity of NAFLD. Obesity is the most associated condition with NAFLD (69-100%),<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">22,23</span></a> followed by diabetes mellitus type 2 (34-75%). In some cases not only diagnosis is made at an earlier age, more often in males (53%)<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">21</span></a> and most of them are found nondiabetics nor obese and but also in up to 46% cases, underlying factors are not identified then can be inferred that it's genetics what conditions NAFLD and its spectrum.</p><p id="p0120" class="elsevierStylePara elsevierViewall">By ultrasonography was evidenced that severity of hepatic steatosis is greater given the presence of at least one copy of the risk allele for PNPLA3 even in patients without Diabetes Mellitus. The highest percentages of severe steatosis were more common at the sDM2 homo - or heterozygous to allele of risk group, while patients without the risk allele had the lowest percentages regardless co-morbidity DM2.</p><p id="p0125" class="elsevierStylePara elsevierViewall">The allele frequency 77% evidenced in the present study, is higher than the previous 59% documented; finding consistent and alarming at a time, since adding lifestyle, diet and environmental stimuli prevalent in México, it is been enhanced the expression of PNPLA3 and the disease development. In other words, Mexicans have a high genetic predisposition to NAFLD and its complications, furthermore the own specific risk factors of metabolic syndrome that match with our current epidemiological situation; rich in carbohydrates and saturated fats diet, high Diabetes indexes and obesity, strengthens the disease onset since early ages and rapidly towards chronic phases. Not only, we do ignore prevention of a genetics inherent disease, but also we foster it in our habits, forging that way, troubling implications for individual and social health and for a Mexican Health System with no prevention and control schema.</p><p id="p0130" class="elsevierStylePara elsevierViewall">Additive genetic model predominated in this investigation, variant conditioned the expression of fatty liver in heterozygous, but; the effect was even greater in ho-mozygous (<a class="elsevierStyleCrossRef" href="#f0010">Figure 1</a>). PNPLA3 polymorphism PNPLA3 favored predisposition to atherogenesis and cardiovascular risks; primarily, low levels of HDL cholesterol and high levels of insulin resistance. Favored predisposition to increased severity of steatosis, more probability of altered liver function tests, increased risk of NASH and fibrosis, even at lower ages and body mass indexes than those ho-mozygous with wild-type allele. It is now known that NAFLD is an independent factor from cardiovascular risk and that it is associated with long-term morbidity and mortality of cardiovascular, liver and neoplastic complications; however, in non-diabetic population it had been little evidence to support such statements, etiologically related only to diabetes until now.</p><p id="p0135" class="elsevierStylePara elsevierViewall">Being NASH the most likely stage to evolve toward fi-brosis and chronic inflammation its trigger; the risk allele I148M PNLAP3 carrying population would probably be more likely to evolve to chronic and irreversible phases; given that at a greater number of copies of the risk allele, major liver function test increase and higher scoring in NAFLD fibrosis score; which as it is known, these are indirect clinical surrogate markers for inflammation and possible evolution to fibrosis. Elevated levels of liver function test related to PNAPLA3 in Mexicans, had already been described, but only in pediatric<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">24</span></a> population and regardless of weight. So it is plausible to imply that the beginning of the inflammation process at early ages and its perpetuation in adulthood may perform an important role in the evolution of the spectrum from a simple hepatic steatosis to steatohepatitis and fibrosis.</p><p id="p0140" class="elsevierStylePara elsevierViewall">It is clear the usefulness and validity of NAFLD fibro-sis score as a tool to predict fibrosis, given that, the presence of scores at ranges of “indeterminate” or “presence” fibrosis, place certainty to diagnose liver fibrosis. Using this desktop tool in all NASH diagnosis, allows addressing a preventive perspective in chronic liver diseases such as cirrhosis.</p><p id="p0145" class="elsevierStylePara elsevierViewall">Partial not total histological material collected from patients is the limitation in this study. Fact given by our adherence to research protocols bioethics committee recommendations; however, it is very evident the presence of this genetic polymorphism in our population.</p></span><span id="s0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0105">Conclusions</span><p id="p0150" class="elsevierStylePara elsevierViewall">The documented polymorphism PNPLA3 I148M in the Mexican studied population, has a frequency higher than reported, which is 77% <span class="elsevierStyleItalic">vs.</span> 59%; this favors severe hepatic steatosis in patients of the risk allele, even in those with lower body mass indexes and at a younger ages. PNP-LA3 predisposes increased cardiovascular risk given lower levels of HDL cholesterol and increased probability of insulin resistance.</p><p id="p0155" class="elsevierStylePara elsevierViewall">In the Mexican studied population, PNPLA3 conditioned more severe hepatic steatosis, also most likely to present steatohepatitis, liver fibrosis and abnormal liver function tests; so it can be assumed that PNPLA3 can play a decisive role in NAFLD pathogenesis. It is necessary that those environmental factors that promote its expression such as, obesity, diabetes, dyslipidemia, etc. must be countered by effective measures in national prevention programs.</p></span><span id="s0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0110">Data Analysis and Responsibility</span><p id="p0160" class="elsevierStylePara elsevierViewall">Author's contributions: L.A.M., E.L., J.J.C, D.K. and A.T. contributed to the study design. L.A.M., A.T. and J.J.C. collected the data. E.L. performed the genetic data analysis L.A.M., J.J.C., A.T. performed the statistical data analysis and article preparation. D.K., A.T. and J.J.C. contributed to the editing and revision and also gave the final approval.</p></span><span id="s0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0115">Potential Conflicts of Interest</span><p id="p0165" class="elsevierStylePara elsevierViewall">None.</p></span><span id="s0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0120">Financial Support</span><p id="p0170" class="elsevierStylePara elsevierViewall">The National Council of Science and Technology (CONACyT) provided a master degree scholarship for the principal investigator (L.A.M.). The CONACyT took no part in design, conduct of the study, collection, management, analysis, interpretation of the data, preparation, review, and approval of the manuscript.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1199344" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abs0010" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abs0015" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abs0020" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abs0025" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1117801" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "s0010" "titulo" => "Introduction" ] 3 => array:2 [ "identificador" => "s0015" "titulo" => "Objective" ] 4 => array:3 [ "identificador" => "s0020" "titulo" => "Material and Methods" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "s0025" "titulo" => "Ethnicity and ethics" ] 1 => array:2 [ "identificador" => "s0030" "titulo" => "Design" ] 2 => array:2 [ "identificador" => "s0035" "titulo" => "Study population" ] 3 => array:2 [ "identificador" => "s0040" "titulo" => "Clinical and demographic factors" ] 4 => array:2 [ "identificador" => "s0045" "titulo" => "Ultrasound as diagnostic method for NAFLD" ] 5 => array:2 [ "identificador" => "s0050" "titulo" => "SNP selection and genotyping" ] 6 => array:2 [ "identificador" => "s0055" "titulo" => "Statistics analysis" ] 7 => array:2 [ "identificador" => "s0060" "titulo" => "Variables analysis" ] ] ] 5 => array:2 [ "identificador" => "s0065" "titulo" => "Results" ] 6 => array:2 [ "identificador" => "s0070" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "s0075" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "s0080" "titulo" => "Data Analysis and Responsibility" ] 9 => array:2 [ "identificador" => "s0085" "titulo" => "Potential Conflicts of Interest" ] 10 => array:2 [ "identificador" => "s0090" "titulo" => "Financial Support" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-03-07" "fechaAceptado" => "2017-05-17" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1117801" "palabras" => array:5 [ 0 => "Patatine-like phosphatas in domain 3" 1 => "Hepatic steatosis" 2 => "NAFLD" 3 => "Sllele I148M" 4 => "Mexico" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">Background</span><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">Nonalcoholic fatty liver disease (NAFLD) encompasses: fatty liver (SS), steatohepatitis (NASH) with or without fi-brosis and cirrhosis. Patatine-like phosphatas in domain 3 (PNPLA3; adiponutrin; SNP rs738409 C/G, M148I) shows anabolic and catabolic activities on lipid metabolism and significant association to fatty liver content; however, I148M demographics and ethnics, as its role with NAFLD have not been fully elucidated.</p></span> <span id="abs0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Material and methods</span><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">PNPLA3 genotyping from peripheral blood DNA by polymerase chain reaction (PCR) and direct sequencing, 211 patients diagnosed with NAFLD including SS, NASH and fibrosis spectrum.</p></span> <span id="abs0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Results</span><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">Eighty nine per cent showed the G risk allele [CC: 23 (10.5%), GC: 73 (34.7%), GG 115 (54.7%)], the allele frequency was 77%, NASH (71%), SS (80%) and fibrosis (73%). GG genotype carriers showed 3.8 times (CI 95%: 3.03 - 4.79) of increased risk of steatohepatitis and 2.3 times more (CI 95%: 1.77 ~ 3.23) risk of having liver fibrosis (CC). PNPLA3 (GC, GG) conditioned higher probability of low levels of HDL cholesterol (p < 0.010), SS even in normal weight (p < 0.007), insulin resistance by HOMA (p < 0.029), NAFLD fibrosis score showed > 0.675 (p < 0.001) and altered serum alanine aminotransferase (p < 0.05).</p></span> <span id="abs0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Conclusion</span><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall">PNPLA3 expression in Hispanics could be decisive in NAFLD pathogenesis, it's highly prevalent and it's a key to condition and determine the spectrum associated, SS, NASH and fibrosis.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abs0010" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abs0015" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abs0020" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abs0025" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 691 "Ancho" => 999 "Tamanyo" => 77773 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">PNPLA3 additive genetic model in NAFLD.</p>" ] ] 1 => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 692 "Ancho" => 999 "Tamanyo" => 55518 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Increased likelihood of NASH determined by the presence of the risk allele.</p>" ] ] 2 => array:7 [ "identificador" => "f0020" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1663 "Ancho" => 2075 "Tamanyo" => 157922 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Increased likelihood of fibrosis according NAFLD fibrosis score and liver biopsy conditioned by the presence of the risk allele.</p>" ] ] 3 => array:7 [ "identificador" => "t0010" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Risk allele G = C = wild-type allele. Data are expressed as means ± standard deviation/frequencies (percentages),<span class="elsevierStyleBold">*</span> p < 0.05.</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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Everyone (n = 211) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CC (n = 23) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CG/GG (n = 188) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47.3 ± 10.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49.3 ± 11.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39.7 ± 9.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.002 * \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gender (%M/%F) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36 / 65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 / 61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 / 71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.131 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMI (kg/m<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">2</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.2 ± 7.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33.6 ±6.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27.4 ± 8.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.007 * \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total cholesterol (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">181.8 ± 38.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">179.4 ±38.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">185.9 ± 37.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.237 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Triglycerides (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">165.2 ± 79.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">158.9 ±78.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">175.9 ± 79.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.137 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HDL (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44.3 ± 11.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44.1 ±11.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37.6 ± 7.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.010 * \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NAFLD fibrosis score \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-1.51 ± 0.035 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-1.41 ±.044 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.68 ± 0.043 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p < 0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diabetes mellitus type 2 (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80 (40) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 (52) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 (48) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.165 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HOMA IR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9 ± 2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.1 ±1.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.8 ± 2.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.029 * \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALT (UI/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44.2 ± 29.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36.3 ±19.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63.5 ± 17.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.047 * \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AST (UI/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.0 ± 20.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33.3 ±17.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39.1 ± 23.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0570 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2048457.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Demographic characteristics and main variables.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:24 [ 0 => array:3 [ "identificador" => "bib0010" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Chalasani N." 1 => "Younossi Z." 2 => "Lavine J.E." 3 => "Diehl A.M." 4 => "Brunt E.M." 5 => "Cusi K." 6 => "Charlton M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2012.04.001" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2012" "volumen" => "142" "paginaInicial" => "1592" "paginaFinal" => "1609" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22656328" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0015" "etiqueta" => "2." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Trends in liver disease prevalence in Mexico from 2005 to 2050 through mortality data" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Méndez-Sánchez N." 1 => "Villa A." 2 => "Chávez-Tapia N." 3 => "Ponciano-Rod-riguez G." 4 => "Almeda-Valdés P." 5 => "González D." 6 => "Uribe M." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Annals of Hepatology" "fecha" => "2005" "volumen" => "4" "paginaInicial" => "52" "paginaFinal" => "55" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15798662" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0020" "etiqueta" => "3." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The natural history of nonalcoholic steatohepati-tis: a follow-up study of forty-two patients for up to 21 years" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Powell E.E." 1 => "Cooksley W.G." 2 => "Hanson R." 3 => "Searle J." 4 => "Halliday J.W." 5 => "Powell L.W." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1990" "volumen" => "11" "paginaInicial" => "74" "paginaFinal" => "80" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2295475" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0025" "etiqueta" => "4." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Romeo S." 1 => "Kozlitina J." 2 => "Xing C." 3 => "Pertsemlidis A." 4 => "Cox D." 5 => "Pennac-chio L.A." 6 => "Boerwinkle E." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ng.257" "Revista" => array:6 [ "tituloSerie" => "Nature Genetics" "fecha" => "2008" "volumen" => "40" "paginaInicial" => "1461" "paginaFinal" => "1465" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18820647" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0030" "etiqueta" => "5." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Unravelling the Pathogenesis of Fatty Liver Disease: Patatin-like Phospholipase Domain-Containing 3 Protein" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Stefano R." 1 => "Huang-Doran I." 2 => "Baroni M.G." 3 => "Kotronen A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Current opinion in lipidology" "fecha" => "2010" "volumen" => "21" "paginaInicial" => "247" "paginaFinal" => "252" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20480550" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0035" "etiqueta" => "6." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Speliotes E.K." 1 => "Yerges-Armstrong L.M." 2 => "Wu J." 3 => "Hernaez R." 4 => "Kim L.J." 5 => "Palmer C.D." 6 => "Gudnason V." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pgen.1001324" "Revista" => array:5 [ "tituloSerie" => "PLoS genetics" "fecha" => "2011" "volumen" => "7" "paginaInicial" => "e1001324" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21423719" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0040" "etiqueta" => "7." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Qiao A." 1 => "Liang J." 2 => "Ke Y." 3 => "Li C." 4 => "Cui Y." 5 => "Shen L." 6 => "Zhang H." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.24402" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2011" "volumen" => "54" "paginaInicial" => "509" "paginaFinal" => "521" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21547936" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0045" "etiqueta" => "8." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "American Gas-troenterological Association medical position statement: nonalcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "American Gastroenterological Association" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2002" "volumen" => "123" "paginaInicial" => "1702" "paginaFinal" => "1704" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12404244" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0050" "etiqueta" => "9." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A PNPLA3 Gene Polymorphism is Associated With Nonalcoholic Fatty Liver Disease (NAFLD) in Mexican Patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:8 [ 0 => "Gutierrez-Grobe Y." 1 => "Villalobos-Blasquez I." 2 => "Canizales-Quinter-os S." 3 => "Dominguez-Lopez A." 4 => "Sanchez-Muñoz F." 5 => "García-Corona C." 6 => "Uribe M." 7 => "Méndez-Sánchez N." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Gastroenterology" "fecha" => "2010" "volumen" => "138" "paginaInicial" => "S-803" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0055" "etiqueta" => "10." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Dowman J.K." 1 => "Tomlinson J.W." 2 => "Newsome P.N." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/pharmacy7020045" "Revista" => array:6 [ "tituloSerie" => "Alimentary Pharmacology & Therapeutics" "fecha" => "2011" "volumen" => "33" "paginaInicial" => "525" "paginaFinal" => "540" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31083620" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0060" "etiqueta" => "11." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Matteoni C.A." 1 => "Younossi Z.M." 2 => "Gramlich T." 3 => "Boparai N." 4 => "Liu Y.C." 5 => "McCullough A.J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "1999" "volumen" => "116" "paginaInicial" => "1413" "paginaFinal" => "1419" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10348825" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0065" "etiqueta" => "12." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Endpoints and clinical trial design for nonalcoholic steatohepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Sanyal A.J." 1 => "Brunt E.M." 2 => "Kleiner D.E." 3 => "Kowdley K.V." 4 => "Chalasani N." 5 => "Lavine J.E." 6 => "Ratziu V." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.24376" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2011" "volumen" => "54" "paginaInicial" => "344" "paginaFinal" => "353" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21520200" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0070" "etiqueta" => "13." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Harmonizing the Metabolic Syndrome: A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Alberti K.MM." 1 => "Eckel R.H." 2 => "Grundy S.M." 3 => "Zimmet P.Z." 4 => "Cleeman J.I." 5 => "Donato K.A." 6 => "Fruchart J.C." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Circulation" "fecha" => "2003" "volumen" => "16" "paginaInicial" => "1640" "paginaFinal" => "1645" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0075" "etiqueta" => "14." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nonalcoholic fatty liver, steatohep-atitis, and the metabolic syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Marchesini G." 1 => "Bugianesi E." 2 => "Forlani G." 3 => "Cerrelli F." 4 => "Lenzi M." 5 => "Manini R." 6 => "Natale S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2003.50161" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2003" "volumen" => "37" "paginaInicial" => "917" "paginaFinal" => "923" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12668987" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0080" "etiqueta" => "15." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Mishra P." 1 => "Younossi Z.M." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am J Gastroen-terol" "fecha" => "2007" "volumen" => "102" "paginaInicial" => "2716" "paginaFinal" => "2717" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0085" "etiqueta" => "16." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Obesity is the only independent factor associated with ultrasound-diagnosed non-alcoholic fatty liver disease: a cross-sectional case-control study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Lee S." 1 => "Jin Kim Y." 2 => "Yong Jeon T." 3 => "Hoi Kim H." 4 => "Woo Oh S." 5 => "Park Y." 6 => "Soo Kim S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/00365520500319591" "Revista" => array:6 [ "tituloSerie" => "Scand J Gastroenterol" "fecha" => "2006" "volumen" => "41" "paginaInicial" => "566" "paginaFinal" => "572" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16638699" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0090" "etiqueta" => "17." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The use of ultrasound in clinical setting for children affected by NAFLD: is it safe and accurate?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Nobili V." 1 => "Corte C.D." 2 => "Monti L." 3 => "Alisi A." 4 => "Feldstein A." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1824-7288-37-36" "Revista" => array:5 [ "tituloSerie" => "Ital J Pediatr" "fecha" => "2011" "volumen" => "37" "paginaInicial" => "36" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21810223" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0095" "etiqueta" => "18." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of radiologic modalities in the management of non-alcoholic steatohepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Charatcharoenwitthaya P." 1 => "Lindor K.D." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cld.2007.02.014" "Revista" => array:6 [ "tituloSerie" => "Clin Liver Dis" "fecha" => "2007" "volumen" => "11" "paginaInicial" => "37" "paginaFinal" => "54" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17544971" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0100" "etiqueta" => "19." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Mottin C.C." 1 => "Moretto M." 2 => "Padoin A.V." 3 => "Swarowsky A.M." 4 => "Toneto M.G." 5 => "Glock L." 6 => "Repetto G." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1381/096089204323093408" "Revista" => array:6 [ "tituloSerie" => "Obes Surg" "fecha" => "2004" "volumen" => "14" "paginaInicial" => "635" "paginaFinal" => "637" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15186630" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0105" "etiqueta" => "20." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and pathological correlations in liver disease: approaching the next Milennium" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Bloomer J.R." 1 => "Goodman Z.D." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:4 [ "titulo" => "Chicago, Illinois: AASLD Postrgraduate Course" "paginaInicial" => "187" "paginaFinal" => "193" "serieFecha" => "2008" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0110" "etiqueta" => "21." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Garcia-Monzon C." 1 => "Martin-Perez E." 2 => "Iacono O.L." 3 => "Fernandez-Bermejo M." 4 => "Majano P.L." 5 => "Apolinario A." 6 => "Larranaga E." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2000" "volumen" => "33" "paginaInicial" => "716" "paginaFinal" => "724" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11097478" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0115" "etiqueta" => "22." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Should nonalcoholic fatty liver disease be included in the definition of metabolic syndrome? A cross-sectional comparison with Adult Treatment Panel III criteria in nonobese nondiabetic subjects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Musso G." 1 => "Gambino R." 2 => "Bo S." 3 => "Uberti B." 4 => "Biroli G." 5 => "Pagano G." 6 => "Cas-sader M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc07-1526" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2008" "volumen" => "31" "paginaInicial" => "562" "paginaFinal" => "568" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18056890" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0120" "etiqueta" => "23." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Obesity as a medical problem" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Kopelman P.G." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/35007508" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2000" "volumen" => "404" "paginaInicial" => "635" "paginaFinal" => "643" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10766250" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0125" "etiqueta" => "24." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of the I148M/PNPLA3 variant with elevated alanine transaminase levels in normal-weight and overweight/obese Mexican children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Larrieta-Carrasco E." 1 => "Leon-Mimila P." 2 => "Villarreal-Molina T." 3 => "Vil-lamil-Ramirez H." 4 => "Romero-Hidalgo S." 5 => "Jacobo-Albavera L." 6 => "Gutierrez-Vidal R." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.gene.2013.03.038" "Revista" => array:6 [ "tituloSerie" => "Gene" "fecha" => "2013" "volumen" => "520" "paginaInicial" => "185" "paginaFinal" => "188" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23510779" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/16652681/0000001600000006/v1_201906040957/S1665268119304582/v1_201906040957/en/main.assets" "Apartado" => array:4 [ "identificador" => "77721" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Article" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/16652681/0000001600000006/v1_201906040957/S1665268119304582/v1_201906040957/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119304582?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 0 | 6 |
| 2024 October | 47 | 5 | 52 |
| 2024 September | 45 | 5 | 50 |
| 2024 August | 46 | 2 | 48 |
| 2024 July | 74 | 6 | 80 |
| 2024 June | 38 | 5 | 43 |
| 2024 May | 26 | 4 | 30 |
| 2024 April | 29 | 4 | 33 |
| 2024 March | 50 | 2 | 52 |
| 2024 February | 40 | 13 | 53 |
| 2024 January | 53 | 9 | 62 |
| 2023 December | 44 | 5 | 49 |
| 2023 November | 51 | 3 | 54 |
| 2023 October | 70 | 6 | 76 |
| 2023 September | 52 | 14 | 66 |
| 2023 August | 55 | 2 | 57 |
| 2023 July | 54 | 10 | 64 |
| 2023 June | 53 | 5 | 58 |
| 2023 May | 61 | 2 | 63 |
| 2023 April | 82 | 0 | 82 |
| 2023 March | 56 | 8 | 64 |
| 2023 February | 43 | 2 | 45 |
| 2023 January | 61 | 13 | 74 |
| 2022 December | 55 | 4 | 59 |
| 2022 November | 42 | 17 | 59 |
| 2022 October | 26 | 9 | 35 |
| 2022 September | 51 | 17 | 68 |
| 2022 August | 34 | 4 | 38 |
| 2022 July | 32 | 10 | 42 |
| 2022 June | 26 | 6 | 32 |
| 2022 May | 66 | 18 | 84 |
| 2022 April | 29 | 27 | 56 |
| 2022 March | 50 | 17 | 67 |
| 2022 February | 31 | 9 | 40 |
| 2022 January | 42 | 6 | 48 |
| 2021 December | 23 | 9 | 32 |
| 2021 November | 31 | 10 | 41 |
| 2021 October | 27 | 16 | 43 |
| 2021 September | 34 | 16 | 50 |
| 2021 August | 56 | 16 | 72 |
| 2021 July | 29 | 15 | 44 |
| 2021 June | 32 | 17 | 49 |
| 2021 May | 65 | 19 | 84 |
| 2021 April | 113 | 38 | 151 |
| 2021 March | 78 | 6 | 84 |
| 2021 February | 66 | 9 | 75 |
| 2021 January | 47 | 13 | 60 |
| 2020 December | 32 | 9 | 41 |
| 2020 November | 26 | 12 | 38 |
| 2020 October | 15 | 4 | 19 |
| 2020 September | 29 | 13 | 42 |
| 2020 August | 32 | 15 | 47 |
| 2020 July | 26 | 19 | 45 |
| 2020 June | 17 | 9 | 26 |
| 2020 May | 28 | 9 | 37 |
| 2020 April | 19 | 6 | 25 |
| 2020 March | 18 | 1 | 19 |
| 2020 February | 20 | 9 | 29 |
| 2020 January | 16 | 7 | 23 |
| 2019 December | 5 | 7 | 12 |
| 2019 November | 2 | 2 | 4 |
| 2019 October | 8 | 2 | 10 |
| 2019 September | 8 | 2 | 10 |
| 2019 August | 1 | 0 | 1 |
| 2019 July | 11 | 8 | 19 |
| 2019 June | 12 | 19 | 31 |
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