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family members&#44; and healthcare professionals&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Usually&#44; hepatobiliary manifestations associated with CF start at the end of the patients&#8217; first decade of life&#44; and its prevalence ranges from 5&#46;7&#37; to 39&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">4&#8211;11</span></a> Hepatobiliary disease is the third leading cause of mortality in CF patients&#44; preceded by deaths associated with pulmonary involvement and complications inherent to organ transplants&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">12</span></a> Additionally&#44; some studies have shown that patients with advanced liver disease are at risk of developing and&#47;or exacerbating other extrahepatic CF manifestations&#44; such as malnutrition&#44; diabetes mellitus&#44; hepatic osteodystrophy&#44; and pulmonary disease&#44; leading to increased morbidity caused by the underlying disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">3&#44;13</span></a> Thus&#44; hepatobiliary disease has been considered a risk predictor of an unfavorable evolution and prognosis of CF&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">14</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Few studies have been carried out on CF-associated hepatobiliary disease in the Brazilian population&#44; being fundamental to know the disease particularities in Brazil&#44; which has peculiar ethnic&#47;racial characteristics in the different geographic regions&#46; The objectives of the study were to determine the frequency of hepatobiliary disease in CF patients and to describe the sociodemographic&#44; clinical&#44; and laboratory profile of these patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">This was a retrospective&#44; descriptive&#44; and analytical study of patients treated at a referral center in a university hospital&#46; The records of all patients&#44; aged 3 months to 21 years&#44; followed-up between January 2008 and June 2016&#44; with a diagnosis of CF confirmed by two positive sweat tests and&#47;or genetic study&#44; and who had been followed-up for at least three months in this service&#44; were analyzed&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Patients with comorbidities that affected the hepatobiliary system &#40;use of hepatotoxic drugs and&#47;or primary hepatobiliary diseases&#44; or secondary involvement of the liver&#44; gallbladder&#44; and&#47;or spleen&#41; were excluded&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Data were collected from medical records between June and July 2016&#44; consisting of sociodemographic and clinical characteristics &#8211; age &#40;months&#41;&#44; weight &#40;kg&#41;&#44; height &#40;cm&#41;&#44; and body mass index &#40;BMI&#41; at CF diagnosis&#59; time of follow-up at the service&#59; presence of hepatobiliary &#40;jaundice&#44; hepatomegaly&#44; splenomegaly&#44; collateral circulation&#41;&#44; pulmonary &#40;recurrent pneumonia&#44; wheezing&#44; colonization by <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#41;&#44; and gastrointestinal &#40;diarrhea&#44; steatorrhea&#44; low weight gain&#44; meconium ileus&#41; manifestations&#59; Shwachman&#8211;Kulczycki score&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">15</span></a> laboratory&#47;imaging tests&#44; and genetic study&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Information on histopathological tests &#40;liver biopsy&#41; and upper digestive endoscopy &#40;UDE&#41; were recorded&#44; when present&#46; Weight&#44; height&#44; and BMI were evaluated by <span class="elsevierStyleItalic">Z</span>-score&#44; according to the World Health Organization &#40;WHO&#44; 2006&#41; classification&#46; Patients with fecal elastase &#60;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;g were classified as having severe pancreatic insufficiency&#46; Abdominal ultrasonography &#40;USG&#41; was performed annually in patients older than 7 years&#44; or earlier in those with signs&#44; symptoms&#44; or alterations in laboratory tests suggestive of hepatobiliary disease&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The age at the CF diagnosis was defined as the time of the second positive sweat test or genetic study result&#46; The time of follow-up of each patient corresponded to the period between June 2016 and the first consultation or first hospitalization at the service&#46; Skin color was defined by one of the researchers&#44; medical coordinator of the multidisciplinary CF outpatient clinic&#44; based on the phenotypic characteristics of the patients and their parents&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">All patients underwent a genetic study&#44; and the following mutations in the <span class="elsevierStyleItalic">CFTR</span> gene were screened through polymerase chain reaction &#40;PCR&#41; or enzymatic digestion<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">16</span></a>&#58; F508del&#44; G542X&#44; R1162X&#44; R334W&#44; 3120&#43;1G-A&#44; G551D&#44; and R553X&#46; Infection by cytomegalovirus &#40;CMV&#41; was investigated through serological tests &#40;IgM and IgG antibodies&#41; in patients with hepatobiliary disease criteria&#44; whereas PCR was also performed&#44; when available&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">CF-associated hepatobiliary disease was defined as compatible alterations at the liver biopsy or evidence of cholangiopathy &#40;microvesicles&#44; biliary lithiasis&#44; or bile duct stenosis&#41; or the presence&#44; for three consecutive months&#44; of at least two of the following criteria&#58; &#40;1&#41; hepatomegaly on physical examination &#40;liver &#62;2<span class="elsevierStyleHsp" style=""></span>cm from the right costal border&#44; confirmed by abdominal USG&#41;&#59; &#40;2&#41; elevation above the upper limit of normal of aspartate aminotransferase and&#47;or alanine aminotransferase and&#47;or gamma-glutamyl transferase levels&#59; and &#40;3&#41; alteration in the abdominal USG &#40;increased hepatic echogenicity&#44; nodularity&#44; irregular liver border&#44; liver fibrosis&#44; or portal hypertension signs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">7</span></a> The age at diagnosis of hepatobiliary disease was determined at the moment when some of the criteria were observed&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The software SPSS<span class="elsevierStyleSup">&#174;</span> &#40;IBM SPSS Statistics for Windows&#44; Version 20&#46;0&#44; NY&#44; USA&#41;&#44; was used to create the database and carry out the statistical analysis&#46; The descriptive analysis of sociodemographic&#44; clinical&#44; and laboratory characteristics&#44; characterized by measures of central tendency and dispersion &#40;means and standard deviation&#44; median and interquartile range&#41; was performed&#44; as well as the comparison of groups with and without hepatobiliary disease using the Mann&#8211;Whitney test for numerical variables and Fisher&#39;s exact test for categorical variables&#46; <span class="elsevierStyleItalic">p</span>-values &#8804;0&#46;05 were considered statistically significant in all analyses&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The study was approved by the Research Ethics Committee of the institution&#44; under registration number 121&#47;2011&#46; All participants and their guardians received verbal and written information about the nature&#44; proposal&#44; and objective of the study and its possible risks and benefits&#44; and signed the informed consent form&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0070" class="elsevierStylePara elsevierViewall">A total of 55 patients with CF were analyzed&#46; The median &#40;IQR&#41; of the follow-up time of these patients was 35 &#40;15&#8211;78&#41; months&#44; ranging from three to 102 months&#46; The distribution of the number of new CF and hepatobiliary disease cases per year of follow-up is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">CF-associated hepatobiliary disease was diagnosed in 16&#46;4&#37; &#40;9&#47;55&#41; of CF patients&#46; The median age &#40;IQR&#41; of these patients was 54 &#40;27&#8211;91&#41; months&#44; ranging from 10 months to 9 years and 11 months&#46; Seven &#40;77&#46;8&#37;&#41; patients were females&#59; and all were considered non-white&#46; The other sociodemographic&#44; clinical&#44; and laboratory characteristics of the group of CF patients with and without hepatobiliary disease are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The median age &#40;IQR&#41; at the diagnosis of hepatobiliary disease associated with CF was 7 months &#40;3&#8211;47&#41;&#46; This diagnosis occurred before and&#47;or concomitantly with that of CF in 88&#46;9&#37; of the patients&#44; and the presence of hepatobiliary manifestations was among the first signs and symptoms of CF in five of the nine patients &#40;55&#46;6&#37;&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Patients with hepatopathy had a higher frequency of severe mutations in the <span class="elsevierStyleItalic">CFTR</span> gene &#40;77&#46;8&#37; <span class="elsevierStyleItalic">vs</span>&#46; 39&#46;6&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41; and severe pancreatic insufficiency &#40;88&#46;9&#37; <span class="elsevierStyleItalic">vs</span>&#46; 31&#46;6&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41; than the group without hepatobiliary disease&#46; Although not statistically significant&#44; the children with hepatobiliary disease had a much earlier CF diagnosis in comparison with the second group&#44; with a median &#40;IQR&#41; of 7 &#40;4&#46;5&#8211;47&#41; <span class="elsevierStyleItalic">vs</span>&#46; 59 &#40;7&#8211;104&#46;5&#41; months&#44; respectively &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;059&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Regarding the clinical characteristics of the nine patients with CF-associated hepatobiliary disease&#44; no cases with meconium ileus were observed&#44; and one patient had normal pancreatic function with asymptomatic biliary disease&#46; The others &#40;88&#46;9&#37;&#41; had severe pancreatic insufficiency&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the clinical characteristics at the time of CF diagnosis of patients with hepatobiliary disease&#46; Some nutritional impairment &#40;<span class="elsevierStyleItalic">Z</span>-score for weight&#47;age and&#47;or height&#47;age and&#47;or BMI&#47;age &#60;&#8722;2&#41; was observed in six &#40;66&#46;7&#37;&#41; of these patients&#46; The medians of <span class="elsevierStyleItalic">Z</span>-scores for weight&#47;age and height&#47;age in this group of patients were &#8722;3&#46;27 and &#8722;3&#46;08&#44; with minimum values of &#8722;9&#46;49 and &#8722;6&#46;82&#44; respectively&#46; The BMI&#47;age <span class="elsevierStyleItalic">Z</span>-scores were &#62;&#8722;2 in 77&#46;8&#37; of the cases&#44; due to the proportional reduction in weight and height values &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">The type of presentation of CF-associated hepatobiliary disease is described in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46; Hepatomegaly was the most frequently identified finding&#44; in seven patients &#40;77&#46;8&#37;&#41;&#44; followed by increased hepatic echogenicity in five children &#40;55&#46;5&#37;&#41;&#46; All patients underwent CMV screening&#44; which was positive in two cases&#44; one of which was also confirmed by PCR&#46; One patient with negative serology had CMV infection confirmed by PCR&#46; These patients had liver biopsy findings compatible with CF-associated hepatobiliary disease&#46; Regarding the complications of hepatopathy&#44; portal hypertension was observed in two patients&#44; splenomegaly in only one case&#44; and esophageal varices in one of the four patients who underwent UDE&#46; Only one child developed signs of acute liver failure&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">The present study demonstrated that 16&#46;4&#37; of the patients with CF had hepatobiliary disease&#46; This frequency is similar to that described by Wagener et al&#46; &#40;16&#46;3&#37;&#41;&#44; who evaluated 30&#44;727 CF patients from a multicenter study in the United States and Canada between 1999 and 2004&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">10</span></a> However&#44; Fagundes et al&#46; followed-up 106 Brazilian patients with CF for approximately one year and found a lower frequency &#40;9&#46;4&#37;&#41; of hepatobiliary disease associated with CF&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">2</span></a> In addition to the short follow-up period&#44; those authors used only biochemical and&#47;or clinical alterations as diagnostic criteria&#44; which may have led to the underdiagnosis of this complication&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The prevalence of CF-associated hepatobiliary disease is quite variable in the literature&#44; due to the heterogeneous clinical presentation&#44; absence of universal diagnostic criteria&#44; and the variation of characteristics inherent to the population &#40;age&#44; gender&#44; survival rate&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a> Longitudinal studies in Europeans&#44; North-Americans&#44; and Brazilians have shown prevalence rates varying between 5&#46;7&#37; and 39&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">4&#8211;11</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Male gender has been considered a risk factor for the development of hepatobiliary disease associated with CF&#46; Colombo et al&#46; demonstrated a 2&#46;5-fold higher risk of hepatobiliary disease in males&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">7</span></a> However&#44; the present study showed a higher frequency of males in the group without hepatobiliary disease &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;042&#41;&#46; The predominance of females among the patients with hepatobiliary disease &#40;77&#46;8&#37;&#41; is in agreement with data from the study by Lindblad et al&#46;&#44; in which 68&#46;6&#37; of patients with CF and hepatopathy were females&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">6</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In this study&#44; the age at the diagnosis of hepatobiliary disease associated with CF was early &#40;median of 7 months&#41;&#44; ranging from 3 months to 3 years and 11 months&#59; hepatobiliary manifestations were among the first signs and symptoms of CF in 55&#46;6&#37; &#40;5&#47;9&#41; of these patients&#46; Additionally&#44; it is important to emphasize that the diagnosis of hepatobiliary disease occurred before and&#47;or concomitantly with that of CF in 88&#46;9&#37; &#40;8&#47;9&#41; of them&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">However&#44; Ciuc&#227; et al&#46;&#44; when studying 66 Romanians with CF&#44; demonstrated that only three patients &#40;4&#46;5&#37;&#41; had hepatobiliary disease as the first manifestation of CF&#44; with a mean interval of four years between the CF diagnosis and hepatopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> Other studies have also demonstrated a later onset of hepatobiliary disease&#44; ranging from 3 to 8 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">2&#44;7&#8211;9&#44;18&#44;19</span></a> Therefore&#44; the findings of the present study demonstrate the early onset of this manifestation in this population of patients with CF and the importance of investigating CF in patients with hepatopathy&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Among the possible justifications for the early presentation is the fact that patients with hepatobiliary disease have more severe CF phenotypes&#44; which was corroborated by the association between the presence of severe pancreatic insufficiency &#40;88&#46;9&#37; <span class="elsevierStyleItalic">vs</span>&#46; 31&#46;6&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41; and severe mutations in the <span class="elsevierStyleItalic">CFTR</span> gene &#40;77&#46;8&#37; <span class="elsevierStyleItalic">vs</span>&#46; 39&#46;6&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41; in this group&#44; compared to those without hepatobiliary disease&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Moreover&#44; Lamireau et al&#46; demonstrated that pancreatic insufficiency is an independent factor associated with an increased prevalence of hepatobiliary disease in CF&#44; leading to a 9&#46;8-fold higher risk of liver disease in patients with CF&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a> Although the literature does not describe an association between any mutation related to the <span class="elsevierStyleItalic">CFTR</span> gene and the presence or severity of hepatobiliary disease&#44; some studies have demonstrated that more severe genotypes may be considered risk factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Cirrhosis occurs predominantly in individuals with Class I&#44; II&#44; and III mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">1&#44;10&#44;22&#44;23</span></a> A study of 174 Romanians with CF disclosed a five-fold higher risk of developing hepatobiliary disease in patients with severe mutations &#40;OR&#58; 4&#46;79&#41;&#44; which were identified in 78&#37; of those with hepatobiliary disease&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> However&#44; it is known that liver disease development is very variable among patients with the same <span class="elsevierStyleItalic">CFTR</span> mutations&#44; suggesting a possible multigenic role of the genetic polymorphism and environmental factors&#44; not evaluated in the study&#44; in the pathogenesis of this complication&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">1&#44;3&#44;13&#44;21&#44;24</span></a> Therefore&#44; later studies may assess the role of these variables in the development of hepatobiliary disease&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Poor lung function and nutritional status indicators in CF have also been studied as risk factors for hepatobiliary disease&#44; and could justify the severity and early onset of this complication&#46; Fagundes et al&#46; identified an association between W&#47;A <span class="elsevierStyleItalic">Z</span>-score &#60;&#8722;2 and development of hepatobiliary disease&#59; these authors also observed that Shwachman&#8211;Kulczycki score values &#8804;70 conferred a 7&#46;5-fold higher risk of developing this complication in patients with CF&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">25</span></a> In the present study&#44; 44&#46;4&#37; of the patients with hepatobiliary disease presented Shwachman&#8211;Kulczycki score &#8804;70&#44; and some degree of nutritional impairment was observed in 66&#46;7&#37; of them&#46; However&#44; it is necessary to compare these variables with the group without hepatobiliary disease to reinforce the importance of these findings&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Although not statistically significant&#44; it is worth mentioning that the CF diagnosis was attained much earlier in the group with hepatobiliary disease&#44; when compared to those without this complication &#40;median of 7 <span class="elsevierStyleItalic">vs</span>&#46; 59 months&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;059&#41;&#46; Similarly&#44; Fagundes et al&#46; demonstrated that the age at CF diagnosis was independently associated with the development of liver disease&#44; being inversely proportional&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">25</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">It is possible that hepatobiliary disease is part of a spectrum of worse prognosis and severity of CF&#44; which would justify the earlier disease diagnosis in these patients&#46; It is possible that a larger sample could demonstrate this association&#44; since this study evaluated only 55 children&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Liver disease with cirrhosis and its complications tend to occur in approximately 7&#8211;12&#37; of CF patients between the ages of 7 and 10&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">6&#44;18&#44;19</span></a> Lamireau et al&#46; demonstrated a median time of 10 years for the evolution of hepatopathy associated with CF to portal hypertension&#46; In the present study&#44; only two patients with CF &#40;3&#46;6&#37;&#41;&#44; who already had portal hypertension since the diagnosis&#44; presented liver cirrhosis at 5 months and 3 years of age&#46; Non-performance of hepatic biopsy in all patients and the young age of children with hepatobiliary disease &#40;median of 7 months&#41; may justify the lower frequency of cirrhosis&#44; since it is a late consequence&#44; secondary to progressive hepatocyte lesion due to biliary thickening and its toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">However&#44; it is noteworthy the precocity of cirrhosis and portal hypertension onset in the present study&#44; suggesting a more severe spectrum of liver disease in this population&#46; A possible justification would be the presence of concomitant CMV infection&#44; worsening the liver status&#46; This infection occurs in 50&#37; of the children in the first year of life in places with high seropositivity rates&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a> which is associated with precarious socioeconomic conditions &#40;found in the studied population&#41;&#46; However&#44; this association has not been confirmed&#46; In turn&#44; although this infection was investigated in all patients through serology&#44; only two were identified using the PCR technique and&#44; thus&#44; underdiagnosis may have occurred&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Among the study limitations&#44; the authors emphasize the small sample of patients with CF and the number of patients with hepatobiliary disease&#46; Moreover&#44; only four patients underwent a liver biopsy&#44; which may have underestimated the occurrence of liver disease&#46; Additionally&#44; it was not possible to confirm the genetic diagnosis of CF in all patients&#44; since only seven mutations were investigated&#46; Furthermore&#44; the role of genetic polymorphisms in the development of this complication was not evaluated&#46; Nonetheless&#44; the results were significant&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In conclusion&#44; this study found a high frequency of hepatobiliary disease in patients with CF &#40;16&#46;4&#37;&#41;&#44; which occurred as an initial manifestation of the latter in 55&#46;6&#37; of patients with liver disease&#46; It is worth mentioning the earlier occurrence of hepatobiliary disease&#44; as well as the early onset of complications in relation to the literature&#46; This emphasizes the importance of including CF in the differential diagnosis of all liver diseases in childhood&#46; Additionally&#44; an association was observed between the presence of pancreatic insufficiency and severe mutations in the <span class="elsevierStyleItalic">CFTR</span> gene and the occurrence of hepatobiliary disease&#46; However&#44; further studies involving a larger number of patients should be carried out&#44; aiming to better assess other risk factors for the development of hepatobiliary disease in CF&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Funding</span><p id="par0180" class="elsevierStylePara elsevierViewall">Partial funding from <span class="elsevierStyleGrantSponsor" id="gs1">Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado da Bahia &#40;FAPESB&#41;</span> under No&#46; <span class="elsevierStyleGrantNumber" refid="gs1">020&#47;2013</span> &#8211; Programa de Pesquisa para o SUS da Bahia&#58; gest&#227;o partilhada de sa&#250;de &#8211; FAPESB&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The aims of the study were to determine the frequency of hepatobiliary disease in patients with cystic fibrosis and to describe the sociodemographic&#44; clinical&#44; and laboratory profile of these patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This was a retrospective&#44; descriptive&#44; and analytical study of 55 patients diagnosed with cystic fibrosis&#44; aged between 3 months and 21 years&#44; followed-up from January 2008 to June 2016 in a referral center&#46; Medical records were consulted and sociodemographic&#44; clinical and laboratory data&#44; including hepatobiliary alterations&#44; imaging studies&#44; genetic studies&#44; liver biopsies&#44; and upper digestive endoscopies were registered&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Hepatobiliary disease was diagnosed in 16&#46;4&#37; of the patients and occurred as an initial manifestation of cystic fibrosis in 55&#46;6&#37; of these cases&#46; The diagnosis of hepatopathy occurred before or concomitantly with the diagnosis of cystic fibrosis in 88&#46;9&#37; of the children&#46; All patients with hepatobiliary disease were considered non-white&#44; with a predominance of females &#40;77&#46;8&#37;&#41; and median &#40;IQR&#41; of 54 &#40;27&#8211;91&#41; months&#46; Compared with the group without hepatobiliary disease&#44; children with liver disease had a higher frequency of severe mutations identified in the <span class="elsevierStyleItalic">CFTR</span> gene &#40;77&#46;8&#37; <span class="elsevierStyleItalic">vs</span>&#46; 39&#46;6&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41; and severe pancreatic insufficiency &#40;88&#46;9&#37; <span class="elsevierStyleItalic">vs</span>&#46; 31&#46;6&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The frequency of hepatobiliary disease was high&#44; with a very early diagnosis of the disease and its complications in the studied series&#46; A statistical association was observed between the occurrence of hepatobiliary disease and the presence of pancreatic insufficiency and severe mutations in the <span class="elsevierStyleItalic">CFTR</span> gene&#46; It is emphasized that cystic fibrosis is an important differential diagnosis of liver diseases in childhood&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusion"
          ]
        ]
      ]
      "pt" => array:3 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Os objetivos do estudo foram determinar a frequ&#234;ncia da doen&#231;a hepatobiliar em pacientes com fibrose c&#237;stica e descrever o perfil sociodemogr&#225;fico&#44; cl&#237;nico e laboratorial destes&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudo retrospectivo&#44; descritivo e anal&#237;tico de 55 pacientes com diagn&#243;stico de fibrose c&#237;stica&#44; entre tr&#234;s meses e 21 anos&#44; acompanhados de janeiro de 2008 a junho de 2016 em um centro de refer&#234;ncia&#46; Foi realizada consulta aos prontu&#225;rios m&#233;dicos&#44; registrando-se os dados sociodemogr&#225;ficos&#44; cl&#237;nicos e laboratoriais&#44; incluindo-se altera&#231;&#245;es hepatobiliares&#44; exames de imagem&#44; estudos gen&#233;ticos&#44; bi&#243;psias hep&#225;ticas e endoscopias digestivas altas&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A doen&#231;a hepatobiliar foi diagnosticada em 16&#44;4&#37; dos pacientes e ocorreu como manifesta&#231;&#227;o inicial da fibrose c&#237;stica em 55&#44;6&#37; destes casos&#46; O diagn&#243;stico da hepatopatia ocorreu antes ou concomitante ao diagn&#243;stico da fibrose c&#237;stica em 88&#44;9&#37; das crian&#231;as&#46; Todos os pacientes com doen&#231;a hepatobiliar foram considerados n&#227;o brancos&#44; havendo predomin&#226;ncia do sexo feminino &#40;77&#44;8&#37;&#41; e mediana &#40;I&#46;I&#46;Q&#41; de idade de 54 &#40;27-91&#41; meses&#46; Em compara&#231;&#227;o com o grupo sem doen&#231;a hepatobiliar&#44; as crian&#231;as com hepatopatia tiveram maior frequ&#234;ncia de muta&#231;&#245;es graves no gene CFTR identificadas &#40;77&#44;8&#37; vs 39&#44;6&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;033&#41; e de insufici&#234;ncia pancre&#225;tica grave &#40;88&#44;9&#37; vs 31&#44;6&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;007&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A frequ&#234;ncia de doen&#231;a hepatobiliar foi elevada&#44; observando-se um diagn&#243;stico muito precoce da mesma e de suas complica&#231;&#245;es na casu&#237;stica estudada&#46; Houve associa&#231;&#227;o estat&#237;stica entre a ocorr&#234;ncia de doen&#231;a hepatobiliar e a presen&#231;a de insufici&#234;ncia pancre&#225;tica e de muta&#231;&#245;es graves do gene CFTR&#46; Enfatiza-se que a fibrose c&#237;stica represente um importante diagn&#243;stico diferencial de hepatopatias na inf&#226;ncia&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclus&#227;o"
          ]
        ]
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Please cite this article as&#58; Nascimento FS&#44; Sena NA&#44; Ferreira TA&#44; Marques CD&#44; Silva LR&#44; Souza EL&#46; Hepatobiliary disease in children and adolescents with cystic fibrosis&#46; J Pediatr &#40;Rio J&#41;&#46; 2018&#59;94&#58;504&#8211;10&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0055">Study carried out at Universidade Federal da Bahia &#40;UFBA&#41;&#44; Salvador&#44; BA&#44; Brazil&#46;</p>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
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          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
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        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
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              "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">Year&nbsp;\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">2008&nbsp;\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">2009&nbsp;\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">2010&nbsp;\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">2011&nbsp;\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">2012&nbsp;\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">2013&nbsp;\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">2014&nbsp;\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">2015&nbsp;\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">2016&nbsp;\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">New cases of cystic fibrosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\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">New cases of hepatobiliary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\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">Total number of included cases&#47;year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&nbsp;\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">Deaths&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Number of new cases of cystic fibrosis and hepatobiliary disease&#44; deaths and total number of cases followed-up between January 2008 and June 2016 in a referral center&#46;</p>"
        ]
      ]
      1 => array:8 [
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">IQR&#44; interquartile range&#59; <span class="elsevierStyleItalic">N</span>&#44; number of patients&#46;</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="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\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">Group with hepatobiliary disease &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&nbsp;\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">Group without hepatobiliary disease &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>46&#41;&nbsp;\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">p</span>-value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">Sociodemographic variables</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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Age &#40;months&#41; median &#40;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54 &#40;27&#8211;91&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">127 &#40;60&#46;5&#8211;169&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;004<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a>&nbsp;\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><span class="elsevierStyleItalic">Male gender &#40;n&#47;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;22&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27 &#40;58&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;042<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">g</span></a>&nbsp;\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><span class="elsevierStyleItalic">Non-white &#40;n&#47;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\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><span class="elsevierStyleItalic">Income &#40;Brazilian reais&#41; median &#40;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1058&#46;5 &#40;788&#8211;2355&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1000 &#40;788&#8211;1576&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;879<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">Clinical and laboratory variables</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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Age at cystic fibrosis diagnosis &#40;months&#41; median &#40;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;4&#46;5&#8211;47&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59 &#40;7&#8211;104&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;059<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a>&nbsp;\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><span class="elsevierStyleItalic">Time of follow-up &#40;months&#41; median &#40;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33 &#40;10&#8211;55&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27 &#40;15&#8211;83&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;169<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a>&nbsp;\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><span class="elsevierStyleItalic">Fecal elastase &#60;15</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#956;g&#47;</span>g <span class="elsevierStyleItalic">&#40;n&#47;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;88&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;31&#46;6&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;007<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">g</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Mutation in the CFTR gene &#40;n&#47;&#37;&#41;</span><a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a></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><span class="elsevierStyleHsp" style=""></span>Class I&#47;II<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;77&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;36&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;033<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">g</span></a>&nbsp;\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><span class="elsevierStyleHsp" style=""></span>Not found&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;22&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28 &#40;60&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Sociodemographic&#44; clinical and laboratory characteristics of patients with cystic fibrosis&#44; followed-up between January 2008 and June 2016&#44; in a referral center&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Weight&#47;age Z-score &#40;median&#47;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;3&#46;27 &#40;&#8722;4&#46;34 to &#8722;0&#46;26&#41;&nbsp;\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">Height&#47;age Z-score &#40;median&#47;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;3&#46;08 &#40;&#8722;4&#46;4 to &#8722;0&#46;46&#41;&nbsp;\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">Weight&#47;height Z-score &#40;median&#47;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;43 &#40;&#8722;2&#46;39 to 0&#46;41&#41;&nbsp;\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">Body Mass Index&#47;age Z-score &#40;median&#47;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;26 &#40;1&#46;86 to &#8722;0&#46;15&#41;&nbsp;\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">Pulmonary manifestations &#40;n&#47;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;100&#41;&nbsp;\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">Shwachman&#8211;Kulczycki score value &#40;median&#47;IQR&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">85 &#40;57&#46;5 to 87&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Shwachman&#8211;Kulczycki score classification &#40;n&#47;&#37;&#41;</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="elsevierStyleHsp" style=""></span>Excellent or good &#40;100&#8211;71&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;66&#46;6&#41;&nbsp;\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>Medium &#40;70&#8211;56&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;11&#46;1&#41;&nbsp;\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>Moderate or severe &#40;&#8804;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Clinical characteristics at the time of cystic fibrosis diagnosis of patients with hepatobiliary disease&#44; followed between January 2008 and June 2016&#44; at a referral center&#46;</p>"
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                  <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">Case&nbsp;\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">Gender&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genotype&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Abdominal USG&nbsp;\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">Liver biopsy&nbsp;\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">UDE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F508del&#47;3120&#43;1G-A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Persistent aspartate aminotransferase&#47;gamma-glutamyl transferase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F508del&#47;G542X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly<br>Collateral circulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Persistent Alkaline Phosphatase<br>&#8595; Persistent prothrombin time&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatosplenomegaly<br>&#8593; of hepatic echogenicity<br>Microvesicles<br>Portal hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Biliary cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Esophageal varices&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F508del&#47;F508del&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly<br>Jaundice<br>Collateral circulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Persistent aspartate aminotransferase&#47;alanine aminotransferase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly<br>&#8593; of hepatic echogenicity<br>Lobular liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver steatosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not found&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Biliary lithiasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not found&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly<br>Jaundice&#47;Choluria<br>Fecal acolia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Transient aspartate aminotransferase&#47;alanine aminotransferase&#47;gamma-glutamyl transferase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intrahepatic cholestasis<br>Bile in portal space&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F508del&#47;F508del&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Persistent Alkaline Phosphatase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F 508del&#47;3120&#43;1G-A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Persistent Alkaline Phosphatase<br>&#8595; Persistent prothrombin time&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly<br>&#8593; of hepatic echogenicity<br>Liver steatosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fibrosis portal&#47;septal and presinusoidal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">G542X&#47;R1162X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly<br>Jaundice&#47;Choluria<br>Fecal acolia<br>Collateral circulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Persistent aspartate aminotransferase&#47;alanine aminotransferase<br>Alkaline Phosphatase&#47;gamma-glutamyl transferase&#47;direct bilirubin<br>&#8595; Persistent prothrombin time&#47;Albumin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly<br>&#8593; of hepatic echogenicity<br>Nodular liver and irregular border<br>Portal hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Biliary cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F508del&#47;F508del&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Persistent aspartate aminotransferase&#47;alanine aminotransferase&#47;Alkaline Phosphatase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatomegaly<br>&#8593; of hepatic echogenicity<br>Hepatic steatosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Clinical presentation of patients from a referral center with hepatobiliary disease associated with cystic fibrosis&#44; between January 2008 and June 2016&#46;</p>"
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    "bibliografia" => array:2 [
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                  "contribucion" => array:1 [
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                      "autores" => array:1 [
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