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Original article
Temporal histopathological changes in biliary atresia: A perspective for rapid fibrosis progression
Hanaa A El-Arabya, Magdy A Sabera, Noha M Radwana, Doha M Taieb, Nermin M Adawya, Ahmad M Siraa,
Corresponding author
asira@liver.menofia.edu.eg

Corresponding author.
a Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-Koom, Menoufia, Egypt
b Department of Pathology, National Liver Institute, Menoufia University, 32511 Shebin El-Koom, Menoufia, Egypt
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0050">Introduction</span><p id="par0140" class="elsevierStylePara elsevierViewall">Biliary atresia &#40;BA&#41; is the commonest cause of neonatal cholestasis&#46; It is associated with a unique feature&#44; namely progressive fibrosis&#46; In most cases&#44; even after timely Kasai portoenterostomy &#40;KP&#41; with successful biliary drainage&#44; fibrosis progresses with the development of cirrhosis and portal hypertension &#91;<a class="elsevierStyleCrossRef" href="#bib0005">1</a>&#93;&#46; Mechanisms underlying this rapid fibrosis progression are unknown&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">A younger infant with BA could exhibit a more advanced grade of fibrosis than an older infant &#91;<a class="elsevierStyleCrossRef" href="#bib0010">2</a>&#93;&#46; This suggests that fibrosis progression is not related to aging alone and there are driving forces behind the different grades of fibrosis among different cases&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The word fibrosis is used to describe the recovery process of an injured liver&#46; Progressive fibrosis leads to harmful effects with the development of portal hypertension and its hazardous consequences &#91;<a class="elsevierStyleCrossRef" href="#bib0015">3</a>&#93;&#46; It is well known that there is a rapid progression to obliterative fibrosis in BA patients&#46; However&#44; preventing fibrosis progression that occurs even after successful KP remains challenging &#91;<a class="elsevierStyleCrossRef" href="#bib0020">4</a>&#93;&#46; Investigating early histopathological changes in BA that might be related to rapid progression of fibrosis could have an impact on ameliorating this rapidly progressive disease&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Histopathological criteria of BA are well studied&#46; Most of the studies have shown that bile ductular proliferation &#40;BDP&#41;&#44; bile plugs&#44; and portal fibrosis are the most important pathological features of BA along with different grades of other pathological features such as portal cellular infiltrates&#44; giant cells&#44; and hepatocellular swelling &#91;<a class="elsevierStyleCrossRef" href="#bib0025">5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0030">6</a>&#93;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Some previous &#91;<a class="elsevierStyleCrossRef" href="#bib0035">7</a>&#93; and recent &#91;<a class="elsevierStyleCrossRef" href="#bib0040">8</a>&#93; studies have demonstrated the prognostic significance of various histopathological features such as BDP in BA&#46; However&#44; dynamic changes in these histopathological criteria and their relationship with progression of fibrosis have not been adequately recognized&#46; The present study aimed to assess the relationship between temporal histopathological changes and fibrosis progression in BA within a short time interval&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0055">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0060">Study population</span><p id="par0165" class="elsevierStylePara elsevierViewall">This observational prospective cohort study included 98 specimens of liver tissue from 49 infants with BA&#44; which included two sequential specimens from each patient &#40;a preoperative diagnostic liver biopsy specimen and an intraoperative liver biopsy specimen&#41;&#46; The patients were recruited consecutively from June 2015 to May 2018 from the Department of Pediatric Hepatology&#44; Gastroenterology&#44; and Nutrition&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Within the duration of the study&#44; all infants diagnosed with BA were recruited&#46; Those who had undergone a diagnostic &#40;first&#41; and an intraoperative &#40;second&#41; liver biopsy were included in the study&#46; The exclusion criteria were &#40;1&#41; inadequate liver biopsy &#91;<a class="elsevierStyleCrossRef" href="#bib0045">9</a>&#93;&#44; &#40;2&#41; loss of liver tissue during the processing procedures for staining&#44; and &#40;3&#41; cytomegalovirus positive cases&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Preoperative diagnosis of BA was made according to a variety of criteria after full history taking&#44; thorough clinical examination&#44; routine investigations&#44; and liver biopsy&#44; as reported by us previously in the BA scoring system &#91;<a class="elsevierStyleCrossRef" href="#bib0050">10</a>&#93;&#46; The diagnosis of BA was confirmed by operative cholangiography and&#47;or intraoperative laparotomy findings immediately before proceeding to KP&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">All BA cases included in the present study were isolated forms of BA&#46; One case of biliary atresia splenic malformation was excluded due to inadequate tissue in the diagnostic liver biopsy&#46; One case of cystic variant of BA was excluded due to cytomegalovirus positivity&#46; Thus&#44; the study cohort consisted of patients with isolated&#44; typical variant of BA &#91;<a class="elsevierStyleCrossRef" href="#bib0020">4</a>&#93;&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">In compliance with the 1975 Declaration of Helsinki and its later amendments&#44; approval for this study was obtained from the Research Ethics Committee of the National Liver Institute&#46; Signed informed consents were obtained from the parents of all patients&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0065">Biochemical&#44; hematological&#44; and ultrasonographic evaluation</span><p id="par0190" class="elsevierStylePara elsevierViewall">Liver function tests &#40;total and direct bilirubin&#44; total proteins&#44; albumin&#44; alanine transaminase&#44; aspartate transaminase&#44; &#947;-glutamyl transpeptidase&#44; and alkaline phosphatase&#41;&#44; determination of international normalized ratio&#44; and complete blood count were performed for each infant&#46; Abdominal ultrasound and Doppler study were performed for all cases&#44; as described by us previously &#91;<a class="elsevierStyleCrossRef" href="#bib0055">11</a>&#93;&#46; All of these investigations were performed at the time of the diagnostic liver biopsy&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0070">Liver biopsy</span><p id="par0195" class="elsevierStylePara elsevierViewall">All recruited patients underwent an ultrasound-guided diagnostic liver biopsy &#40;first liver biopsy&#41; using a Tru-cut needle at the initial assessment and an intraoperative wedge biopsy &#40;second liver biopsy&#41; during KP&#46; All intraoperative biopsies were sampled 5&#8239;mm deeper to the capsule to avoid the subcapsular fibrosis and to obtain tissue comparable to that sampled by the Tru-cut biopsy &#91;<a class="elsevierStyleCrossRef" href="#bib0060">12</a>&#93;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0075">Histopathological evaluation</span><p id="par0200" class="elsevierStylePara elsevierViewall">For histopathological evaluation&#44; tissue sections were stained with hematoxylin and eosin&#44; diastase periodic acid-Schiff&#44; orcein&#44; and Masson&#8217;s trichrome stains&#46; Specimens containing ten or more portal tracts were considered adequate &#91;<a class="elsevierStyleCrossRef" href="#bib0045">9</a>&#93;&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">All specimens were assessed for the presence of &#40;1&#41; BDP&#44; &#40;2&#41; bile plugs&#44; &#40;3&#41; portal infiltrate with lymphocytes&#44; neutrophils&#44; and eosinophils&#44; &#40;4&#41; giant cell transformation of hepatocytes&#44; &#40;5&#41; hepatocyte swelling&#44; &#40;6&#41; rosette formation&#44; and &#40;7&#41; extramedullary hematopoiesis &#40;EMH&#41;&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">BDP&#44; giant cell transformation of hepatocytes&#44; and bile plugs were graded according to the method reported by Lee and Looi &#91;<a class="elsevierStyleCrossRef" href="#bib0025">5</a>&#93;&#46; The other features were graded based on the experience of our pathology department with the criteria for each grade clearly defined to avoid subjective assessment&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">BDP was graded as 1&#41; none&#58; the average number of bile ductules per portal tract &#60;5&#44; 2&#41; mild&#58; the average number of bile ductules per portal tract between 5 and 9&#44; 3&#41; moderate&#58; the average number of bile ductules per portal tract &#8805;10&#44; or 4&#41; marked&#58; elongated&#44; attenuated&#44; or angulated bile ductules in addition to proliferation &#40;average number of bile ductules per portal tract &#8805;10&#41;&#46; Presence of giant cells was reported as none&#44; giant cells around the central vein&#44; or diffuse&#46; Bile plugs were reported as absent or present&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Lymphocytic infiltration in the portal region was reported as none &#40;presence of up to four normal resident lymphocytes in the portal tract&#41;&#44; mild &#40;presence of a large number of lymphocytes in the portal tract without the presence of lymphoid aggregates&#41;&#44; or moderate to marked &#40;presence of a large number of lymphocytes in the portal tract with the presence of lymphoid aggregates&#41;&#46; Neutrophilic infiltration in the portal region was reported as 1&#41; absent or mild &#40;presence of a few neutrophils around some bile ducts&#41; or 2&#41; moderate to marked &#40;presence of a large number of neutrophils around some bile ducts&#41;&#46; Eosinophilic infiltration in the portal region was reported as 1&#41; absent or mild &#40;presence of a few eosinophils around some bile ducts&#41; or 2&#41; moderate to marked &#40;presence of a large number of eosinophils around some bile ducts&#41;&#46; Hepatocyte swelling was reported as 1&#41; none&#44; 2&#41; mild&#47;focal&#44; or 3&#41; periportal&#47;diffuse&#46; EMH and rosette formation were reported as absent or present&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Liver fibrosis was classified into five grades &#91;<a class="elsevierStyleCrossRef" href="#bib0065">13</a>&#93;&#46; Grade 0 indicated absence of fibrosis or fibrous expansion of some portal areas&#44; grade 1 indicated fibrous expansion of most of the portal areas&#44; grade 2 indicated focal porto-portal bridging&#44; grade 3 indicated marked bridging&#44; and grade 4 indicated cirrhosis&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Temporal histopathological changes were assessed by comparing the diagnostic and the intraoperative liver biopsies&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">All histopathological findings were interpreted by two senior pathologists who were blinded to the diagnosis of the patients or the type of biopsy&#46; All pathological criteria were assessed three times&#44; one month apart and median values were reported&#46; Intraobserver and interobserver kappa values for different pathological parameters were 0&#46;831&#8211;0&#46;886 and 0&#46;795&#8211;0&#46;827&#44; respectively&#46; For the histopathological findings that showed no concordance between the two pathologists&#44; a shared reassessment was performed&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0080">Statistical analysis</span><p id="par0240" class="elsevierStylePara elsevierViewall">Quantitative parametric data were expressed as mean&#8239;&#177;&#8239;standard deviation and non-parametric data were expressed as median &#40;minimum&#8211;maximum&#41;&#46; Qualitative data were presented as number &#40;percentage&#41; of individuals with a particular condition&#46; Chi-squared test or Fisher&#8217;s exact test was used to determine the level of significance for the qualitative data&#46; Correlation of temporal changes in fibrosis with other parameters was tested using Spearman&#8217;s test&#46; Stepwise regression analysis was performed to determine the independent temporal histopathological changes&#46; The kappa coefficient was calculated to measure the intraobserver and interobserver agreement&#46; The value of the kappa coefficient was used to denote the following agreement categories&#58; excellent &#40;&#8805;0&#46;80&#41;&#44; good &#40;0&#46;60&#8211;0&#46;79&#41;&#44; moderate &#40;0&#46;40&#8211;0&#46;59&#41;&#44; poor &#40;0&#46;20&#8211;0&#46;39&#41;&#44; and very poor &#40;&#60;0&#46;20&#41;&#46; A p-value of less than 0&#46;05 was used to indicate statistically significant results&#46; SPSS 16&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41; was used to perform the statistical analysis&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0090">Demographic&#44; clinical&#44; laboratory&#44; and radiologic data of the group</span><p id="par0245" class="elsevierStylePara elsevierViewall">The mean age at diagnostic liver biopsy was 59&#8239;&#177;&#8239;12 days &#40;range&#58; 33&#8211;98 days&#41;&#44; while the mean age at KP and the intraoperative liver biopsy was 74&#8239;&#177;&#8239;12 days &#40;range&#58; 49&#8211;117 days&#41;&#46; The interval between the two liver biopsies ranged from 5 days to 31 days with a median of 14 days&#46; Females constituted 53&#37; of the cases and one case &#40;2&#37;&#41; had a positive family history&#46; All cases exhibited clay-colored stools&#44; 94&#37; of the cases had hepatomegaly&#44; and 77&#46;6&#37; of the cases exhibited abnormal gall bladder contractility on ultrasound evaluation&#46; Splenic malformation syndrome was not reported in any of the cases&#46; Other clinical&#44; laboratory&#44; and radiological data are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0095">Histopathological findings in the diagnostic and the intraoperative liver biopsies</span><p id="par0250" class="elsevierStylePara elsevierViewall">BDP was observed in all liver biopsy specimens &#40;100&#37;&#41; irrespective of the type of biopsy&#46; Moreover&#44; all biopsies &#40;100&#37;&#41; showed different grades of fibrosis&#44; with established cirrhosis in 14&#46;3&#37; of the cases at the time of KP&#46; Both bile plugs and rosette formation were also prevalent histopathological findings&#46; They were observed in 89&#46;8&#37; of the cases in the initial liver biopsy and in 93&#46;9&#37; of the cases in the intraoperative liver biopsy&#46; On the other hand&#44; EMH was present in a few cases either in the first or in the second liver biopsy &#40;34&#46;7&#37; and 16&#46;3&#37; of the cases&#44; respectively&#41;&#46; Additional histopathological findings are presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0100">Temporal histopathological changes</span><p id="par0255" class="elsevierStylePara elsevierViewall">We performed a univariate analysis for temporal histopathological changes in BA by comparing the pathological findings in the first liver biopsy with those in the second liver biopsy&#44; with an interval ranging from 5 days to 31 days &#40;median&#58; 14 days&#41;&#46; There was a significant increase in BDP &#40;p&#8239;&#61;&#8239;0&#46;001&#41;&#44; portal tract cellular infiltrate &#40;lymphocytic&#44; neutrophilic&#44; and eosinophilic&#58; p&#8239;&#61;&#8239;0&#46;001&#44; p&#8239;&#61;&#8239;0&#46;004&#44; and p&#8239;&#61;&#8239;0&#46;004&#44; respectively&#41;&#44; giant cells &#40;p&#8239;&#61;&#8239;0&#46;018&#41;&#44; hepatocellular swelling &#40;p&#8239;&#61;&#8239;0&#46;001&#41;&#44; and fibrosis &#40;p&#8239;&#61;&#8239;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; On the other hand&#44; EMH showed a significant decrease &#40;p&#8239;&#61;&#8239;0&#46;037&#41; with no significant changes in bile plugs and rosette formation &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0260" class="elsevierStylePara elsevierViewall">BDP showed a temporal increase from the diagnostic biopsy to the intraoperative biopsy by one grade in 28 cases and by two grades in four cases&#46; This was followed by fibrosis&#44; which showed a temporal increase by one grade in 26 cases and by two grades in five cases&#46; No change was observed in the grade of fibrosis in 18 cases&#46; Temporal changes in the other histopathological findings are depicted in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0265" class="elsevierStylePara elsevierViewall">In the multivariate analysis&#44; BDP was the only histopathological feature that showed a significant difference between the first and the second liver biopsies &#40;p&#8239;&#61;&#8239;0&#46;021&#44; 95&#37; confidence interval&#58; 1&#46;249&#8211;16&#46;017&#41;&#46; It showed a significant increase in the grades from 4&#37; in the diagnostic liver biopsy to 49&#37; in the intraoperative liver biopsy &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0105">Relationship of temporal changes in fibrosis with other parameters</span><p id="par0270" class="elsevierStylePara elsevierViewall">Temporal changes in fibrosis showed a significant positive correlation with temporal changes in BDP &#40;<span class="elsevierStyleItalic">r</span>&#8239;&#61;&#8239;0&#46;456&#44; p&#8239;&#61;&#8239;0&#46;001&#41;&#46; On the other hand&#44; they showed no correlation with the interval between the two liver biopsies &#40;<span class="elsevierStyleItalic">r</span>&#8239;&#61;&#8239;0&#46;148&#44; p&#8239;&#61;&#8239;0&#46;309&#41; or with the age of the infants at KP &#40;<span class="elsevierStyleItalic">r</span>&#8239;&#61;&#8239;0&#46;156&#44; p&#8239;&#61;&#8239;0&#46;283&#41;&#46; Moreover&#44; temporal changes in fibrosis showed no correlation with other laboratory parameters under study and with histopathological temporal changes &#40;p&#8239;&#62;&#8239;0&#46;05 for all&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0275" class="elsevierStylePara elsevierViewall">Even with successful biliary drainage&#44; most of the operated BA cases exhibit progression of fibrosis at variable rates with the development of portal hypertension &#91;<a class="elsevierStyleCrossRef" href="#bib0005">1</a>&#93;&#46; Since fibrosis is a significant determinant of morbidity even in BA cases operated in a timely manner &#91;<a class="elsevierStyleCrossRef" href="#bib0065">13</a>&#93;&#44; studying the factors that are related to fibrosis progression in this disease is of utmost importance&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">In the present study&#44; different grades of liver fibrosis were observed in all cases in the early stages of BA &#40;59&#8239;&#177;&#8239;12 days&#41;&#46; Fibrosis progressed after a short duration &#40;5&#8211;31 days&#44; median&#58; 14 days&#41; to significantly higher grades &#40;p&#8239;&#61;&#8239;0&#46;001&#41;&#46; Kim et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0070">14</a>&#93; reported that in BA&#44; liver fibrosis may progress rapidly and even cirrhosis may ensue at as early as 2 months of age&#46; Rastogi et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0075">15</a>&#93; and Russo et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0065">13</a>&#93; also reported high grades of fibrosis in the early stage of BA&#46; In the present study&#44; 14&#46;3&#37; of the cases progressed to cirrhosis at the time of KP&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">The present study and other previous studies showed that a high grade of fibrosis is a feature of BA&#46; Interestingly&#44; fibrosis progression was not correlated with the age of the infant at KP or with the interval between the two biopsies &#40;p&#8239;&#61;&#8239;0&#46;283 and p&#8239;&#61;&#8239;0&#46;309&#44; respectively&#41;&#46; Thus&#44; fibrosis progression in BA is not related to time alone&#46; Unique factors could drive this rapid progression that could even lead to a more advanced grade of fibrosis in a younger infant when compared with that in an older infant&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">BDP was observed in all cases of BA &#40;in the diagnostic liver biopsy as well as in the subsequent intraoperative liver biopsy&#41;&#46; With progression of BA from early to late stages&#44; there was a significant increase in the grades of BDP &#40;p&#8239;&#61;&#8239;0&#46;001&#41; and increased inflammatory activity in the form of cellular infiltrate&#44; hepatocellular swelling&#44; and rosette formation&#46; All of these histopathological changes are expected to encourage fibrogenesis and its progression &#91;<a class="elsevierStyleCrossRefs" href="#bib0080">16&#8211;19</a>&#93;&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">Understanding the dynamic histopathological changes in BA that are suggested to have a relationship with fibrogenesis &#91;<a class="elsevierStyleCrossRef" href="#bib0010">2</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib0100">20&#8211;22</a>&#93; might have a therapeutic implication in interventions to prevent or to ameliorate this unique rapid process&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">It is well known that BDP has a prognostic value in BA &#91;<a class="elsevierStyleCrossRef" href="#bib0035">7</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0040">8</a>&#93;&#46; The novel factor in the present study is the description of the changes &#40;decrease&#44; no change&#44; increase&#41; in the histopathological criteria of BA within a short time interval&#46; Moreover&#44; testing the correlation of these temporal changes with fibrosis progression is also a novel factor compared to testing at a cross sectional level&#44; as reported in previous studies&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">In the present study&#44; we observed a significant temporal increase in BDP&#44; cellular &#40;lymphocytes&#44; neutrophils&#44; and eosinophils&#41; infiltrate&#44; and fibrosis within a short time interval &#40;5&#8211;31 days&#41; in the univariate analysis&#46; Fibrosis and BDP increased by more than 60&#37;&#46; However&#44; in the multivariate regression analysis&#44; BDP was the only histopathological finding that showed a significant temporal increase &#40;p&#8239;&#61;&#8239;0&#46;021&#44; 95&#37; confidence interval&#58; 1&#46;249&#8211;16&#46;017&#41;&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Zhang et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0010">2</a>&#93; reported a temporal increase in BDP&#44; inflammation&#44; and fibrosis grade from the intraoperative liver biopsy to the postoperative liver biopsy&#46; They also reported that the severity of fibrosis was positively correlated with the severity of BDP&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">In the present study&#44; the finding that BDP was the only independent factor showing a temporal histopathological increase in BA cases within a short time interval puts this histopathological feature in the scope of interest in this devastating disease&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">Previous studies &#91;<a class="elsevierStyleCrossRef" href="#bib0010">2</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0115">23</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0120">24</a>&#93; have proposed that portal fibrosis in cholestatic liver diseases appears to be induced by reactive cholangiocytes forming the proliferating bile ductules of BDP&#46; It has been shown that ductal epithelium can express proteins that attract and activate hepatic stellate cells&#44; leading to collagen deposition&#46; Many studies proved the relationship between BDP and the activation of these hepatic stellate cells &#91;<a class="elsevierStyleCrossRef" href="#bib0125">25</a>&#93;&#46; Clouston et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0125">25</a>&#93;&#44; Fabris et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0130">26</a>&#93; and Zhang et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0135">27</a>&#93; reported that the severity of fibrosis was significantly correlated with the grade of BDP&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">The proliferating bile ductular epithelial cells are implicated in the secretion of many profibrogenic factors &#91;<a class="elsevierStyleCrossRef" href="#bib0140">28</a>&#93;&#46; Sedlaczek et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0145">29</a>&#93; found that these cells are the main source of connective tissue growth factor&#46; Moreover&#44; they were found to exhibit increased expression and secretion of neuroendocrine hormones and increased expression of the receptors of these hormones &#91;<a class="elsevierStyleCrossRef" href="#bib0150">30</a>&#93;&#46; Targeting the profibrogenic factors secreted by these cells and the neuroendocrine profile could constitute a mechanism for modulating BDP and the progression of liver disease&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">Bile duct epithelia that form BDP express P2Y receptors &#91;<a class="elsevierStyleCrossRef" href="#bib0155">31</a>&#93;&#46; P2Y receptors are present in many human tissues and are responsible for various biological functions &#91;<a class="elsevierStyleCrossRef" href="#bib0160">32</a>&#93;&#46; It has been shown that extracellular nucleotides can stimulate BDP via P2Y receptors &#91;<a class="elsevierStyleCrossRef" href="#bib0165">33</a>&#93;&#46; Hence&#44; it is hypothesized that blockade of the P2Y receptors can suppress BDP&#46; Moreover&#44; signaling via extracellular nucleotides could be another target for the suppression of BDP&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">The postsurgical outcome of BA is not associated with just a single factor despite many studies concentrating on the age at KP&#46; Moreover&#44; there is still a lack of understanding about the relationship between histopathology and clinical outcome &#91;<a class="elsevierStyleCrossRef" href="#bib0170">34</a>&#93;&#46; Muthukanagarajan et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0035">7</a>&#93; and Gunadi et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0040">8</a>&#93; reported poor outcomes in children with advanced hepatic fibrosis&#44; whereas Santos et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0175">35</a>&#93; reported a lack of such correlation&#46; Despite these observations&#44; it is believed that suppression of ongoing rapid fibrosis to avoid consequent portal hypertension is still a therapeutic target&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">A possible limitation of this study is the comparison between a diagnostic Tru-cut biopsy &#40;first liver biopsy&#41; and an intraoperative wedge biopsy &#40;second liver biopsy&#41;&#46; Higher grades of fibrosis might be reported in the wedge biopsy due to the inclusion of the subcapsular area with possibly more amount of fibrosis&#46; Rawlins et al&#46; &#91;<a class="elsevierStyleCrossRef" href="#bib0060">12</a>&#93; found a concordance between a Tru-cut needle biopsy and a wedge biopsy in terms of reporting of fibrosis when the wedge biopsy was sampled 2&#8239;mm deeper to the capsule&#46; In the present study&#44; this issue was avoided by sampling the wedge biopsy 5&#8239;mm deeper to the capsule&#46;</p><p id="par0345" class="elsevierStylePara elsevierViewall">A strength of this study lies in the assessment of changes in fibrosis and correlation of these changes with other histopathological changes within a short time interval&#44; which is different from some of the previous studies &#91;<a class="elsevierStyleCrossRef" href="#bib0010">2</a>&#93; that assessed this correlation after a long time interval&#46; Moreover&#44; studying the relationship of fibrosis progression with histopathological changes could be more informative than merely assessing its relationship with static pathological findings&#46; It was apparent that cases with a greater increase in BDP would exhibit a more significant increase in fibrosis&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">In conclusion&#44; the present study provided an important insight regarding the orchestrators of fibrosis progression in BA&#46; It demonstrated that fibrosis is rapidly progressive and the driving force for this unique rapid progression is not arbitrary or related to time alone&#46; A younger infant could exhibit a higher grade of fibrosis&#46; Moreover&#44; an infant could exhibit progression from a lower grade of fibrosis to a higher grade within a shorter time interval compared to the progression of fibrosis in other infants within a longer time interval&#46; Increase in BDP was the only independent factor that showed a correlation with fibrosis progression&#46; Assessment of manipulating BDP as an adjuvant therapy for this devastating disease to prevent or to ameliorate the rapid progression of fibrosis could be considered&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Financial support</span><p id="par0355" class="elsevierStylePara elsevierViewall">This research received funding from <span class="elsevierStyleGrantSponsor" id="gs0005">the National Liver Institute&#44; Menoufia University&#44; Egypt</span>&#44; without its involvement in the research design&#44; enrolment of participants&#44; data collection and analysis&#44; or the report write-up&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Author&#39;s contributions</span><p id="par0360" class="elsevierStylePara elsevierViewall">El-Araby HA&#44; Saber MA&#44; Radwan NM&#44; Taie DM&#44; Adawy NM&#44; Sira AM involved in the study concept and design&#59; El-Araby HA&#44; Saber MA&#44; Radwan NM&#44; Sira AM involved in recruitment of patients&#44; clinical management and follow up&#44; and contributed to data acquisition&#59; Taie DM performed the histopathological examination&#59; Sira AM performed statistical analysis and designed the figures&#59; El-Araby HA&#44; Saber MA&#44; Radwan NM&#44; Taie DM&#44; Adawy NM&#44; Sira AM performed data interpretation&#59; El-Araby HA&#44; Saber MA&#44; Radwan NM&#44; Adawy NM&#44; Sira AM wrote the manuscript&#59; all the authors reviewed the manuscript and finally approved it for submission&#46; Ahmad M Sira is the corresponding author&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0365" class="elsevierStylePara elsevierViewall">The authors declare that they have no competing interests&#46;</p></span></span>"
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              "titulo" => "Introduction and Objectives"
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              "titulo" => "Patients and Methods"
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              "titulo" => "Results"
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              "titulo" => "Biochemical&#44; hematological&#44; and ultrasonographic evaluation"
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              "titulo" => "Liver biopsy"
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          "titulo" => "Results"
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              "titulo" => "Demographic&#44; clinical&#44; laboratory&#44; and radiologic data of the group"
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              "identificador" => "sec0050"
              "titulo" => "Histopathological findings in the diagnostic and the intraoperative liver biopsies"
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              "identificador" => "sec0055"
              "titulo" => "Temporal histopathological changes"
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              "titulo" => "Relationship of temporal changes in fibrosis with other parameters"
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          "titulo" => "Discussion"
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    "fechaRecibido" => "2020-08-03"
    "fechaAceptado" => "2020-09-19"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1340227"
          "palabras" => array:5 [
            0 => "Bile ductular proliferation"
            1 => "Biliary atresia"
            2 => "Fibrogenesis"
            3 => "Fibrosis"
            4 => "Temporal changes"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviation"
          "identificador" => "xpalclavsec1340226"
          "palabras" => array:4 [
            0 => "BD"
            1 => "BA"
            2 => "EMH"
            3 => "KP"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Introduction and Objectives</span><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Biliary atresia &#40;BA&#41; is characterized by rapid progression of fibrosis with no definite causes&#46; Histopathological findings have been extensively described&#44; but very few studies have assessed temporal changes in BA&#46; Understanding these short-term changes and their relationship with fibrosis progression could have an impact on ameliorating rapid fibrogenesis&#46; We aimed to study the relationship between temporal histopathological changes and fibrosis progression in BA within a short time interval&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Patients and Methods</span><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Forty-nine infants with BA who underwent Kasai portoenterostomy&#44; a diagnostic liver biopsy&#44; and an intraoperative liver biopsy were recruited&#46; Histopathological characteristics of the two biopsies were examined&#46; Temporal histopathological changes were assessed by comparing the two types of biopsies&#46; Correlation of temporal changes in fibrosis with age&#44; interval between biopsies&#44; laboratory profiles&#44; and temporal histopathological changes were studied&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Results</span><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">In the univariate analysis&#44; bile ductular proliferation &#40;BDP&#41;&#44; portal infiltrate&#44; giant cells&#44; hepatocellular swelling&#44; and fibrosis showed significant temporal changes within a short interval &#40;5&#8211;31 days&#41;&#46; BDP and fibrosis showed the most frequent increase in their grades &#40;32&#47;49 and 31&#47;49 cases&#44; respectively&#41;&#46; In the multivariate analysis&#44; BDP was the only independent pathological feature showing a significant temporal increase &#40;p&#8239;&#61;&#8239;0&#46;021&#44; 95&#37; confidence interval&#58; 1&#46;249&#8211;16&#46;017&#41;&#46; Fibrosis progression was correlated with temporal changes in BDP &#40;r&#8239;&#61;&#8239;0&#46;456&#44; p&#8239;&#61;&#8239;0&#46;001&#41;&#44; but not with age &#40;p&#8239;&#61;&#8239;0&#46;283&#41; or the interval between the biopsies &#40;p&#8239;&#61;&#8239;0&#46;309&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusions</span><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Fibrosis in BA progresses rapidly and is significantly correlated with BDP&#46; Assessment of targeting BDP as an adjuvant medical therapy is recommended&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0015"
            "titulo" => "Introduction and Objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Patients and Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Conclusions"
          ]
        ]
      ]
    ]
    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="lis0120"><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#8226;</span><p id="par0120" class="elsevierStylePara elsevierViewall">Liver fibrosis in biliary atresia &#40;BA&#41; progresses within a short time&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">A younger infant with BA could exhibit a higher grade of fibrosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#8226;</span><p id="par0130" class="elsevierStylePara elsevierViewall">Pathological findings in BA are well studied&#44; but there are very few studies regarding temporal changes&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">&#8226;</span><p id="par0135" class="elsevierStylePara elsevierViewall">Bile ductular proliferation was the only independent feature showing temporal increase&#46;</p></li></ul></p></span>"
    ]
    "multimedia" => array:6 [
      0 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 3148
            "Ancho" => 2925
            "Tamanyo" => 2754237
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
            "detalle" => "Fig&#46; "
            "rol" => "short"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Temporal histopathological changes in biliary atresia&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A&#58;</span> Mild bile ductular proliferation &#40;BDP&#41; &#40;arrows&#41; and <span class="elsevierStyleBold">C&#58;</span> giant cells &#40;arrows&#41; around the CV in the first liver biopsy of a 61-day-old infant&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">B&#58;</span> Moderate BDP and <span class="elsevierStyleBold">D&#58;</span> giant cells with diffuse distribution &#40;arrows&#41; in the second liver biopsy of the same infant at an age of 79 days&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">E&#58;</span> Grade-2 fibrosis &#40;arrow&#41; in the first liver biopsy of another 71-day-old infant that progressed to &#40;<span class="elsevierStyleBold">F&#41;</span> grade-4 fibrosis &#40;stars&#41; in his second liver biopsy at an age of 82 days Slides&#58; A to D &#40;Hematoxylin and eosin&#44; &#215;200&#41;&#44; E and F &#40;Masson&#8217;s trichrome stain&#44; &#215;40&#41;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">CV&#58; central vein&#44; PT&#58; portal tract&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1921
            "Ancho" => 3008
            "Tamanyo" => 350848
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        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0010"
            "detalle" => "Fig&#46; "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Temporal changes in all histopathological parameters from the diagnostic biopsy to the intraoperative biopsy&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">BDP showed the highest temporal change with an increase by one grade in 28 cases and an increase by two grades in four cases&#46; This was followed by an increase in fibrosis by one grade in 26 cases and by two grades in five cases&#46; All other histopathological parameters showed different temporal changes&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">BDP&#58; bile ductular proliferation&#44; EMH&#58; extramedullary hematopoiesis</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0015"
            "detalle" => "Table "
            "rol" => "short"
          ]
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">ALP&#44; alkaline phosphatase&#59; ALT&#44; alanine transaminase&#59; AST&#44; aspartate transaminase&#59; BA&#44; biliary atresia&#59; cm&#44; centimeter&#59; dl&#44; deciliter&#59; g&#44; gram&#59; GB&#44; gall bladder&#59; GGT&#44; &#947;-glutamyltransferase&#59; HA&#44; hepatic artery&#59; HSF&#44; hepatic subcapsular flow&#59; INR&#44; international normalized ratio&#59; Kg&#44; kilogram&#59; mg&#44; milligram&#59; &#181;l&#44; microliter&#59; PT&#44; prothrombin time&#59; PTT&#44; partial thromboplastin time&#59; PV&#44; portal vein&#59; TC&#44; triangular cord sign&#59; TLC&#58; total leucocyte count&#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="\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">Variable&nbsp;\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">N&#8239;&#61;&#8239;49&nbsp;\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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age at diagnostic liver biopsy &#40;days&#41;&nbsp;\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">59&#8239;&#177;&#8239;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age at intraoperative liver biopsy &#40;days&#41;&nbsp;\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">74&#8239;&#177;&#8239;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interval between the two biopsies &#40;days&#41;&nbsp;\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">14 &#40;5&#8722;31&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&#44; n &#40;&#37;&#41;&nbsp;\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">26 &#40;53&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive family history&nbsp;\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 &#40;2&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clay stool&nbsp;\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 &#40;100&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatomegaly&nbsp;\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">46 &#40;94&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Splenomegaly&nbsp;\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">15 &#40;31&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ascites&nbsp;\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 &#40;0&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total bilirubin &#40;mg&#47;dl&#41;&nbsp;\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">10&#46;5&#8239;&#177;&#8239;3&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Direct bilirubin &#40;mg&#47;dl&#41;&nbsp;\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">7&#46;3&#8239;&#177;&#8239;2&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total proteins &#40;g&#47;dl&#41;&nbsp;\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">5&#46;4&#8239;&#177;&#8239;0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albumin &#40;g&#47;dl&#41;&nbsp;\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&#46;8&#8239;&#177;&#8239;0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALT &#40;U&#47;L&#41;&nbsp;\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">139 &#40;35&#8722;698&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AST &#40;U&#47;L&#41;&nbsp;\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">202 &#40;72&#8722;614&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALP &#40;U&#47;L&#41;&nbsp;\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">609 &#40;208&#8722;2749&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GGT &#40;U&#47;L&#41;&nbsp;\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">765 &#40;399&#8722;3&#44;128&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">INR&nbsp;\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&#46;1&#8239;&#177;&#8239;0&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hemoglobin &#40;g&#47;dl&#41;&nbsp;\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">9&#46;6&#8239;&#177;&#8239;1&#46;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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLC &#40;&#215;10<span class="elsevierStyleSup">3</span>&#47;&#181;l&#41;&nbsp;\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">13 &#40;8&#8722;35&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Platelets &#40;&#215;10<span class="elsevierStyleSup">3</span>&#47;&#181;l&#41;&nbsp;\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">464&#8239;&#177;&#8239;145&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GB length &#40;mm&#41;&nbsp;\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">15&#46;9 &#40;0&#8722;28&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GB contractilityNormalAbnormalNon visualizedAtreticNon contractile&nbsp;\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">11 &#40;22&#46;4&#37;&#41;38 &#40;77&#46;6&#37;&#41;5 5 28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TC sign&nbsp;\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">14 &#40;28&#46;6&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HA diameter &#40;mm&#41;&nbsp;\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">2&#8239;&#177;&#8239;0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PV diameter &#40;mm&#41;&nbsp;\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">5&#46;1&#8239;&#177;&#8239;0&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSF&nbsp;\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">25 &#40;51&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Demographic&#44; clinical&#44; laboratory&#44; and radiologic parameters at the timing of diagnostic liver biopsy&#46;</p>"
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      3 => array:8 [
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
            "identificador" => "at0020"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Bolding of p value indicates statistical significance&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Abbreviations&#58;</span> BA&#58; biliary atresia&#59; BDP&#58; bile ductular proliferation&#59; EMH&#58; Extramedullary hematopoiesis&#59; G&#58; grade&#46;</p>"
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            0 => array:2 [
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                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">Variable&nbsp;\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">Diagnostic liver biopsy &#40;n&#8239;&#61;&#8239;49&#41;&nbsp;\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">Intraoperative liver biopsy &#40;n&#8239;&#61;&#8239;49&#41;&nbsp;\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">P value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">BDP</span>&nbsp;\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">&nbsp;\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">&nbsp;\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"><span class="elsevierStyleBold">0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0005" class="elsevierStylePara elsevierViewall">Mild</p></li></ul>&nbsp;\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">16 &#40;32&#46;7&#41;&nbsp;\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">2 &#40;4&#46;1&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0010" class="elsevierStylePara elsevierViewall">Moderate</p></li></ul>&nbsp;\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">31 &#40;63&#46;3&#41;&nbsp;\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">23 &#40;46&#46;9&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0015" class="elsevierStylePara elsevierViewall">Marked</p></li></ul>&nbsp;\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">2 &#40;4&#41;&nbsp;\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">24 &#40;49&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Bile plugs</span>&nbsp;\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">&nbsp;\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">&nbsp;\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&#46;715&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0020" class="elsevierStylePara elsevierViewall">Absent</p></li></ul>&nbsp;\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">5 &#40;10&#46;2&#41;&nbsp;\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 &#40;6&#46;1&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0025" class="elsevierStylePara elsevierViewall">Present</p></li></ul>&nbsp;\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 &#40;89&#46;8&#41;&nbsp;\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">46 &#40;93&#46;9&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Lymphocytic infiltration</span>&nbsp;\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">&nbsp;\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">&nbsp;\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"><span class="elsevierStyleBold">0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall">None</p></li></ul>&nbsp;\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 &#40;2&#41;&nbsp;\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 &#40;0&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">Mild</p></li></ul>&nbsp;\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 &#40;67&#46;3&#41;&nbsp;\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">17 &#40;34&#46;7&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall">Moderate&#47; marked</p></li></ul>&nbsp;\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">15 &#40;30&#46;6&#41;&nbsp;\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">32 &#40;65&#46;3&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Neutrophilic infiltration</span>&nbsp;\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">&nbsp;\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">&nbsp;\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"><span class="elsevierStyleBold">0&#46;004</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">Absent or mild</p></li></ul>&nbsp;\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">26 &#40;53&#46;1&#41;&nbsp;\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">12 &#40;24&#46;5&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Moderate&#47; marked</p></li></ul>&nbsp;\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">23 &#40;46&#46;9&#41;&nbsp;\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 &#40;75&#46;5&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Eosinophilic infiltration</span>&nbsp;\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">&nbsp;\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">&nbsp;\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"><span class="elsevierStyleBold">0&#46;004</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Absent or mild</p></li></ul>&nbsp;\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">26 &#40;53&#46;1&#41;&nbsp;\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">12 &#40;24&#46;5&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall">Moderate&#47; marked</p></li></ul>&nbsp;\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">23 &#40;46&#46;9&#41;&nbsp;\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 &#40;75&#46;5&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Giant cells</span>&nbsp;\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">&nbsp;\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">&nbsp;\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"><span class="elsevierStyleBold">0&#46;018</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">None</p></li></ul>&nbsp;\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">17 &#40;34&#46;7&#41;&nbsp;\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">11 &#40;22&#46;4&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">Around central vein</p></li></ul>&nbsp;\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">23 &#40;46&#46;9&#41;&nbsp;\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">16 &#40;32&#46;7&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">Diffuse</p></li></ul>&nbsp;\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">9 &#40;18&#46;5&#41;&nbsp;\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">22 &#40;44&#46;9&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Hepatocellular swelling</span>&nbsp;\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">&nbsp;\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">&nbsp;\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"><span class="elsevierStyleBold">0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">-</span><p id="par0080" class="elsevierStylePara elsevierViewall">None</p></li></ul>&nbsp;\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 &#40;8&#46;2&#41;&nbsp;\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 &#40;6&#46;1&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0085" class="elsevierStylePara elsevierViewall">Focal</p></li></ul>&nbsp;\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">22 &#40;44&#46;9&#41;&nbsp;\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">6 &#40;12&#46;2&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">Diffuse</p></li></ul>&nbsp;\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">23 &#40;46&#46;9&#41;&nbsp;\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">40 &#40;81&#46;6&#41;&nbsp;\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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Rosette formation</span>&nbsp;\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 &#40;89&#46;8&#41;&nbsp;\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">46 &#40;93&#46;9&#41;&nbsp;\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&#46;715&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">EMH</span>&nbsp;\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">17 &#40;34&#46;7&#41;&nbsp;\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">8 &#40;16&#46;3&#41;&nbsp;\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"><span class="elsevierStyleBold">0&#46;037</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Fibrosis grading</span>&nbsp;\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">&nbsp;\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">&nbsp;\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"><span class="elsevierStyleBold">0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  """
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Bolding of P value means statistical significance&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Laboratory parameters are those at the timing of the diagnostic liver biopsy&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Abbreviations&#58; ALT</span>&#58; alanine aminotransferase&#59; <span class="elsevierStyleBold">ALP</span>&#58; alkaline phosphatase&#59; <span class="elsevierStyleBold">AST</span>&#58; aspartate aminotransferase&#59; <span class="elsevierStyleBold">BDP</span>&#58; bile ductular proliferation&#59; <span class="elsevierStyleBold">GGT</span>&#58; gamma glutamyl transferase&#59; <span class="elsevierStyleBold">INR</span>&#58; international normalized ratio&#59; <span class="elsevierStyleBold">TLC</span>&#58; total leucocyte count&#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="\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">Parameter&nbsp;\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  " colspan="2" align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Temporal changes of fibrosis</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">R&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Interval between the two biopsies &#40;days&#41;&nbsp;\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&#46;148&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;309&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age at Kasai operation &#40;days&#41;&nbsp;\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
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                  \t\t\t\t">0&#46;156&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;283&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total bilirubin&nbsp;\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
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                  \t\t\t\t">&#8722;0&#46;064&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;662&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Direct bilirubin&nbsp;\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&#46;049&nbsp;\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
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                  \t\t\t\t">0&#46;740&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total protein&nbsp;\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&#46;020&nbsp;\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&#46;889&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albumin&nbsp;\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&#46;006&nbsp;\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&#46;965&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AST&nbsp;\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&#46;078&nbsp;\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&#46;593&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALT&nbsp;\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&#46;110&nbsp;\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&#46;450&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALP&nbsp;\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&#46;130&nbsp;\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&#46;372&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GGT&nbsp;\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&#46;032&nbsp;\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&#46;828&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">INR&nbsp;\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&#46;173&nbsp;\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&#46;240&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hemoglobin&nbsp;\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">&#8722;0&#46;096&nbsp;\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&#46;642&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLC&nbsp;\t\t\t\t\t\t\n
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ISSN: 16652681
Original language: English
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