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        "titulo" => "Hepatite autoimune em 828 crian&#231;as e adolescentes brasileiros&#58; achados cl&#237;nicos e laboratoriais&#44; perfil histol&#243;gico&#44; tratamentos e resultados"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Kaplan&#8211;Meier survival of patients with autoimmune hepatitis&#46; Survival was significantly higher in AIH type 2 patients&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Autoimmune hepatitis &#40;AIH&#41; is a chronic liver disease that is typically progressive and histologically characterized by periportal inflammation&#44; bridging necrosis&#44; liver cell rosetting&#44; and marked plasma cell infiltration&#46; Although the etiology is unknown&#44; its pathogenesis is based at least partly on aberrant autoreactivity&#46; The classical phenotype has been characterized by certain serological markers&#44; especially antinuclear antibodies&#44; smooth muscle antibodies &#40;SMAs&#41;&#44; and antibodies to liver kidney microsome type 1 &#40;anti-LKM1s&#41;&#44; regardless of the association with anti-liver cytosol type 1 antibodies&#44; hypergammaglobulinemia&#44; increased serum immunoglobulin &#40;Ig&#41;G levels&#44; interface hepatitis on histological examination&#44; and corticosteroid therapy responsiveness&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Studies on the epidemiology and natural history of pediatric AIH have been published&#44;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">4&#44;5</span></a> which is important given that much of the knowledge on AIH is derived from studies on adults&#46; The limited studies on children demonstrated the peculiarities of this disease in pediatric patients&#46; The authors aimed to evaluate the clinical presentation&#44; laboratory findings&#44; histological profile&#44; treatments&#44; and outcomes of children and adolescents with AIH in South America in a large study with a long-term follow-up&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">This retrospective multicenter study was conducted to assess the clinical outcomes of 828 children and adolescents with a well-documented long-term AIH course according to the modified AIH International Study Group criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> Data were collected from reports of single centers&#46; A questionnaire assessed anonymous data on demographic characteristics&#44; clinical presentation&#44; biochemical and histological findings&#44; and treatments&#46; The patients were followed-up from 1983 to 2015 in 17 pediatric gastroenterology&#47;hepatology centers throughout Brazil&#46; This study was approved by the ethical committees of the institutions &#40;CAAE No&#46; 53562116&#46;5&#46;1001&#46;0068&#41;&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">All children and adolescents were submitted to a clinical and laboratory protocol&#44; including assessment of biochemical parameters&#44; such as alanine aminotransferase&#44; aspartate aminotransferase&#44; &#947;-glutamyl transpeptidase &#40;GGTP&#41;&#44; alkaline phosphatase &#40;ALP&#41;&#44; albumin&#44; gamma globulin&#44; international normalized ratio &#40;INR&#41;&#44; total and direct-reacting bilirubin &#40;DB&#41;&#44; serum glucose&#44; triiodothyronine&#44; thyroxine&#44; and thyroid stimulating hormone measured using radioimmunoassay&#46; Serum Ig and complement levels were measured using nephelometry&#44; which were expressed in g&#47;L and varied by center&#46; The results were recorded as normal&#44; increased&#44; or decreased&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">All patients were screened at presentation for anti-nuclear&#44; anti-SMA&#44; anti-LKM1&#44; and anti-mitochondrial antibodies&#46; Serum samples were titered up to 1&#47;320&#46; Titers of &#62;1&#58;40 and 1&#47;20 were considered positive for anti-SMA and anti-LKM1&#44; respectively&#46; Additionally&#44; the patients had negative findings for hepatitis A&#44; B&#44; and C virus&#44; human immunodeficiency virus&#44; cytomegalovirus&#44; Epstein&#8211;Barr virus&#46; They had no history of drug or alcohol use or exposure to hepatotoxic drugs&#46; Patients with alpha-1 antitrypsin deficiency and Wilson&#39;s disease were excluded&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Cholangiography was performed either via magnetic resonance cholangiopancreatography &#40;MRCP&#41; or via endoscopy in patients who did not respond to immunosuppressive drugs or had increased GGTP levels during disease monitoring&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Liver biopsy was performed in 664 &#40;80&#46;2&#37;&#41; patients before the immunosuppressive treatment via percutaneous needle biopsy using a Tru-Cut needle or surgery&#46; A total of 253 children underwent more than one biopsy during follow-up to document relapses or as a criterion for therapy cessation after two years in cases of clinical and biochemical remissions&#46; Formalin-fixed paraffin-embedded sections were inspected via hematoxylin-eosin&#44; periodic acid-Schiff after diastase digestion&#44; reticulin silver impregnation&#44; and Masson staining in all cases&#46; Histological features were recorded in accordance with staging using a semi-quantitative four-point scoring system &#40;<span class="elsevierStyleItalic">i&#46;e</span>&#46;&#44; absent&#44; minimal&#44; moderate&#44; and severe&#41;&#46; The parameters included architectural changes&#59; portal and periportal infiltrates&#59; liver cell damage and necrosis&#44; such as focal &#40;spotty&#41; lytic necrosis and periportal or periseptal interface hepatitis &#40;piecemeal necrosis&#41;&#59; confluent necrosis&#59; bridging necrosis&#59; and submassive necrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">6</span></a> Other features&#44; such as bile duct injury and ductular reaction&#44; were also evaluated&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Immunosuppressive therapy included a combination of prednisone &#40;1&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; maximum of 60<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; and azathioprine &#40;1&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#46; Prednisone monotherapy was performed whenever severe thrombocytopenia was present&#46; Prednisone dose was reduced at each visit until a maintenance dose of 2&#46;5&#8211;5<span class="elsevierStyleHsp" style=""></span>mg was achieved&#44; while maintaining stable clinical and laboratory parameters&#46; Complete response and relapse were both defined in accordance with the modified AIH International Study Group criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">SPSS v&#46; 24 &#40;SPSS &#8211; Chicago&#44; IL&#44; United States&#41; was used for the statistical analysis&#46; All data are summarized in <a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1&#8211;3</a>&#46; Normal data distribution was tested using the Kolmogorov-Smirnov test&#46; In order to verify the existence of associations between the groups and all categorical variables&#44; logistic regression was used with the logit link function&#46; Odds ratios were estimated&#44; and the respective 95&#37; confidence intervals were presented&#46; The Mann&#8211;Whitney test was used to compare the two AIH types in relation to the quantitative variables&#46; The significance level was set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; Categorical variables were expressed as counts and percentages&#44; and continuous variables were expressed as median &#40;minimal&#59; maximal&#41; values&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">Of the 828 patients&#44; 742 &#40;89&#46;6&#37;&#41; had AIH-1 and 86 &#40;10&#46;4&#37;&#41; had AIH-2&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Demographic and clinical data &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall">The female sex was predominant among the patients &#40;AIH-1&#58; 74&#46;9&#37;&#44; AIH-2&#58; 84&#46;9&#37;&#41;&#46; The median age at symptom onset were 111&#46;5 &#40;6&#59; 210&#41; and 53&#46;5 &#40;8&#59; 165&#41; months for the patients with AIH-1 and AIH-2&#44; respectively &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Children with LKM1-positive findings were significantly younger &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Patients had a median AIH score according to the 1999 and 2008 International AIH Scoring Systems of 17 &#40;7&#59; 28&#41; and 7 &#40;2&#59; 10&#41; for AIH-1 and 15&#46;5 &#40;3&#59; 123&#41; and 6 &#40;3&#59; 9&#41; for AIH-2&#44; respectively&#44; revealing a significant difference between the groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Acute clinical onset was observed in 410 &#40;56&#46;1&#37;&#41; and 50 &#40;58&#46;8&#37;&#41; patients with AIH-1 and AIH-2&#44; respectively&#46; Insidious clinical symptoms were observed in 321 &#40;43&#46;9&#37;&#41; and 35 &#40;41&#46;2&#37;&#41; children with AIH-1 and AIH-2&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The risk for these two clinical presentations was not significantly different &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;630&#41;&#46; Hepatic failure &#40;INR<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46;5&#41; was observed in 226 &#40;30&#46;7&#37;&#41; and 31 &#40;40&#46;3&#37;&#41; patients with AIH-1 and AIH-2&#44; respectively&#46; The risk of hepatic failure was 1&#46;6-fold higher in the AIH-2 group&#44; which was only marginally significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;060&#41;&#46; A total of 27 &#40;3&#46;6&#37;&#41; children with AIH-1 and nine &#40;10&#46;6&#37;&#41; children with AIH-2 had fulminant hepatic failure at initial presentation&#44; and the difference was significant between the groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#46; Additionally&#44; the risk was 3&#46;1-fold higher in AIH-2&#46; A family history of autoimmune disease&#44; including diabetes&#44; thyroid disease&#44; Beh&#231;et&#39;s disease&#44; psoriasis&#44; and vitiligo&#44; was observed in 161 &#40;21&#46;9&#37;&#41; patients with AIH-1 and in 18 &#40;21&#46;2&#37;&#41; patients with AIH-2 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;883&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Extrahepatic autoimmune manifestations were present in 183 &#40;24&#46;8&#37;&#41; and 12 &#40;14&#46;1&#37;&#41; patients with AIH-1 and AIH-2&#44; respectively&#44; with a significant difference between the groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;031&#41;&#46; The risk of extrahepatic autoimmune manifestations was two-fold higher in patients with AIH-1&#46; The associated autoimmune diseases included systemic lupus erythematosus&#44; Weber panniculitis&#44; type 1 diabetes&#44; thyroid disease&#44; celiac disease&#44; inflammatory bowel disease&#44; glomerulopathies&#44; and arthritis&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Laboratory and radiologic findings &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Regarding laboratory tests&#44; no significant differences in serum DB&#44; aminotransferase&#44; GGTP&#44; and ALP levels were observed between the groups&#46; However&#44; the albumin&#44; gamma globulin&#44; and&#47;or IgG levels were significantly higher in the patients with AIH-1 than in those with AIH-2 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;030 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41;&#59; the levels were lower in the patients with AIH-2 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Significantly lower C3 levels were noted in the children with AIH-2 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;032&#41;&#44; and no significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;317&#41; in C4 levels were noted&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">MRCP&#47;cholangiography was performed in 309 children and adolescents&#44; and the results were compatible with autoimmune sclerosing cholangitis &#40;ASC&#41; in 60 patients &#40;58 patients with AIH-1 and two patients with AIH-2&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Histological findings &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Based on the results of the liver biopsies performed before the immunosuppressive treatment&#44; hepatocyte rosettes and plasma cells were more prevalent in patients with AIH-1 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;007 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; 2&#46;1-fold and 2&#46;6-fold increased risk&#44; respectively&#41;&#46; Bile duct injury occurred in 61 patients&#59; fibrosis was present in 513 patients and cirrhosis in 148 patients&#44; without a significant difference between the groups&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Treatments and outcomes &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;</span><p id="par0090" class="elsevierStylePara elsevierViewall">In 94&#46;1&#37; of the 828 patients&#44; the initial treatment for AIH was a combination of prednisone and azathioprine&#46; A combination treatment including ursodeoxycholic acid was administered to 30&#46;3&#37;&#44; mycophenolate mofetil to 3&#46;7&#37;&#44; and cyclosporine to 6&#46;3&#37; of the patients&#46; Follow-up duration was up to 23&#46;8 years &#40;mean&#44; 7&#46;08 years&#59; median&#44; 6&#46;4 years&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">After immunosuppression initiation&#44; biochemical remission was achieved in 76&#46;2&#37; of the overall patients &#40;AIH-1&#58; 74&#46;7&#37;&#59; AIH-2&#58; 89&#46;4&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46; The median time to biochemical remission were seven &#40;0&#59; 250&#41; and four &#40;1&#59; 149&#41; months for AIH-1 and AIH-2&#44; respectively &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Treatment was discontinued in 57 patients after complete remission&#46; A total of 13 patients had relapsed post-suspension&#44; and their treatment returned with immunosuppressive drugs&#46; All patients with AIH-2 who discontinued the treatment did so on their own or&#44; if for medical reasons&#44; occurred prior to the recommendation of non-discontinuation of treatment&#44; which currently exists&#44; according to the international consensus&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">7</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">During treatment&#44; the median number of biochemical relapses was three &#40;0&#59; 13&#41; and the &#40;0&#59; 6&#41; in the groups of patients with AIH-1 and AIH-2&#44; respectively&#44; with no difference between them &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;433&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Adverse effects during treatment&#44; including alopecia&#44; Cushing&#39;s syndrome&#44; obesity&#44; diabetes types 1 and 2&#44; pulmonary embolism&#44; stretch marks&#44; infections &#40;urinary and upper respiratory tract infections&#41;&#44; pneumonia&#44; tonsillitis relapses&#44; and meningitis&#44; were observed in 38&#46;8&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>322&#41; of the patients&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">During the study period&#44; 37 adolescents &#40;4&#46;5&#37;&#41; became pregnant&#44; and none had complications during gestation or post-partum&#46; All babies were born alive without complications&#46; Azathioprine was discontinued during the pregnancy&#44; and the prednisone dose was not altered&#46; After delivery&#44; only those who breastfed did not receive azathioprine&#46; There was no relapse in any of the 37 patients&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Morbidity and mortality &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;</span><p id="par0120" class="elsevierStylePara elsevierViewall">A total of 38 patients underwent liver transplantation &#40;LTx&#41;&#58; 35 &#40;4&#46;7&#37;&#41; patients had AIH-1 and three &#40;3&#46;5&#37;&#41; patients had AIH-2&#46; During the study period&#44; 57 patients died&#58; 55 &#40;7&#46;5&#37;&#41; patients with AIH-1 and two &#40;2&#46;4&#37;&#41; patients with AIH-2 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;047&#41;&#46; Deaths were related to AIH and its comorbidities&#46; The actuarial survival rate was 92&#46;5&#37; and 97&#46;6&#37; in patients with AIH-1 and AIH-2&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#59; at 96 months of follow-up&#44; these probabilities were &#8764;94&#37; and 98&#37;&#44; respectively&#46; At 150 months&#44; the probabilities were 86&#37; and 98&#37;&#44; respectively&#46; At the end of follow-up &#40;AIH-1&#58; 278 months&#59; AIH-2&#58; 286 months&#41;&#44; the survival probabilities were &#8764;70&#37; and 90&#37;&#44; respectively&#46; The survival curve for patients with AIH-1 was almost equal to the overall survival curve&#44; as only two deaths were observed among the 84 patients with AIH-2&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0125" class="elsevierStylePara elsevierViewall">This study was the largest clinical series of children and adolescents with AIH published to date&#46; In this Brazilian group&#44; AIH-1 was more frequent&#46; Moreover&#44; patients with AIH-1 had a higher risk of undergoing LTx and death&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The earlier disease onset for AIH-2 in this study is similar to that found in the literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">8&#8211;10</span></a> The female&#47;male sex distribution for AIH also corresponds to that in the literature&#44; <span class="elsevierStyleItalic">i&#46;e</span>&#46;&#44; female sex predominance&#44; especially among patients with AIH-1&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The clinical presentations of AIH-1 and AIH-2 were analogous&#44; except for the fulminant form&#46; Fulminant hepatitis is a very rare presentation of the disease&#44; and when it occurs&#44; it is more associated with AIH-2&#46; In this study&#44; the fulminant presentation occurred more frequently in the presence of anti-LKM1 positivity&#44; which is consistent with Di Giorgio et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">11</span></a> and others in the literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">10&#8211;14</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">The extrahepatic manifestations associated with AIH are variable in both frequency and prevalence&#46; Thyroid disorders are most frequently described&#44; similar to the study by Bittencourt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">15</span></a> Gregorio et al&#46; reported extrahepatic manifestations&#44; including thyroiditis&#44; vitiligo&#44; type 1 diabetes&#44; and inflammatory bowel disease&#44; in 20&#37; of children with AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">13</span></a> The present findings are different from those of Gregorio et al&#46;&#44; which may correspond to the regional differences and genetic susceptibility&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">16</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The scores &#40;1999 and 2008&#41; for both AIH types were consistent with those of other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">1&#44;2&#44;17</span></a> The patients who did not undergo biopsy at diagnosis met the international criteria for AIH&#44; and no disagreements in the scores were observed in the present series&#46; Mileti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">17</span></a> examined the diagnostic effectiveness of the score in children&#46; Initially&#44; the pediatric population was not evaluated in accordance with the 1999 criteria&#46; Subsequently&#44; two studies presented controversial results regarding the use of both scores&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">18&#44;19</span></a> Mileti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">17</span></a> reported high sensitivity and specificity with the use of scores in the pediatric population&#59; however&#44; some limitations were also observed&#46; The therapeutic response remains a fundamental diagnostic criterion&#44; particularly in patients without autoimmunity markers&#44; even if they do not attain a score indicating a definitive AIH diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">20&#8211;22</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The albumin levels reinforced disease severity&#44; particularly in AIH-1&#44; with worsening liver function&#46; Elevated gamma globulin levels&#44; particularly in AIH-1&#44; are a significant sign in the differential diagnosis between the AIH types&#46; This test is an important marker in AIH-1 diagnosis and the result may be normal in AIH-2&#44; which reinforces the difference between the groups&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">No IgM level differences or significant increases were found in the present patients&#46; These data differ from those of Di Giorgio et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">11</span></a> who found elevated IgM levels without a real explanation&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">11</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Diagnosing sclerosing cholangitis remains a challenge&#46; Bile duct lesion detection does not definitively indicate ASC&#46; Histology or MRCP alterations compatible with sclerosing cholangitis are not always observed in affected patients&#46; Persistently elevated GGTP levels suggest biliary tract involvement&#44; and long-term follow-up or explant evaluation allows diagnosis&#46; Cholangiography was not performed in all patients&#46; Several factors contributed to the difficulty in performing this test&#44; <span class="elsevierStyleItalic">e&#46;g</span>&#46;&#44; need for anesthesia and costs&#46; Since the study had a retrospective design&#44; and there was no recommendation in the literature&#44; several services performed this test only when the GGTP level did not decrease or when there was no therapeutic response to immunosuppressants&#46; Thus&#44; there may be a bias in this study regarding ASC prevalence&#44; which is part of retrospective studies&#59; however&#44; the results remain important given the large number of patients included&#46; The ESPGHAN Hepatology Committee recommends screening for overlap syndrome in patients with AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">7</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">In this study&#44; some patients did not undergo liver biopsy due to contraindications&#44; such as coagulopathy &#40;high INR&#41;&#44; ascites&#44; or severe thrombocytopenia&#46; However&#44; all these patients scored for AIH according to the international criteria&#44; even without a scoring histology&#46; Moreover&#44; liver biopsy findings were not evaluated by a single pathologist&#44; as this was a retrospective study that collected data from several centers&#44; but followed the consensus criteria of Brazilian pathologists&#46; Liver tissue examination prior to treatment is an important diagnosis component&#44; and the guidelines recommend this exam to be performed at presentation&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">7</span></a> Despite these endorsements&#44; the need for pre-treatment liver tissue examination has been challenged in children&#44; as they usually exhibit significant liver dysfunction and coagulopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">22</span></a> Bj&#246;rnsson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">23</span></a> mentioned the importance of histology in typical AIH diagnosis and concluded that the majority of patients with AIH features are likely to have compatible liver histologies&#46; In adults&#44; the presence of cirrhosis at initial clinical presentation worsens the disease course&#44; leading to a ten-year survival rate of &#8764;60&#37; compared with 80&#37; in patients without cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">23</span></a> However&#44; Radhakrishnan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">24</span></a> observed that the presence of cirrhosis did not affect long-term survival in children&#46; Cirrhosis was a predominant finding in the initial presentation of both AIH types&#59; however&#44; this observation differs from the data obtained by Gregorio et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">16</span></a> and Saadah et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">25</span></a> who reported a cirrhosis prevalence of 69&#37; and 38&#37; among patients with AIH-1 and AIH-2&#44; respectively&#46; In the current study&#44; differences in the liver histopathological results were noted between the AIH groups&#44; with a higher prevalence of rosettes and plasma cells in AIH-1&#44; a finding that has not been reported in the literature&#46; The presence of cirrhosis at the first disease presentation indicates AIH severity&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Therapeutic response is one of the best parameters to determine whether the clinical profile of hepatitis is attributable to an immunological cause&#46; Disease remission is always the main immunosuppressive treatment goal&#46; Generally&#44; the therapeutic response is above 70&#37; in patients with AIH-1 and 85&#37; in those with AIH-2&#44;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">16&#44;26</span></a> findings similar with those of the present study&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">This study revealed a reduced time to remission in patients with AIH-2&#46; This finding is inconsistent with those by Gregorio et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">16</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">An important concern is non-adherence to treatment&#44; particularly among adolescents&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">13</span></a> In this study&#44; treatment was discontinued in both groups by the physician&#59; treatment was also discontinued in some patients due to non-adherence&#46; Ferreira et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">14</span></a> studied children who attained clinical-laboratory remission after a 24-month immunosuppression course and observed a 54&#46;5&#37; incidence of disease relapse after treatment&#44; even in the presence of histological remission&#46; They did not identify the predictive factors associated with relapse&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">LTx is necessary for AIH treatment in &#8764;10&#37; of cases<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">26&#44;27</span></a>&#59; it was performed in 10&#37; of pediatric patients with AIH and 23&#37; of patients with sclerosing cholangitis&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">26</span></a> In this study&#44; LTx was performed in 4&#46;7&#37; and 3&#46;5&#37; of the patients with AIH-1 and AIH-2&#44; respectively&#44; indicating that the disease was well controlled with immunosuppressants&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The limiting factors of this study include the fact that it is retrospective and&#44; consequently&#44; there is the possibility of biases and incomplete data for some patients&#59; however&#44; importantly&#44; it included patients from several secondary and tertiary reference centers&#44; being the largest series of children and adolescents with AIH published to date&#46; The data presented do not represent the actual prevalence of pediatric patients with autoimmune hepatitis in Brazil&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">In summary&#44; in this large clinical series of Brazilian children and adolescents with AIH&#44; AIH-1 was more frequent&#59; AIH-2 affected younger children&#44; had higher remission rates&#44; and had an earlier onset than AIH-1&#59; and patients with AIH-1 had a higher risk of LTx and death&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflicts of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This large study with a long-term follow-up aimed to evaluate the clinical presentation&#44; laboratory findings&#44; histological profile&#44; treatments&#44; and outcomes of children and adolescents with autoimmune hepatitis&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The medical records of 828 children and adolescents with autoimmune hepatitis were reviewed&#46; A questionnaire was used to collect anonymous data on clinical presentation&#44; biochemical and histological findings&#44; and treatments&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of all patients&#44; 89&#46;6&#37; had autoimmune hepatitis-1 and 10&#46;4&#37; had autoimmune hepatitis-2&#46; The female sex was predominant in both groups&#46; The median age at symptom onset was 111&#46;5 &#40;6&#59; 210&#41; and 53&#46;5 &#40;8&#59; 165&#41; months in the patients with autoimmune hepatitis 1 and autoimmune hepatitis-2&#44; respectively&#46; Acute clinical onset was observed in 56&#46;1&#37; and 58&#46;8&#37; and insidious symptoms in 43&#46;9&#37; and 41&#46;2&#37; of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2&#44; respectively&#46; The risk of hepatic failure was 1&#46;6-fold higher for autoimmune hepatitis-2&#46; Fulminant hepatic failure occurred in 3&#46;6&#37; and 10&#46;6&#37; of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2&#44; respectively&#59; the risk was 3&#46;1-fold higher for autoimmune hepatitis-2&#46; The gamma globulin and immunoglobulin G levels were significantly higher in autoimmune hepatitis-1&#44; while the immunoglobulin A and C3 levels were lower in autoimmune hepatitis-2&#46; Cirrhosis was observed in 22&#46;4&#37; of the patients&#59; biochemical remission was achieved in 76&#46;2&#37;&#46; The actuarial survival rate was 93&#46;0&#37;&#46; A total of 4&#46;6&#37; underwent liver transplantation&#44; and 6&#46;9&#37; died &#40;autoimmune hepatitis-1&#58; 7&#46;5&#37;&#59; autoimmune hepatitis-2&#58; 2&#46;4&#37;&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In this large clinical series of Brazilian children and adolescents&#44; autoimmune hepatitis-1 was more frequent&#44; and patients with autoimmune hepatitis-2 exhibited higher disease remission rates with earlier response to treatment&#46; Patients with autoimmune hepatitis-1 had a higher risk of death&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objective"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      "pt" => array:3 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Este estudo com acompanhamento de longo prazo visou avaliar o quadro cl&#237;nico&#44; os achados laboratoriais&#44; o perfil histol&#243;gico&#44; os tratamentos e os resultados de crian&#231;as e adolescentes com hepatite autoimune&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Foram analisados os prontu&#225;rios m&#233;dicos de 828 crian&#231;as e adolescentes com HAI&#46; Foi usado um question&#225;rio para coletar os dados an&#244;nimos sobre o quadro cl&#237;nico&#44; os achados bioqu&#237;micos e histol&#243;gicos e os tratamentos&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">De todos os pacientes&#44; 89&#44;6&#37; tinham hepatite autoimune-1 e 10&#44;4&#37; hepatite autoimune-2&#46; O sexo feminino foi predominante nos dois grupos&#46; A idade m&#233;dia no in&#237;cio dos sintomas foi 111&#44;5 &#40;6&#59; 210&#41; e 53&#44;5 &#40;8&#59; 165&#41; meses nos pacientes com hepatite autoimune-1 e hepatite autoimune-2&#44; respectivamente&#46; Foi observado in&#237;cio cl&#237;nico agudo em 56&#44;1&#37; e 58&#44;8&#37; e sintomas insidiosos em 43&#44;9&#37; e 41&#44;2&#37; dos pacientes com hepatite autoimune -1 e hepatite autoimune-2&#44; respectivamente&#46; A probabilidade de insufici&#234;ncia hep&#225;tica foi 1&#44;6 vezes maior para hepatite autoimune-2&#59; 3&#44;6&#37; e 10&#44;6&#37; dos pacientes com hepatite autoimune-1 e hepatite autoimune-2&#44; respectivamente&#44; apresentaram insufici&#234;ncia hep&#225;tica fulminante&#59; o risco foi 3&#44;1 vezes maior para hepatite autoimune-2&#46; Os n&#237;veis de gamaglobulina e imunoglobulina G foram significativamente maiores nos pacientes com hepatite autoimune-1&#44; ao passo que os n&#237;veis de imunoglobulina A e C3 foram menores em pacientes com hepatite autoimune-2&#59; 22&#44;4&#37; dos pacientes apresentaram cirrose e a remiss&#227;o bioqu&#237;mica foi atingida em 76&#44;2&#37;&#46; A taxa de sobrevida atuarial foi de 93&#44;0&#37;&#46; Um total de 4&#44;6&#37; pacientes foram submetidos a transplante de f&#237;gado e 6&#44;9&#37; morreram &#40;hepatite autoimune-1&#58; 7&#44;5&#37;&#59; hepatite autoimune-2&#58; 2&#44;4&#37;&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#245;es</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nesta grande s&#233;rie cl&#237;nica de crian&#231;as e adolescentes brasileiros&#44; a hepatite autoimune-1 foi mais frequente e os pacientes com hepatite autoimune-2 mostraram maiores taxas de remiss&#227;o da doen&#231;a com respostas mais r&#225;pidas aos tratamentos&#46; Os pacientes com hepatite autoimune-1 apresentaram maior risco de &#243;bito&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
            "titulo" => "Objetivo"
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          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclus&#245;es"
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        ]
      ]
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as&#58; Porta G&#44; Carvalho E&#44; Santos JL&#44; Gama J&#44; Borges CV&#44; Seixas RB&#44; et al&#46; Autoimmune hepatitis in 828 Brazilian children and adolescents&#58; clinical and laboratory findings&#44; histological profile&#44; treatments&#44; and outcomes&#46; J Pediatr &#40;Rio J&#41;&#46; 2019&#59;95&#58;419&#8211;27&#46;</p>"
      ]
    ]
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      0 => array:7 [
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        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Kaplan&#8211;Meier survival of patients with autoimmune hepatitis&#46; Survival was significantly higher in AIH type 2 patients&#46;</p>"
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        "etiqueta" => "Table 1"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">AIH&#44; autoimmune hepatitis&#59; OR&#44; odds ratio&#59; CI&#44; confidence interval&#59; SD&#44; standard deviation&#59; min&#44; minimum&#59; max&#44; maximum&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">122&#46;5 &#40;6&#59; 219&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;001<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">50 &#40;58&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">321 &#40;43&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">35 &#40;41&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AIH-1&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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AIH-2&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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ORAIH-1&#47;AIH-2&#40;95&#37; CI&#41;&#59;Logistic regression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">AST &#40;&#215; UNL&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">18 &#40;0&#59; 169&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;0&#46;7&#59; 153&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;315<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">ALT &#40;&#215; UNL&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;0&#59; 156&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">12&#46;5 &#40;0&#46;8&#59; 88&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">GGTP &#40;&#215; UNL&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3 &#40;0&#59; 37&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3 &#40;0&#59; 17&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">ALP &#40;&#215; UNL&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;3 &#40;0&#59; 47&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;365<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">TB &#40;mg&#47;dL&#41;</span></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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#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
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                  \t\t\t\t">3&#46;2 &#40;0&#59; 32&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#46;9 &#40;0&#46;3&#59; 66&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;334<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">DB &#40;mg&#47;dL&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;8 &#40;0&#46;1&#59; 37&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Albumin &#40;g&#47;dL&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#46;6 &#40;1&#46;3&#59; 5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Gammaglobulin &#40;g&#47;dL&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;min&#59; max&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;001<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">IgA &#8211; low&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">12 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;29&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;10 &#40;0&#46;04&#59; 0&#46;24&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;001<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">IgM &#8211; high&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yes&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">276 &#40;47&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Plasma cells</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yes&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">315 &#40;53&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;63 &#40;1&#46;54&#59; 4&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
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                    0 => array:2 [
                      "titulo" => "International Autoimmune Hepatitis Group Report&#58; review of criteria for diagnosis of autoimmune hepatitis"
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                          "etal" => true
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                            3 => "L&#46; Bianchi"
                            4 => "A&#46;K&#46; Burroughs"
                            5 => "E&#46;L&#46; Cancado"
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                      "doi" => "10.1016/s0168-8278(99)80297-9"
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                            4 => "G&#46;N&#46; Dalekos"
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                      "titulo" => "Diagnosis and management of autoimmune hepatitis"
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                            4 => "L&#46;S&#46; Book"
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