Autoimmune hepatitis: From mechanisms to therapy

array:23 ["pii" => "S0014256516300248" "issn" => "00142565" "doi" => "10.1016/j.rce.2016.04.003" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "1260" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "copyrightAnyo" => "2016" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Rev Clin Esp. 2016;216:372-83" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 96 "formatos" => array:2 [ "HTML" => 66 "PDF" => 30 ] ] "itemSiguiente" => array:19 [ "pii" => "S0014256516300315" "issn" => "00142565" "doi" => "10.1016/j.rce.2016.04.010" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "1267" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Rev Clin Esp. 2016;216:384-92" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 146 "formatos" => array:2 [ "HTML" => 104 "PDF" => 42 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "REVISIÓN" "titulo" => "Consideraciones clínicas sobre la posología de los anticoagulantes orales de acción directa" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "384" "paginaFinal" => "392" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Clinical considerations on the posology of direct oral anticoagulants" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Sáez-Peñataro, C. Avendaño-Solá, J.R. González-Juanatey" "autores" => array:3 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Sáez-Peñataro" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Avendaño-Solá" ] 2 => array:2 [ "nombre" => "J.R." "apellidos" => "González-Juanatey" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S225488741630042X" "doi" => "10.1016/j.rceng.2016.04.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S225488741630042X?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300315?idApp=WRCEE" "url" => "/00142565/0000021600000007/v1_201609280158/S0014256516300315/v1_201609280158/es/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0014256516300789" "issn" => "00142565" "doi" => "10.1016/j.rce.2016.05.005" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "1280" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "edi" "cita" => "Rev Clin Esp. 2016;216:370-1" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 47 "formatos" => array:2 [ "HTML" => 34 "PDF" => 13 ] ] "es" => array:10 [ "idiomaDefecto" => true "cabecera" => "Editorial" "titulo" => "Proteína C reactiva en líquido pleural. ¿Ayuda a predecir los derrames paraneumónicos complicados?" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "370" "paginaFinal" => "371" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "C-reactive protein in pleural fluid. Does it help predict complicated parapneumonic effusions?" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Ferreiro, L. Valdés" "autores" => array:2 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Ferreiro" ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Valdés" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300789?idApp=WRCEE" "url" => "/00142565/0000021600000007/v1_201609280158/S0014256516300789/v1_201609280158/es/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Autoimmune hepatitis: From mechanisms to therapy" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "372" "paginaFinal" => "383" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "R. Liberal, G. Mieli-Vergani, D. Vergani" "autores" => array:3 [ 0 => array:3 [ "nombre" => "R." "apellidos" => "Liberal" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 1 => array:3 [ "nombre" => "G." "apellidos" => "Mieli-Vergani" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:4 [ "nombre" => "D." "apellidos" => "Vergani" "email" => array:1 [ 0 => "diego.vergani@kcl.ac.uk" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine, London, UK" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Gastroenterology, Centro Hospitalar São João and Faculty of Medicine, University of Porto, Porto, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La hepatitis autoinmune: de los mecanismos al tratamiento" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1502 "Ancho" => 2481 "Tamanyo" => 170596 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of liver damage. Liver damage is initiated by the presentation of a self-antigenic peptide within a major histocompatibility molecule (MHC) by professional antigen presenting cells (APCs). The presence of appropriate costimulation alongside exposure to various cytokines drives the differentiation of uncommitted CD4 helper T-cells (Th0). IL-6 and IL-1β lead to differentiation into pathogenic Th17 cells that secrete the proinflammatory cytokine IL-17. Th17 cells promote hepatocyte secretion of IL-6, which in turn further enhances Th17 development. Exposure to IL-12 leads to the differentiation of Th1 cells secreting IFN-γ, which induces monocyte (MΦ) differentiation, activates cytotoxic CD8 T-cells and promotes NK cell killing. IFN-γ also increases MHC class I and induces class II expression by hepatocytes, further exacerbating inflammation. Exposure to IL-4 leads to Th2 differentiation. Th2 cells secrete IL-13, IL-4 and IL-10 that enable B cell maturation into plasma cells with the consequent production of autoantibodies. Autoantibodies are in turn involved in antibody-mediated cellular cytotoxicity and complement activation." ] ] ] "textoCompleto" => "IntroductionAutoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease characterised serologically by hypergammaglobulinaemia and the presence of non-organ and liver-specific autoantibodies, and histologically by a dense mononuclear cell infiltrate in the portal tract.<a class="elsevierStyleCrossRef" href="#bib0400">1</a> Two types of AIH are recognised: AIH type 1 (AIH-1), defined by the presence of anti-smooth muscle (SMA) and/or anti-nuclear (ANA) antibodies; and AIH type 2 (AIH-2), defined by positivity for anti-liver kidney microsomal type 1 (anti-LKM-1) and/or anti-liver cytosol type 1 (anti-LC-1) antibodies.<a class="elsevierStyleCrossRefs" href="#bib0405">2,3</a>AIH occurs globally, affecting children and adults of all ages and both sexes, although it is more commonly found in females.<a class="elsevierStyleCrossRef" href="#bib0415">4</a> There are no robust epidemiological data on AIH. Available studies show an incidence of 1.5–2.0 cases per 100,000 people per year in Northern Europe.<a class="elsevierStyleCrossRefs" href="#bib0420">5,6</a> Prevalence estimates range from 16.9 cases per 100,000 people in Northern Europe to 35.9 cases per 100,000 people in Alaskan natives.<a class="elsevierStyleCrossRefs" href="#bib0420">5,7</a> While AIH-1 affects both children and adults, AIH-2 is mainly a paediatric condition.<a class="elsevierStyleCrossRef" href="#bib0435">8</a> Female predominance is a feature of both types.<a class="elsevierStyleCrossRef" href="#bib0435">8</a>The mechanisms responsible for its development include genetic predisposition to autoimmunity through possession of specific human leucocyte antigen (HLA) alleles, immune reactions to liver cell antigens, possibly triggered by a mechanism of molecular mimicry, and impairment in immune regulation.<a class="elsevierStyleCrossRef" href="#bib0440">9</a>AIH has variable modes of presentation: it can present insidiously, with complications of portal hypertension, or with a clinical picture of acute hepatitis, or more rarely with acute liver failure (ALF).<a class="elsevierStyleCrossRefs" href="#bib0415">4,10</a> In addition, variant forms of the disease, presenting with concomitant features of primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) are increasingly recognised.<a class="elsevierStyleCrossRef" href="#bib0450">11</a> AIH should be considered during the diagnostic workup of any increase in liver enzyme levels.<a class="elsevierStyleCrossRef" href="#bib0455">12</a> A set of inclusion and exclusion criteria for the diagnosis of AIH have been established, and meanwhile revised, by the International Autoimmune Hepatitis Group (IAIHG).<a class="elsevierStyleCrossRefs" href="#bib0460">13,14</a> Immunosuppressive therapy with steroids, with or without azathioprine, remains the mainstay of treatment, and should be instituted as soon as the diagnosis is made.<a class="elsevierStyleCrossRef" href="#bib0400">1</a> Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil (MMF) or calcineurin inhibitors (CNI).<a class="elsevierStyleCrossRefs" href="#bib0400">1,4</a> Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. Patients with end-stage liver disease, and those with ALF at diagnosis, will require liver transplantation (LT).<a class="elsevierStyleCrossRef" href="#bib0470">15</a>This review aims to discuss the recent advances in the understanding of AIH pathogenesis, diagnosis, and treatment.GeneticsAIH is a “complex trait” disease that does not follow a Mendelian pattern of inheritance. The mode of inheritance of a complex trait disorder is unknown, though it involves one or more genes, operating alone or in concert, to increase or reduce the risk of the trait and interacting with environmental factors.Predisposition to AIH is linked to Major Histocompatibility Complex (MHC) class II genes, more specifically to the Human Leucocyte Antigen (HLA)-DR locus, located on the short arm of chromosome 6 – which are involved in the presentation of antigenic peptides to T-cells, and are therefore implicated in the initiation of an adaptive immune response.<a class="elsevierStyleCrossRefs" href="#bib0475">16,17</a> In Europe and North America, the alleles conferring susceptibility to AIH-1 are DRB1*0301 and DRB1*0401, which encode the HLA DR3 and DR4 antigens, respectively.<a class="elsevierStyleCrossRef" href="#bib0485">18</a> The first genome wide association study (GWAS) in AIH performed in Dutch AIH-1 patients and replicated in a cohort of German patients confirmed the HLA association, DRB1*0301 and DRB1*0401 being primary and secondary susceptibility genotypes, respectively.<a class="elsevierStyleCrossRef" href="#bib0490">19</a>Susceptibility to AIH-2 is conferred by the possession of HLA DR7 (DRB1*0701) and DR3 (DRB1*0301),<a class="elsevierStyleCrossRef" href="#bib0495">20</a> and those patients who are positive for DRB1*0701 have a more aggressive form of the disease with worse overall prognosis.<a class="elsevierStyleCrossRef" href="#bib0500">21</a>A number of genes outside the MHC have also been linked to AIH susceptibility. For example, a substitution from A (adenine) to G (guanine) in exon 1 of the CTLA-4 gene confers susceptibility to AIH-1 in Caucasians from North America.<a class="elsevierStyleCrossRef" href="#bib0505">22</a> Additionally, a polymorphism at position 308 in the tumour necrosis factor α (TNFA) gene promoter is particularly frequent in patients with AIH-1 from Europe and North America, and is associated with a poorer response to steroids.<a class="elsevierStyleCrossRef" href="#bib0510">23</a> A FAS gene promoter polymorphism at position 670 also enhances susceptibility to AIH and influences progression to a more aggressive form characterised by the early development of cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0515">24</a> Polymorphisms in the vitamin D receptor can also be predisposing factors to the development of autoimmune liver disease.<a class="elsevierStyleCrossRef" href="#bib0520">25</a> The first AIH GWAS reported that AIH-1 is associated with variants of CARD10 and SH2B3 genes.<a class="elsevierStyleCrossRef" href="#bib0490">19</a>A form of AIH resembling AIH-2 has been described in some 20% of patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), an autosomal recessive condition due to homozygous mutations in the AIRE1 gene and characterised by a variety of organ-specific autoimmune diseases. Additionally, AIRE1 mutations have been reported in three children with severe AIH-2 with extra-hepatic autoimmune manifestations, as well as in four children with AIH-1 with a family history of autoimmune disease.<a class="elsevierStyleCrossRef" href="#bib0525">26</a>Potential triggersIn patients with increased genetic susceptibility, a potential trigger for AIH development is an immune response to exogenous pathogens that cross-reacts with structurally similar liver autoantigens, a phenomenon known as molecular mimicry. The strongest support for this model is in the context of viral hepatitis, where autoimmunity is a common feature during chronic infection. Indeed, 50% of patients with chronic hepatitis B or C (HCV) eventually develop autoantibody seropositivity.<a class="elsevierStyleCrossRefs" href="#bib0530">27,28</a> In chronic HCV, some 10% of patients are anti-LKM-1 positive, the autoantibody titre correlating with disease severity and being associated with adverse reactions to interferon treatment.<a class="elsevierStyleCrossRef" href="#bib0540">29</a> The molecular target of anti-LKM-1 is cytochrome P4502D6 (CYP2D6) and within anti-LKM-1 positive chronic HCV patients, reactivity against the key autoantigenic epitope CYP2D6193–212 can be seen in 50% of cases. There is direct evidence of cross-reactivity between anti-LKM-1 and antibodies directed against homologous regions of HCV (NS5B HCV2985–2990) and cytomegalovirus (exon CMV130–135).<a class="elsevierStyleCrossRef" href="#bib0545">30</a> There is also sequence homology between CYP2D6254–271 and amino acids present in the E1 HCV and the IE1 75 of the Herpes Simplex Virus 1 (HSV-1). As anti-LKM-1 antibodies cross-react with homologous regions of CYP2D6, HCV, CMV and HSV, a “multi-hit” mechanism for the generation of autoantibody seropositivity and possibly for the development AIH-2 can be envisaged. In this model, on a background of genetic susceptibility, sequential exposure to common viral pathogens favours the development of cross-reactive T cells. It is therefore conceivable that as yet unidentified single or repeated viral infections could contribute to the initiation of the autoimmune attack in AIH.<a class="elsevierStyleCrossRef" href="#bib0440">9</a> One case-report describes a 10-year-old girl who acquired HCV infection following liver transplant for end-stage liver disease caused by α1-anti-trypsin deficiency. Two weeks after HCV infection IgM anti-LKM-1 antibodies appeared, followed by IgG anti-LKM-1 antibodies. This finding is suggestive of HCV as a trigger of a primary anti-LKM-1/anti-CYP2D6 autoimmune response.<a class="elsevierStyleCrossRef" href="#bib0550">31</a> Interestingly, 10 years later, the patient developed florid AIH type 2, which responded satisfactorily to immunosuppressive treatment; by this time there was no trace of the previous HCV infection (unpublished data). Moreover, in a recent report, up to 8.7% of patients with autoimmune disease, including cryoglobulinaemia, Hashimoto thyroiditis and inflammatory bowel disease (IBD),<a class="elsevierStyleCrossRef" href="#bib0555">32</a> had serum HCV antibody-positivity, linking HCV infection with a breakdown of immune tolerance.The antibiotics nitrofurantoin and minocycline,<a class="elsevierStyleCrossRef" href="#bib0560">33</a> as well as the statins and the anti-TNF agents adalimumab and infliximab have been reported as non-viral environmental triggers of AIH. However, because drug-induced liver injury with features of AIH does not usually require long-term immunosuppressive treatment, these triggers should be considered independently.<a class="elsevierStyleCrossRef" href="#bib0560">33</a>Though the evidence for molecular mimicry is convincing, a universal trigger has not yet been discovered. Moreover, other non-mutually exclusive mechanisms that may contribute to the initiation and perpetuation of AIH, such as epitope spreading or exposure to previously hidden autoantigens during hepatocellular injury, should also be explored.Effector immune mechanismsThe dense infiltrate of lymphocytes, plasma cells, and macrophages characteristic of the histological picture of AIH suggests that an autoaggressive cellular immune attack is the basis of this condition. Over the past four decades, intense investigations have begun to uncover the mechanisms by which this inflammatory infiltration mediates liver damage.The predominant population within the cellular infiltrate is composed of α/β T cells.<a class="elsevierStyleCrossRef" href="#bib0565">34</a> Amongst these cells, the majority are CD4pos T helper (Th) cells, with a sizable minority of cytotoxic CD8pos T-cells. Immunohistochemically, lymphocytes of a non-T-cell lineage are seen relatively rarely, and include natural killer (NK)-cells, macrophages, B-cells and plasma cells.<a class="elsevierStyleCrossRef" href="#bib0565">34</a>Regardless of the nature of the initial trigger, the immune response in AIH is believed to stem from the recognition by naïve CD4pos lymphocytes of a self-antigenic peptide contained within an HLA class II molecule on an antigen presenting cell (APC). In the presence of the appropriate co-stimulatory signals – provided by the interaction of CD28 expressed by the naïve CD4pos T-cell and CD80/CD86 expressed by the APC – the naïve cell differentiates into an effector cell subtype depending on the cytokines present in the microenvironment and the nature of the antigen. The liver is home to several specialised APC populations, and antigen presentation can occur in situ without the need of trafficking to the regional lymphoid tissue.<a class="elsevierStyleCrossRef" href="#bib0570">35</a>The effector T-cell subsets are largely defined by the cytokines they produce; Th1-cells produce IL-2 as well as the main mediator of the tissue damage in AIH, IFN-γ. IFN-γ stimulates CD8pos T-cells, enhances the expression of HLA class I molecules by hepatocytes, while inducing the aberrant expression of HLA class II molecules and activating monocytes/macrophages, which in turn release IL-1 and tumour necrosis factor alpha (TNF-α). On the other hand, Th2-cells produce IL-4, IL-10 and IL-13, cytokines that induce the maturation of B-cells into plasma cells, with consequent production of autoantibodies. Autoantibodies themselves can contribute to liver damage by triggering antibody-mediated cellular cytotoxicity and complement activation. Th17-cells produce IL-17, IL-22, and TNF-α,<a class="elsevierStyleCrossRef" href="#bib0440">9</a> while inducing hepatocytes to secrete IL-6, which further enhances Th17 activation. Although Th17-cells have been shown to be elevated in the circulation and liver of AIH patients, their precise contribution to the pathogenesis of AIH is unknown and currently under investigation. Mechanisms leading to and/or perpetuating the autoimmune liver attack in AIH are depicted in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Regulatory immune mechanismsThe development of autoimmune diseases is favoured by the breakdown of self-tolerance mechanisms that, in health, prevent the majority of autoreactive T cell clones from entering the periphery. As circulating autoreactive T cells are, however, present in health, there are both intrinsic and extrinsic peripheral tolerance mechanisms to limit autoimmune tissue damage. Key to this is the dominant form of immune suppression exerted by professional regulatory T cells (Tregs).<a class="elsevierStyleCrossRef" href="#bib0575">36</a>Several studies have reported that regulatory T-cells are numerically defective in patients with AIH. A lower circulating frequency of CD4posCD25pos,<a class="elsevierStyleCrossRefs" href="#bib0580">37,38</a> CD4posCD25high<a class="elsevierStyleCrossRef" href="#bib0590">39</a> or CD4posCD25highCD127neg<a class="elsevierStyleCrossRef" href="#bib0595">40</a> Tregs has been reported in AIH patients compared to healthy subjects, and this defect is associated with lower FOXP3 expression.<a class="elsevierStyleCrossRefs" href="#bib0590">39,41</a> Moreover, during immunosuppressive therapy, the circulating Treg frequency has been shown to increase to some extent, although not reaching the levels seen in health.<a class="elsevierStyleCrossRefs" href="#bib0580">37,39</a>When co-cultured with CD4posCD25neg cells, magnetically isolated CD4posCD25pos Tregs from AIH patients have impaired ability to generate an anti-inflammatory cytokine milieu rich in TGF-β, suggesting that they are ineffective promoters of linked-suppression.<a class="elsevierStyleCrossRef" href="#bib0600">41</a> Magnetically isolated CD4posCD25pos Tregs from AIH patients have impaired ability to suppress the proliferation of CD8pos38 and of CD4posCD25neg<a class="elsevierStyleCrossRefs" href="#bib0590">39,42</a> cell populations compared to normal controls. CD4posCD25pos Tregs from AIH patients are also ineffective suppressors of IFN-γ production by CD8 T cells.<a class="elsevierStyleCrossRef" href="#bib0585">38</a> Additionally, Tregs from AIH patients, but not healthy subjects, effectively enhance the activation of pro-inflammatory monocytes, by elevating the level of spontaneous migration and by increasing the production of TNF-α and the expression of TLR-4.<a class="elsevierStyleCrossRef" href="#bib0610">43</a> Magnetically isolated CD4posCD25posCD127neg Tregs from AIH patients are also less able to suppress CD4posCD25neg cell proliferation in AIH compared to health,<a class="elsevierStyleCrossRef" href="#bib0605">42</a> although this defect has not been observed in flow cytometrically isolated CD4posCD25highCD127neg cells.<a class="elsevierStyleCrossRef" href="#bib0615">44</a> Tregs from AIH patients express lower levels of galectin-9 compared to health, and this defect is mirrored by reduced expression of the galectin-9 ligand, T-cell immunoglobulin and mucin domain-3 (TIM-3), by CD4posCD25neg cells, suggesting that AIH may also be associated with effector cell resistance to Treg control.<a class="elsevierStyleCrossRef" href="#bib0605">42</a> We have recently observed that in AIH there is a lower frequency of CD39pos Tregs, these cells failing to hydrolyse adequately pro-inflammatory nucleotides and to suppress the production of IL-17 by effector CD4 T-cells. CD39pos Tregs from AIH patients are also unstable upon pro-inflammatory challenge,<a class="elsevierStyleCrossRef" href="#bib0620">45</a> suggesting that defective immuno-regulation in AIH might result not only from reduced Treg number and function but also from increased conversion of Tregs into effector cells.Clinical presentationAIH can present with diverse clinical manifestations.<a class="elsevierStyleCrossRef" href="#bib0625">46</a> There are basically three patterns of disease presentation: an acute onset, characterised by non-specific symptoms such as malaise, nausea/vomiting, anorexia and abdominal pain, followed by jaundice, dark urine and pale stools; an insidious onset, with an illness characterised by progressive fatigue, relapsing jaundice, headache, anorexia, amenorrhoea and weight loss; and finally a presentation with complications of portal hypertension.<a class="elsevierStyleCrossRef" href="#bib0480">17</a> The mode of presentation of AIH is therefore variable, and the disease should be suspected and excluded in all patients complaining of symptoms and signs of prolonged or severe liver disease. Some patients, however, are completely asymptomatic and are diagnosed after incidental discovery of abnormal liver function tests.Histological evidence of cirrhosis is described in at least 30% of patients, regardless of the mode of presentation, suggesting that subclinical disease has been present for some time. Indeed, advanced fibrosis or cirrhosis can often be found in patients presenting acutely.<a class="elsevierStyleCrossRef" href="#bib0445">10</a>AIH can develop occasionally during pregnancy.<a class="elsevierStyleCrossRef" href="#bib0630">47</a> Post-partum development of AIH and exacerbation of existing disease in patients whose condition improved during pregnancy has also been described.<a class="elsevierStyleCrossRef" href="#bib0635">48</a> Approximately 40% of AIH patients have a family history of autoimmune disease and at least 20% have concomitant autoimmune diseases or will develop them during follow-up.<a class="elsevierStyleCrossRef" href="#bib0640">49</a>The complications associated with AIH mirror those found in other progressive liver diseases. Thus, chronic hepatitis can progress to cirrhosis and to hepatocellular carcinoma (HCC) despite the use of immunosuppressive therapy. HCC is relatively rare in AIH.<a class="elsevierStyleCrossRef" href="#bib0445">10</a> Yeoman et al.<a class="elsevierStyleCrossRef" href="#bib0645">50</a> reported 15 cases of HCC, all with underlying cirrhosis, among 243 patients with AIH who were followed up for 16 years. Wong et al. reported 6 cases of HCC, also all with underlying cirrhosis, among 322 patients followed up for 10 years.<a class="elsevierStyleCrossRef" href="#bib0650">51</a> Surveillance for HCC is therefore warranted.<a class="elsevierStyleCrossRef" href="#bib0415">4</a>DiagnosisThe diagnosis of AIH is based on the presence of elevated serum transaminase and IgG levels, autoantibody seropositivity and histological evidence of interface hepatitis. This tenet has been factored into the IAIHG diagnostic criteria for AIH,<a class="elsevierStyleCrossRefs" href="#bib0460">13,14</a> which were originally developed for use in the research setting. This scoring system incorporates a number of positive and negative scores (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), enabling the researcher to grade clinical, laboratory and histological features of AIH. The score has also proved useful in the clinical context when assessing patients with few or atypical features of the disease. The distinction between a definite and probable diagnosis of AIH predominantly relates to the extent of the increase in serum gamma-globulin/IgG levels or autoantibody titre, as well as exposure to alcohol, hepatotoxic medication or infection. Laboratory and histological features associated with cholestasis carry a negative score. In the rare instances where conventional autoantibodies are not detected, the presence of anti-asialoglycoprotein receptor (anti-ASGPR), anti-soluble liver antigen/liver pancreas (anti-SLA/LP) or atypical perinuclear anti-neutrophil cytoplasmic antibodies (atypical pANCA, currently better referred to as pANNA) weigh towards a probable diagnosis of AIH. The scoring system also incorporates response to corticosteroids, with a definite diagnosis before steroid treatment requiring a score higher than 15, and a definite diagnosis after treatment institution requiring a score greater than 17.<a class="elsevierStyleCrossRef" href="#bib0465">14</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>It is important to note that because healthy children are very rarely autoantibody positive, in the paediatric setting, lower autoantibody titres contribute to the diagnoses of AIH. These titres are 1:20 for ANA and SMA and 1:10 for anti-LKM-1.<a class="elsevierStyleCrossRefs" href="#bib0405">2,12</a>A simplified scoring system (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), for use in clinical practice, has recently been proposed by the IAIHG. This system is based on only four criteria: positivity for autoantibodies, elevated IgG levels, histological evidence of interface hepatitis and the exclusion of viral hepatitis.<a class="elsevierStyleCrossRef" href="#bib0655">52</a> Neither scoring system is immediately applicable to the diagnosis of the juvenile form of AIH.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>AutoantibodiesAutoantibody seropositivity is a key criterion for the diagnosis and classification of AIH. The IAIHG includes positivity for ANA, SMA, anti-LKM-1, anti-LC-1, anti-SLA/LP and ANCAs autoantibodies in their original and revised diagnostic scoring systems.<a class="elsevierStyleCrossRefs" href="#bib0460">13,14</a>Anti-nuclear antibodiesThe target antigens of ANA in AIH are heterogeneous and incompletely defined. Though ANA have been shown to react with single- and double-stranded deoxyribonucleic acid (DNA), small nuclear ribonucleoproteins (sn-RNPs), centromeres, histones, chromatin and cyclin A, all these reactivities can be negative despite positivity of ANA by immunofluorescence (IFL). A better definition of the ANA target antigens will be followed by the development of new techniques using recombinant nuclear antigens and immunoassays.<a class="elsevierStyleCrossRef" href="#bib0410">3</a> In terms of IFL, ANA gives a readily detectable nuclear staining of kidney, stomach and liver sections. In AIH, a homogenous pattern of staining is commonly observed, particularly in the liver, with coarsely or finely speckled patterns visualised less frequently.<a class="elsevierStyleCrossRef" href="#bib0405">2</a> A clearer definition of the nuclear pattern should be sought using human epithelial type 2 (HEp2) cells, which are characterised by prominent nuclei. These, however, should not be used for screening purposes due to a high positivity rate in healthy subjects. A clinically relevant titre of ANA in AIH is considered 1/40 in adults and 1/20 in children, in whom titres correlate with disease activity. ANA can also be identified in up to 52% of patients with PBC. However, in contrast to AIH, in which no disease-specific ANA has been reported, the PBC-specific ANA showing multiple nuclear dot or rim-like membranous patterns are highly diagnostic for this condition. They are recognised by IFL when HEp-2 or HeLa cells are used as substrate. Of note, ANA are present in other autoimmune disorders, such as systemic lupus erythematosus, Sjögren syndrome and systemic sclerosis, as well as non-autoimmune conditions, like viral hepatitis, drug-induced hepatitis, and alcoholic and non-alcoholic fatty liver disease.<a class="elsevierStyleCrossRef" href="#bib0660">53</a>Anti-smooth muscle antibodiesThe first targets of AIH-specific SMA to be recognised – following preincubation of serum with thrombosthenin (platelet actomyosin) or purified thrombosthenin-A (the actin fraction of thrombosthenin) – were constituents of actin. Later, SMA were also shown to be directed against other components of the cytoskeleton such as tubulin, vimentin, desmin, and skeletin.<a class="elsevierStyleCrossRef" href="#bib0665">54</a> SMA IFL patterns can be visualised on kidney, stomach and liver sections, where they stain the artery walls. In the stomach substrate they also bind the muscularis mucosa and the lamina propria. In the kidney, the SMA typical of AIH stains the smooth muscle of the vessels, glomeruli and tubules (VGT pattern). The VG and VGT IFL patterns are much more specific for AIH than the isolated V pattern.<a class="elsevierStyleCrossRef" href="#bib0405">2</a> The AIH-1-specific target of SMA responsible for the VGT pattern remains elusive. However, when vinblastine-arrested cultured fibroblasts were used as a substrate, AIH-1-specific SMA VGT-positive sera predominantly stained the microfilaments. In contrast, non-AIH-1 SMA V-positive sera reacted with non-actin-containing intermediate filaments. Several studies point to actin in its filamentous form as the target of the SMA giving the VGT pattern. However, while this pattern is highly specific for AIH-1, some 20% of SMA-positive AIH patients do not have it. Moreover, when molecular assays using purified F-actin are employed, some AIH VGT positive cases are negative, while anti-F-actin positivity is reported in diseases distinct from AIH-1.<a class="elsevierStyleCrossRefs" href="#bib0405">2,54</a> SMA titres by IFL are usually equal or above 1/80 in AIH, although very young patients may have titres as low as 1/20. SMA giving the V pattern have been reported in advanced liver disease of other aetiologies, infectious diseases and rheumatic disorders; hence, like ANA, these antibodies are not specific for AIH.Anti-liver-kidney-microsomal type 1 antibodiesThe molecular target of anti-LKM-1, the hallmark of AIH-2, is CYP2D6. This autoantibody stains the hepatocellular cytoplasm and the P3 portion of the renal tubules. Some confusion can occur between the IFL patterns of anti-LKM-1 and AMA because both autoantibodies stain the liver as well as the kidney. However, AMA stain the liver more faintly than anti-LKM-1, and mark the renal tubules more diffusely, while accentuating the mitochondrial-reach distal tubules. Importantly, AMA stain gastric parietal cells while anti-LKM-1 do not.<a class="elsevierStyleCrossRefs" href="#bib0405">2,54</a> Since the molecular targets of anti-LKM-1 – CYP2D6 – and of AMA – enzymes of the 2-oxo-acid dehydrogenase complexes – are known, immune-assays based on the use of recombinant or purified antigens have been developed. Commercially available enzyme-linked immunosorbent assays (ELISAs) accurately detect anti-LKM-1, at least in the context of AIH-2, and detect AMA reasonably accurately. These assays can therefore be utilised when there is doubt about IFL patterns.<a class="elsevierStyleCrossRef" href="#bib0405">2</a> A clinically relevant anti-LKM-1 titre is considered equal or above 1/40 in adults and 1/10 in patients under 18 years of age; the titre of this autoantibody is associated with disease activity.<a class="elsevierStyleCrossRef" href="#bib0405">2</a> Interestingly, as mentioned above, anti-LKM-1 are also detected in some 5–10% of patients with chronic hepatitis C virus infection.Anti-liver cytosol type 1 antibodiesAnti-LC-1 react with the folate-metabolising enzyme formiminotransferase cyclodeaminase (FTCD), which is found at high levels within the liver. This autoantibody stains the liver cell cytoplasm with relative sparing of the centrilobular area. Importantly, anti-LC-1 frequently occurs together with anti-LKM-1, which obscure the anti-LC-1 staining. Thus, in the presence of anti-LKM-1, anti-LC-1 can be detected by the use of liver cytosol in double-dimension immunodiffusion or counterimmunoelectrophoresis, with the use of a positive reference serum, or by ELISA detecting reactivity to its target FTCD.<a class="elsevierStyleCrossRef" href="#bib0405">2</a> This autoantibody was originally described, alone or in combination with anti-LKM-1, to define a clinical entity indistinguishable from AIH-2. Although anti-LC-1 was subsequently detected also in patients positive for serological markers associated with AIH-1, and in patients with chronic HCV infection, anti-LC-1 in isolation scores positively towards a diagnosis of AIH-2, allowing prompt initiation of treatment.<a class="elsevierStyleCrossRef" href="#bib0465">14</a> The presence and titre of anti-LC-1 antibodies correlate with disease activity, and represent a potentially useful marker of residual hepatocellular inflammation in AIH.<a class="elsevierStyleCrossRef" href="#bib0665">54</a>Anti-soluble liver antigen/liver-pancreas antibodiesAnti-SLA and anti-LP were originally believed to be distinct antibodies but they were subsequently shown to bind the same target, a UGA tRNA suppressor-associated antigenic protein (tRNP(ser)sec), more precisely O-Phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS).<a class="elsevierStyleCrossRef" href="#bib0670">55</a> They can, therefore, be considered one and the same. Since anti-SLA/LP cannot be detected by IFL, this antibody is detected by radioimmunoassay and ELISA.<a class="elsevierStyleCrossRef" href="#bib0405">2</a> Anti-SLA/LP have been reported in the absence of seropositivity for conventional autoantibodies, suggesting the existence of a third group of AIH patients. However, these early reports used a particularly high cut-off point for conventional autoantibody detection – higher than those currently used for the diagnosis of AIH – therefore the nosological entity of AIH-3 has not been accepted by the IAIHG. Though anti-SLA have been reported in occasional HCV infected anti-LKM-1 positive patients, their presence is highly specific for the diagnosis of AIH, and its detection at the time of diagnosis identifies patients with a more severe disease and a worse prognosis.<a class="elsevierStyleCrossRef" href="#bib0500">21</a>Anti-neutrophil cytoplasmic antibodiesANCAs react to constituents of the cytoplasm of neutrophils to give a perinuclear (pANCA) or cytoplasmic (cANCA) IFL pattern. The predominant target of c-ANCA is proteinase 3 and this autoantibody is frequently detected in Wegener granulomatosis. On the other hand, p-ANCA binds myeloperoxidase and is most commonly found in microscopic polyangiitis. Similar to what observed in PSC and IBD, pANCAs are frequently detected in AIH-1, although the IFL pattern is somewhat atypical. Staining is associated with peripheral nuclear membrane components, hence the name of peripheral anti-nuclear neutrophil antibody (pANNA). The proposed target of pANNA is a 50kDa neutrophil-specific nuclear protein belonging to the nuclear pore complex, potentially the tubulin β chain 5.<a class="elsevierStyleCrossRef" href="#bib0665">54</a> Positivity for pANNA is very rare in AIH-2. In AIH-1, however, its detection can aid in the diagnosis, particularly when other autoantibodies are absent.<a class="elsevierStyleCrossRef" href="#bib0465">14</a>HistologySince transaminases and IgG levels do not reflect the extent of histological inflammatory activity, or the presence or absence of cirrhosis, liver biopsy is mandatory not only to confirm the diagnosis but also to evaluate the severity of liver damage.Hepatitis at the portal-parenchymal interface, known as interface hepatitis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), is typical, but is not exclusively observed in AIH.<a class="elsevierStyleCrossRef" href="#bib0675">56</a> This picture is characterised by a lymphoplasmacytic infiltrate crossing the limiting plate and invading the liver parenchyma. Lymphocytes, plasma cells and histiocytes surround individual dying hepatocytes at the portal-parenchymal interface and in the lobule. Though plasma cells are usually abundant at the interface and throughout the lobule, their presence in low number does not exclude the diagnosis of AIH.<a class="elsevierStyleCrossRef" href="#bib0480">17</a> Other lesions that may be present include hepatocyte swelling and pycnotic necrosis. Fibrosis is present in all but the mildest forms of the disease. In contrast to patients with an insidious course, those presenting with acute liver failure show tissue damage predominantly in the centrilobular area.<a class="elsevierStyleCrossRef" href="#bib0680">57</a> However, many patients presenting with fulminant hepatic failure tend to have massive necrosis and multilobular collapse; importantly, they have less fibrosis than those presenting with a more insidious course.<a class="elsevierStyleCrossRef" href="#bib0445">10</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Despite the fact that sampling variation may occur in needle biopsy specimens, especially in the presence of cirrhosis, the severity of the histological appearance is usually of prognostic value. However, even patients with cirrhosis at presentation respond well to immunosuppressive treatment.<a class="elsevierStyleCrossRef" href="#bib0685">58</a>TreatmentStandard treatmentIn the early 70s, three randomised clinical trials in adults with AIH provided the basis for the current immunosuppressive regimens, collectively suggesting that treatment with prednisolone improves liver function tests, ameliorates symptoms and prolongs survival.<a class="elsevierStyleCrossRefs" href="#bib0690">59–61</a> Although azathioprine was not able to induce remission when used on its own, it did allow the maintenance of remission in association with a significantly reduced dose of steroids.<a class="elsevierStyleCrossRef" href="#bib0705">62</a> Initial treatment with prednisone (or prednisolone), with or without azathioprine, should be instituted as soon as the diagnosis is made, and not delayed for 6 months as suggested in the early studies.<a class="elsevierStyleCrossRef" href="#bib0710">63</a>The initial approach to therapy depends upon the histologic findings.<a class="elsevierStyleCrossRef" href="#bib0445">10</a> Transaminase and IgG levels do not always correlate with histological damage and consequently provide limited help in respect to treatment initiation. Prompt treatment is indicated in patients with aggressive disease, usually children or young adults, and in any patient with evidence of interface hepatitis, with or without fibrosis or cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0415">4</a> In older patients with isolated portal inflammation (without interface hepatitis), institution of therapy is guided by AST and IgG levels, and/or by the presence of symptoms.<a class="elsevierStyleCrossRef" href="#bib0625">46</a> The therapeutic approach in patients with a milder form of the disease – who may be asymptomatic or pauci-symptomatic, and are detected incidentally after discovery of abnormal liver function tests – is less clear.<a class="elsevierStyleCrossRef" href="#bib0715">64</a> In these cases, the benefit of therapy is undefined and may be so low that the risk of corticosteroid side effects might outweigh its possible benefits; this is particularly relevant when starting therapy in post-menopausal women and elderly patients.<a class="elsevierStyleCrossRef" href="#bib0720">65</a>Although some patients may remain in remission after drug treatment is withdrawn, most require long-term maintenance therapy. Despite the absence of firm guidelines, it is cautious not to attempt withdrawal of immunosuppression within 2 years of diagnosis.<a class="elsevierStyleCrossRef" href="#bib0415">4</a> During withdrawal attempts, it is essential to closely monitor the liver function tests, as relapse may be severe and even fatal. Patients who have successfully stopped immunosuppression should undergo long-term follow-up, as relapse can occur even 10 years later.<a class="elsevierStyleCrossRef" href="#bib0715">64</a>Alternative treatmentsIn the group of patients that show failure to standard therapy and intolerance or low compliance to standard immunosuppression, alternative immunosuppressive treatments have been proposed.<a class="elsevierStyleCrossRef" href="#bib0725">66</a> Decisions regarding the use of such regimens have to be based, however, on the scarce data available, mainly on the basis of small series or case reports.Mycophenolate mofetil (MMF) is a purine antagonist that selectively inhibits proliferation of activated lymphocytes.<a class="elsevierStyleCrossRef" href="#bib0730">67</a> It has been reported to be effective in AIH patients intolerant to azathioprine.<a class="elsevierStyleCrossRef" href="#bib0715">64</a> Therefore, in patients for whom standard immunosuppression fails to induce stable remission, or who are intolerant to azathioprine, MMF, together with prednisolone, is currently the treatment of choice.<a class="elsevierStyleCrossRef" href="#bib0415">4</a>Calcineurin inhibitors, cyclosporine and tacrolimus, have been used as a rescue treatment for difficult-to-treat cases of AIH. As no large study in this subgroup of patients has been published, they should be used with caution.<a class="elsevierStyleCrossRef" href="#bib0715">64</a>Anti-TNF-α agents, such as infliximab, are commonly used to treat immune-mediated diseases such as rheumatoid arthritis, psoriasis and IBD. There is anecdotal evidence that infliximab is efficacious in the management of difficult-to-treat cases of AIH.<a class="elsevierStyleCrossRef" href="#bib0735">68</a> In the largest published retrospective series, treatment with infliximab led to a decrease in transaminase and IgG levels in 11 difficult-to-treat adult patients with AIH, but infectious complications occurred in seven of them.<a class="elsevierStyleCrossRef" href="#bib0735">68</a> Moreover, and worryingly, infliximab therapy for other diseases has been associated with the induction of severe de novo AIH.<a class="elsevierStyleCrossRef" href="#bib0740">69</a> Anecdotal evidence also suggests some benefit with the use of the anti B-cell monoclonal antibody rituximab in difficult-to-treat patients.<a class="elsevierStyleCrossRef" href="#bib0745">70</a> However, the occurrence of severe infections is an important risk-factor associated with these biological treatments.Budesonide is a corticosteroid with very high affinity for the glucocorticoid receptor and high first pass liver metabolism; hence, it is presently receiving considerable attention as an alternative to prednisone or prednisolone as primary treatment of AIH. Although initial reports were somewhat contradictory, a recent large European study found that a combination of budesonide and azathioprine could induce remission in 60% of non-cirrhotic patients, while medium-dose standard steroids and azathioprine could only induce remission in 39% of patients. The budesonide group had also fewer adverse effects.<a class="elsevierStyleCrossRef" href="#bib0750">71</a> It should be noted, however, that this reported rate of remission is much lower than that seen in both adults and children (∼80%) when a higher starting dose of prednisone is used. Moreover, because budesonide cannot be used in cirrhotic patients – representing at least a third of the AIH population – its clinical utility has limitations.<a class="elsevierStyleCrossRef" href="#bib0755">72</a>Liver transplantationAIH accounts for 2–3% of paediatric and 4–6% of adult liver transplants (LT) performed in Europe and the United States.<a class="elsevierStyleCrossRef" href="#bib0415">4</a> LT is indicated for AIH patients who present with acute liver failure and do not respond to immunosuppressive treatment, or with end-stage chronic liver disease and for those with hepatocellular carcinoma that meet the transplant criteria.<a class="elsevierStyleCrossRefs" href="#bib0760">73,74</a> Although patients with a chronic presentation of AIH typically respond well to immunosuppressive treatment, approximately 10% will eventually require LT. Patients who fail to reach remission after 4 years of therapy are the most common candidates for LT.<a class="elsevierStyleCrossRef" href="#bib0770">75</a> The indications for LT for end-stage chronic AIH are similar to those for other end-stage liver diseases.<a class="elsevierStyleCrossRefs" href="#bib0400">1,15</a>Novel treatment approachesGiven that loss of immunoregulation is central to the pathogenesis of AIH, Treg cell therapy – aimed at reconstituting self-tolerance – is a highly promising candidate for alternative and effective immune intervention in AIH. To date, this approach has been hindered by the limited ability of Tregs to expand and by their propensity to apoptosis. However, because corticosteroid therapy can partially restore the potency of the Treg population, Tregs in AIH do have the potential to expand and regain their function.<a class="elsevierStyleCrossRefs" href="#bib0580">37,38</a> Using a polyclonal T cell stimulation strategy (that engages the T cell receptor via CD3 and the co-stimulatory molecule CD28, while providing exogenous IL-2, a key cytokine for Treg survival and growth), Tregs can be expanded from circulating CD4posCD25pos Tregs, and also generated de novo from non-regulatory CD4posCD25neg T cells in both healthy subjects and patients with AIH.<a class="elsevierStyleCrossRef" href="#bib0775">76</a> Interestingly, expanded Tregs express higher levels of FOXP3 and are more effective suppressors compared to freshly isolated Tregs.<a class="elsevierStyleCrossRef" href="#bib0775">76</a>Although FOXP3 is the most specific marker of human Tregs, its intracellular location limits its use in the laboratory setting. In addition to the lack of specific cell-surface markers for Tregs, the human CD4pos CD25high population contains a proportion of activated effector T cells. Furthermore, Tregs and effector Th17 cells share a common progenitor, though their developmental pathways differ. Since de novo generation of Tregs relies on strong T cell receptor (TCR) signalling, the risk of concomitant expansion of effector Th17 cells needs to be addressed when considering Treg therapy for AIH.<a class="elsevierStyleCrossRef" href="#bib0440">9</a> The physical removal of IL17pos cells, or the use of small interfering RNAs specific for the Th17-associated transcription factor RORC, leads to elevated FOXP3 expression and increased suppressive function by expanded Tregs from AIH patients.<a class="elsevierStyleCrossRef" href="#bib0780">77</a>The potential for successful Treg therapy is particularly strong in AIH-2, given that the antigenic regions (CYP2D6217–260 and CYP2D6305–348), targeted by B, CD4 and CD8 T cells, are well characterised.<a class="elsevierStyleCrossRef" href="#bib0785">78</a> Several lines of evidence demonstrate that autoantigen-specific Tregs suppress more efficiently than their non-antigen-specific counterparts. In this regard, antigen-specific Tregs generated from AIH-2 patients are able to suppress CD4 and CD8 T cell responses more potently than polyclonally expanded T-regs. The most efficient suppression of autoreactive T cells has been achieved by Treg co-culture with semi-mature dendritic cells loaded with the CYP2D6 peptides.<a class="elsevierStyleCrossRef" href="#bib0790">79</a>Conflict of interestR. Liberal, D. Vergani and G. Mieli-Vergani are supported by grants from the Rosetree Foundation, UK, and PSC Partners Seeking a Cure, USA." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres734853" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec738661" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres734852" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec738660" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Genetics" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Potential triggers" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Effector immune mechanisms" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Regulatory immune mechanisms" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Clinical presentation" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Diagnosis" ] 11 => array:3 [ "identificador" => "sec0040" "titulo" => "Autoantibodies" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Anti-nuclear antibodies" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Anti-smooth muscle antibodies" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Anti-liver-kidney-microsomal type 1 antibodies" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Anti-liver cytosol type 1 antibodies" ] 4 => array:2 [ "identificador" => "sec0065" "titulo" => "Anti-soluble liver antigen/liver-pancreas antibodies" ] 5 => array:2 [ "identificador" => "sec0070" "titulo" => "Anti-neutrophil cytoplasmic antibodies" ] ] ] 12 => array:2 [ "identificador" => "sec0075" "titulo" => "Histology" ] 13 => array:3 [ "identificador" => "sec0080" "titulo" => "Treatment" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0085" "titulo" => "Standard treatment" ] 1 => array:2 [ "identificador" => "sec0090" "titulo" => "Alternative treatments" ] 2 => array:2 [ "identificador" => "sec0095" "titulo" => "Liver transplantation" ] 3 => array:2 [ "identificador" => "sec0100" "titulo" => "Novel treatment approaches" ] ] ] 14 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interest" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-04-01" "fechaAceptado" => "2016-04-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec738661" "palabras" => array:5 [ 0 => "Autoimmune hepatitis" 1 => "Pathogenesis" 2 => "Autoantibodies" 3 => "Diagnosis" 4 => "Immunosuppressive treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec738660" "palabras" => array:5 [ 0 => "Hepatitis autoinmune" 1 => "Patogenia" 2 => "Autoanticuerpos" 3 => "Diagnóstico" 4 => "Tratamiento inmunosupresor" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Autoimmune hepatitis (AIH) is a progressive inflammatory hepatopathy and an important cause of end-stage liver disease. Its aetiology remains unknown, though both genetic and environmental factors are involved in its development. The major mechanism of autoimmune liver damage involves immune reactions against host liver antigens. Numerical and functional defects of regulatory T-cells play a permissive role enabling autoimmune liver injury to occur and persist. The most typical features of AIH are female preponderance, hypergammaglobulinaemia, seropositivity for circulating autoantibodies and a picture of interface hepatitis on histology. Two types of AIH are distinguished according to serological profile: AIH type 1 patients are positive for anti-nuclear and/or anti-smooth muscle antibodies, whereas AIH type 2 patients are defined by the positivity for anti-liver kidney microsomal type 1 antibody and/or for anti-liver cytosol type 1 antibody. Clinical manifestations are variable, and AIH onset is often ill-defined, frequently mimicking acute hepatitis; its course may be fluctuating. AIH responds to immunosuppressive treatment in the majority of cases. Steroids with or without azathioprine should be instituted promptly upon diagnosis. Remission is achieved in some 80% of patients. For the remaining 20% of patients, alternative immunosuppressive agents such as mycophenolate mofetil and calcineurin inhibitors are an option. Liver transplantation should be considered for those patients who progress to cirrhosis and develop complications of end-stage liver disease, as well as for those presenting with acute liver failure; outcomes are excellent, although the disease may recur in the allograft." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La hepatitis autoinmune (HAI) es una hepatopatía inflamatoria progresiva y una causa importante de insuficiencia hepática terminal. Su origen continúa siendo una incógnita, si bien influyen en su evolución factores tanto genéticos como ambientales. El principal mecanismo de daño hepático autoinmune son las reacciones inmunitarias contra los antígenos hepáticos del receptor. Los defectos numéricos y funcionales de los linfocitos T reguladores desempeñan un permisivo papel a la hora de propiciar que la enfermedad hepática autoinmune se produzca y perdure. Las particularidades más típicas de la HAI son el predominio femenino, hipergammaglobulinemia, seropositividad para autoanticuerpos circulantes e imagen de hepatitis de interfase en la histología. Se distinguen 2 tipos de HAI conforme a su perfil serológico: los pacientes con HAI tipo 1 dan positivo para anticuerpos antinucleares y/o antimúsculo liso, mientras que los pacientes con HAI tipo 2 dan positivo para el anticuerpo antimicrosomal de hígado tipo 1 y/o para el anticuerpo contra el citosol hepático 1. Los signos clínicos varían, y el inicio de la HAI suele estar mal definido, imitando hepatitis aguda; su evolución puede fluctuar. La HAI remite con tratamiento inmunodepresor en la mayoría de los casos. Los corticosteroides con o sin azatioprina deberían iniciarse inmediatamente después del diagnóstico. La remisión se consigue en alrededor del 80% de los pacientes. Para el 20% restante, una opción son los fármacos inmunodepresores, como el micofenolato de mofetilo o inhibidores de calcineurina. El trasplante hepático debe ser tenido en cuenta para aquellos pacientes que cursen con cirrosis y padezcan complicaciones de insuficiencia hepática terminal, así como para los que experimenten insuficiencia hepática aguda; los resultados son excelentes, si bien la enfermedad podría recidivar en el alotransplante." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1502 "Ancho" => 2481 "Tamanyo" => 170596 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of liver damage. Liver damage is initiated by the presentation of a self-antigenic peptide within a major histocompatibility molecule (MHC) by professional antigen presenting cells (APCs). The presence of appropriate costimulation alongside exposure to various cytokines drives the differentiation of uncommitted CD4 helper T-cells (Th0). IL-6 and IL-1β lead to differentiation into pathogenic Th17 cells that secrete the proinflammatory cytokine IL-17. Th17 cells promote hepatocyte secretion of IL-6, which in turn further enhances Th17 development. Exposure to IL-12 leads to the differentiation of Th1 cells secreting IFN-γ, which induces monocyte (MΦ) differentiation, activates cytotoxic CD8 T-cells and promotes NK cell killing. IFN-γ also increases MHC class I and induces class II expression by hepatocytes, further exacerbating inflammation. Exposure to IL-4 leads to Th2 differentiation. Th2 cells secrete IL-13, IL-4 and IL-10 that enable B cell maturation into plasma cells with the consequent production of autoantibodies. Autoantibodies are in turn involved in antibody-mediated cellular cytotoxicity and complement activation." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 709 "Ancho" => 950 "Tamanyo" => 315240 ] ] "descripcion" => array:1 [ "en" => "Histology of autoimmune hepatitis. The portal and periportal inflammatory infiltrate characteristic of autoimmune hepatitis is composed of lymphocytes, monocytes/macrophages and plasma cells (interface hepatitis, arrows). Haematoxilin and eosin staining (picture kindly provided by Dr. Alberto Quaglia, Institute of Liver Studies, King's College Hospital)." ] ] 2 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Alvarez F, Berg PA et al. J Hepatol 1999;31:929–938." "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Pre-treatment score >15: definite AIH; 10–15: probable AIH; Post-treatment score >17: definite AIH; 12–17: probable AIH.ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IgG, immunoglobulin G; ANA, anti-nuclear antibody; SMA, anti-smooth muscle antibody; anti-LKM-1, anti-liver kidney microsomal type 1 antibodies; AMA, anti-mitochondrial antibodies; SLA/LP, soluble liver antigen/liver pancreas; ASGPR, asialoglycoprotein receptor; p-ANNA, peripheral anti-nuclear neutrophil antibody (also known as atypical pANCA); HLA, human leucocyte antigen." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Feature \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Score \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ALP: AST (or ALT) ratio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.5–3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serum globulins or IgG (times above normal) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>2.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.5–2.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.0–1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA, SMA or anti-LKM-1 titres \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>1:80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1:40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AMA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Viral markers of active infection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hepatotoxic drug history \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Average alcohol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><25g/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>60g/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Histological features \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Interface hepatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Plasma cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rosettes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None of the above \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Biliary changes<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Atypical changes<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immune diseases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thyroiditis, colitis, other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DR3 or DR4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Seropositivity for other autoantibodies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anti-SLA/LP, actin, ASGPR, pANNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Response to therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Remission \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Relapse \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+3 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1212842.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Including granulomatous cholangitis, concentric periductal fibrosis, ductopenia, marginal bile duct proliferation and cholangiolitis." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Any other prominent feature suggesting a different aetiology." ] ] ] "descripcion" => array:1 [ "en" => "International autoimmune hepatitis group revised diagnostic scoring system." ] ] 3 => array:9 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Hennes EM, Zeniya M et al. Hepatology 2008;48:169–176." "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Score ≥6: probable AIH; ≥7: definite AIH.ANA, anti-nuclear antibody; SMA, anti-smooth muscle antibody; anti-LKM-1, anti-liver kidney microsomal antibody type 1; SLA, soluble liver antigen; IgG, immunoglobulin G; AIH, autoimmune hepatitis." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cut-off \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Points \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA or SMA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥1:40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA or SMA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥1:80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Or anti-LKM-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥1:40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Or SLA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>Upper limit of normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>1.10 times upper limit of normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liver histology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Compatible with AIH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Typical of AIH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Absence of viral hepatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1212843.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "Addition of points achieved for all autoantibodies cannot exceed a maximum of 2 points." ] ] ] "descripcion" => array:1 [ "en" => "Simplified criteria for the diagnosis of autoimmune hepatitis." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:79 [ 0 => array:3 [ "identificador" => "bib0400" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis: a comprehensive review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R. Liberal" 1 => "C.R. Grant" 2 => "G. Mieli-Vergani" 3 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaut.2012.11.002" "Revista" => array:6 [ "tituloSerie" => "J Autoimmun" "fecha" => "2013" "volumen" => "41" "paginaInicial" => "126" "paginaFinal" => "139" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23218932" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0405" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Vergani" 1 => "F. Alvarez" 2 => "F.B. Bianchi" 3 => "E.L. Cançado" 4 => "I.R. Mackay" 5 => "M.P. Manns" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2004.08.002" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2004" "volumen" => "41" "paginaInicial" => "677" "paginaFinal" => "683" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15464251" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0410" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical significance of autoantibodies in autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Liberal" 1 => "G. Mieli-Vergani" 2 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaut.2013.08.001" "Revista" => array:6 [ "tituloSerie" => "J Autoimmun" "fecha" => "2013" "volumen" => "46" "paginaInicial" => "17" "paginaFinal" => "24" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24016388" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0415" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis and management of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.P. Manns" 1 => "A.J. Czaja" 2 => "J.D. Gorham" 3 => "E.L. Krawitt" 4 => "G. Mieli-Vergani" 5 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.23584" "Revista" => array:7 [ "tituloSerie" => "Hepatology" "fecha" => "2010" "volumen" => "51" "paginaInicial" => "2193" "paginaFinal" => "2213" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20513004" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1873994614001482" "estado" => "S300" "issn" => "18739946" ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0420" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K.M. Boberg" 1 => "E. Aadland" 2 => "J. Jahnsen" 3 => "N. Raknerud" 4 => "M. Stiris" 5 => "H. Bell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Scand J Gastroenterol" "fecha" => "1998" "volumen" => "33" "paginaInicial" => "99" "paginaFinal" => "103" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9489916" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0425" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L. Gronbaek" 1 => "H. Vilstrup" 2 => "P. Jepsen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2013.10.020" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2014" "volumen" => "60" "paginaInicial" => "612" "paginaFinal" => "617" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24326217" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0430" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of autoimmune liver disease in Alaska Natives" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K.J. Hurlburt" 1 => "B.J. McMahon" 2 => "H. Deubner" 3 => "B. Hsu-Trawinski" 4 => "J.L. Williams" 5 => "K.V. Kowdley" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2002.06019.x" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "2002" "volumen" => "97" "paginaInicial" => "2402" "paginaFinal" => "2407" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12358264" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0435" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis: contrasts and comparisons in children and adults – a comprehensive review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Floreani" 1 => "R. Liberal" 2 => "D. Vergani" 3 => "G. Mieli-Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaut.2013.08.004" "Revista" => array:6 [ "tituloSerie" => "J Autoimmun" "fecha" => "2013" "volumen" => "46" "paginaInicial" => "7" "paginaFinal" => "16" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24035197" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0440" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathogenesis of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R. Liberal" 1 => "M.S. Longhi" 2 => "G. Mieli-Vergani" 3 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bpg.2011.09.009" "Revista" => array:6 [ "tituloSerie" => "Best Pract Res Clin Gastroenterol" "fecha" => "2011" "volumen" => "25" "paginaInicial" => "653" "paginaFinal" => "664" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22117632" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0445" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "E.L. Krawitt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra050408" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2006" "volumen" => "354" "paginaInicial" => "54" "paginaFinal" => "66" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16394302" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0450" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The variant forms of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A.J. Czaja" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "1996" "volumen" => "125" "paginaInicial" => "588" "paginaFinal" => "598" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8815758" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0455" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic criteria of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Liberal" 1 => "C.R. Grant" 2 => "M.S. Longhi" 3 => "G. Mieli-Vergani" 4 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.autrev.2013.11.009" "Revista" => array:6 [ "tituloSerie" => "Autoimmun Rev" "fecha" => "2014" "volumen" => "13" "paginaInicial" => "435" "paginaFinal" => "440" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24418295" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0460" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meeting report: International Autoimmune Hepatitis Group" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P.J. Johnson" 1 => "I.G. McFarlane" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1993" "volumen" => "18" "paginaInicial" => "998" "paginaFinal" => "1005" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8406375" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0465" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Alvarez" 1 => "P.A. Berg" 2 => "F.B. Bianchi" 3 => "L. Bianchi" 4 => "A.K. Burroughs" 5 => "E.L. Cancado" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "1999" "volumen" => "31" "paginaInicial" => "929" "paginaFinal" => "938" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10580593" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0470" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver transplantation and autoimmune liver diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R. Liberal" 1 => "Y. Zen" 2 => "G. Mieli-Vergani" 3 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/lt.23704" "Revista" => array:6 [ "tituloSerie" => "Liver Transpl" "fecha" => "2013" "volumen" => "19" "paginaInicial" => "1065" "paginaFinal" => "1077" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23873751" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0475" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetics of liver disease: immunogenetics and disease pathogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P.T. Donaldson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gut" "fecha" => "2004" "volumen" => "53" "paginaInicial" => "599" "paginaFinal" => "608" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15016758" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0480" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D. Vergani" 1 => "M.S. Longhi" 2 => "D.P. Bogdanos" 3 => "Y. Ma" 4 => "G. Mieli-Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00281-009-0170-7" "Revista" => array:6 [ "tituloSerie" => "Semin Immunopathol" "fecha" => "2009" "volumen" => "31" "paginaInicial" => "421" "paginaFinal" => "435" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19533129" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0485" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.D. Strettell" 1 => "P.T. Donaldson" 2 => "L.J. Thomson" 3 => "P.J. Santrach" 4 => "S.B. Moore" 5 => "A.J. Czaja" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "1997" "volumen" => "112" "paginaInicial" => "2028" "paginaFinal" => "2035" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9178696" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0490" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genome-wide association study identifies variants associated with autoimmune hepatitis type 1" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y.S. de Boer" 1 => "N.M. van Gerven" 2 => "A. Zwiers" 3 => "B.I. Witte" 4 => "H. Bontkes" 5 => "C.M. van Nieuwkerk" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2014.04.022" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2014" "volumen" => "147" "paginaInicial" => "443" "paginaFinal" => "452" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24768677" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0495" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "I. Djilali-Saiah" 1 => "A. Fakhfakh" 2 => "H. Louafi" 3 => "S. Caillat-Zucman" 4 => "D. Debray" 5 => "F. Alvarez" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2006.07.034" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2006" "volumen" => "45" "paginaInicial" => "844" "paginaFinal" => "850" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17050030" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0500" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Ma" 1 => "M. Okamoto" 2 => "M.G. Thomas" 3 => "D.P. Bogdanos" 4 => "A.R. Lopes" 5 => "B. Portmann" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2002.32092" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2002" "volumen" => "35" "paginaInicial" => "658" "paginaFinal" => "664" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11870381" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0505" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K. Agarwal" 1 => "A.J. Czaja" 2 => "D.E. Jones" 3 => "P.T. Donaldson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510310110" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2000" "volumen" => "31" "paginaInicial" => "49" "paginaFinal" => "53" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10613727" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0510" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A.J. Czaja" 1 => "S. Cookson" 2 => "P.K. Constantini" 3 => "M. Clare" 4 => "J.A. Underhill" 5 => "P.T. Donaldson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "1999" "volumen" => "117" "paginaInicial" => "645" "paginaFinal" => "652" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10464141" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0515" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "K. Agarwal" 1 => "A.J. Czaja" 2 => "P.T. Donaldson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1399-0039.2006.00794.x" "Revista" => array:6 [ "tituloSerie" => "Tissue Antigens" "fecha" => "2007" "volumen" => "69" "paginaInicial" => "227" "paginaFinal" => "235" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17493146" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0520" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Vogel" 1 => "C.P. Strassburg" 2 => "M.P. Manns" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2002.30084" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2002" "volumen" => "35" "paginaInicial" => "126" "paginaFinal" => "131" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11786968" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0525" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "AIRE gene analysis in children with autoimmune hepatitis type I or II" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.O. Lankisch" 1 => "O. Mourier" 2 => "E.M. Sokal" 3 => "D. Habes" 4 => "F. Lacaille" 5 => "L. Bridoux-Henno" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MPG.0b013e31818550de" "Revista" => array:6 [ "tituloSerie" => "J Pediatr Gastroenterol Nutr" "fecha" => "2009" "volumen" => "48" "paginaInicial" => "498" "paginaFinal" => "500" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19322061" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0530" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mimicry between the hepatitis B virus DNA polymerase and the antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis B virus infection" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "G.V. Gregorio" 1 => "K. Choudhuri" 2 => "Y. Ma" 3 => "A. Vegnente" 4 => "G. Mieli-Vergani" 5 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "1999" "volumen" => "162" "paginaInicial" => "1802" "paginaFinal" => "1810" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9973445" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0535" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mimicry between the hepatitis C virus polyprotein and antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis C virus infection" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.V. Gregorio" 1 => "K. Choudhuri" 2 => "Y. Ma" 3 => "P. Pensati" 4 => "R. Iorio" 5 => "P. Grant" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Exp Immunol" "fecha" => "2003" "volumen" => "133" "paginaInicial" => "404" "paginaFinal" => "413" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12930368" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0540" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of non-organ-specific autoantibodies and chronic liver disease in the general population: a nested case–control study of the Dionysos cohort" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Lenzi" 1 => "S. Bellentani" 2 => "G. Saccoccio" 3 => "P. Muratori" 4 => "F. Masutti" 5 => "L. Muratori" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gut" "fecha" => "1999" "volumen" => "45" "paginaInicial" => "435" "paginaFinal" => "441" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10446115" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0545" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cytochrome P4502D6(193–212): a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Kerkar" 1 => "K. Choudhuri" 2 => "Y. Ma" 3 => "A. Mahmoud" 4 => "D.P. Bogdanos" 5 => "L. Muratori" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "2003" "volumen" => "170" "paginaInicial" => "1481" "paginaFinal" => "1489" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12538711" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0550" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Primary and secondary liver/kidney microsomal autoantibody response following infection with hepatitis C virus" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F.D. Mackie" 1 => "M. Peakman" 2 => "M. Yun" 3 => "R. Sallie" 4 => "H. Smith" 5 => "E.T. Davies" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "1994" "volumen" => "106" "paginaInicial" => "1672" "paginaFinal" => "1675" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8194716" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0555" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of hepatitis C serum antibody in autoimmune diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Agmon-Levin" 1 => "M. Ram" 2 => "O. Barzilai" 3 => "B.S. Porat-Katz" 4 => "R. Parikman" 5 => "C. Selmi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaut.2009.02.017" "Revista" => array:6 [ "tituloSerie" => "J Autoimmun" "fecha" => "2009" "volumen" => "32" "paginaInicial" => "261" "paginaFinal" => "266" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19356903" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0560" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug-induced autoimmune hepatitis: clinical characteristics and prognosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Bjornsson" 1 => "J. Talwalkar" 2 => "S. Treeprasertsuk" 3 => "P.S. Kamath" 4 => "N. Takahashi" 5 => "S. Sanderson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.23588" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2010" "volumen" => "51" "paginaInicial" => "2040" "paginaFinal" => "2048" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20512992" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0565" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "G. Senaldi" 1 => "B. Portmann" 2 => "A.P. Mowat" 3 => "G. Mieli-Vergani" 4 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Dis Child" "fecha" => "1992" "volumen" => "67" "paginaInicial" => "1447" "paginaFinal" => "1453" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1489223" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0570" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The liver as a lymphoid organ" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "I.N. Crispe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev.immunol.021908.132629" "Revista" => array:6 [ "tituloSerie" => "Annu Rev Immunol" "fecha" => "2009" "volumen" => "27" "paginaInicial" => "147" "paginaFinal" => "163" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19302037" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0575" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulatory T cells: mechanisms of suppression and impairment in autoimmune liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Liberal" 1 => "C.R. Grant" 2 => "M.S. Longhi" 3 => "G. Mieli-Vergani" 4 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/iub.1349" "Revista" => array:6 [ "tituloSerie" => "IUBMB Life" "fecha" => "2015" "volumen" => "67" "paginaInicial" => "88" "paginaFinal" => "97" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25850692" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0580" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.S. Longhi" 1 => "Y. Ma" 2 => "D.P. Bogdanos" 3 => "P. Cheeseman" 4 => "G. Mieli-Vergani" 5 => "D. Vergani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2004.03.008" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2004" "volumen" => "41" "paginaInicial" => "31" "paginaFinal" => "37" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15246204" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0585" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.S. Longhi" 1 => "Y. Ma" …4 ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaut.2005.10.001" "Revista" => array:6 [ "tituloSerie" => "J Autoimmun" "fecha" => "2005" "volumen" => "25" "paginaInicial" => "63" "paginaFinal" => "71" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0590" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.23792" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2010" "volumen" => "52" "paginaInicial" => "999" "paginaFinal" => "1007" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0595" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.27884" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2015" "volumen" => "62" "paginaInicial" => "863" "paginaFinal" => "875" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0600" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "2006" "volumen" => "176" "paginaInicial" => "4484" "paginaFinal" => "4491" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0605" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.25682" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2012" "volumen" => "56" "paginaInicial" => "677" "paginaFinal" => "686" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0610" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22914" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2009" "volumen" => "50" "paginaInicial" => "130" "paginaFinal" => "142" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0615" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2012.02.029" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2012" "volumen" => "57" "paginaInicial" => "125" "paginaFinal" => "132" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0620" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dysfunctional CD39 regulatory T cells and aberrant control of T helper type 17 cells in autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.26583" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2014" "volumen" => "59" "paginaInicial" => "1007" "paginaFinal" => "1015" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0625" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical features and management of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "World J Gastroenterol" "fecha" => "2008" "volumen" => "14" "paginaInicial" => "3301" "paginaFinal" => "3305" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0630" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe autoimmune hepatitis first presenting in the early post partum period" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Gastroenterol Hepatol" "fecha" => "2004" "volumen" => "2" "paginaInicial" => "622" "paginaFinal" => "624" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0635" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management and outcome of pregnancy in autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gut" "fecha" => "2001" "volumen" => "48" "paginaInicial" => "97" "paginaFinal" => "102" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0640" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis in childhood: a 20-year experience" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510250308" "Revista" => array:7 [ "tituloSerie" => "Hepatology" "fecha" => "1997" "volumen" => "25" "paginaInicial" => "541" "paginaFinal" => "547" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0016508506002617" "estado" => "S300" "issn" => "00165085" ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0645" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: implications for follow-up and screening" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22432" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2008" "volumen" => "48" "paginaInicial" => "863" "paginaFinal" => "870" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0650" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Development of hepatocellular carcinoma in autoimmune hepatitis patients: a case series" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10620-010-1444-6" "Revista" => array:6 [ "tituloSerie" => "Dig Dis Sci" "fecha" => "2011" "volumen" => "56" "paginaInicial" => "578" "paginaFinal" => "585" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0655" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Simplified criteria for the diagnosis of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22322" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2008" "volumen" => "48" "paginaInicial" => "169" "paginaFinal" => "176" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0660" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune liver serology: current diagnostic and clinical challenges" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "World J Gastroenterol" "fecha" => "2008" "volumen" => "14" "paginaInicial" => "3374" "paginaFinal" => "3387" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0665" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoantibodies and their antigens in autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-0029-1233533" "Revista" => array:6 [ "tituloSerie" => "Semin Liver Dis" "fecha" => "2009" "volumen" => "29" "paginaInicial" => "241" "paginaFinal" => "253" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0670" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2000" "volumen" => "355" "paginaInicial" => "1510" "paginaFinal" => "1515" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0675" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Histological findings in chronic hepatitis C with autoimmune features" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510260229" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1997" "volumen" => "26" "paginaInicial" => "459" "paginaFinal" => "466" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0680" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune acute liver failure: proposed clinical and histological criteria" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.24080" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2011" "volumen" => "53" "paginaInicial" => "517" "paginaFinal" => "526" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0685" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis in children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Liver Dis" "fecha" => "2002" "volumen" => "6" "paginaInicial" => "623" "paginaFinal" => "634" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0016508514008002" "estado" => "S300" "issn" => "00165085" ] ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0690" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Controlled prospective trial of corticosteroid therapy in active chronic hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Q J Med" "fecha" => "1971" "volumen" => "40" "paginaInicial" => "159" "paginaFinal" => "185" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0695" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "1972" "volumen" => "63" "paginaInicial" => "820" "paginaFinal" => "833" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0700" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Controlled trial of prednisone and azathioprine in active chronic hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1973" "volumen" => "1" "paginaInicial" => "735" "paginaFinal" => "737" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0705" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Azathioprine for long-term maintenance of remission in autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199510123331502" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "1995" "volumen" => "333" "paginaInicial" => "958" "paginaFinal" => "963" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S187399461200133X" "estado" => "S300" "issn" => "18739946" ] ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0710" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2010.12.012" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2011" "volumen" => "55" "paginaInicial" => "171" "paginaFinal" => "182" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0715" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacological management of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1517/14656566.2011.524206" "Revista" => array:7 [ "tituloSerie" => "Expert Opin Pharmacother" "fecha" => "2011" "volumen" => "12" "paginaInicial" => "607" "paginaFinal" => "613" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0016508508011992" "estado" => "S300" "issn" => "00165085" ] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0720" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2006.04.007" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2006" "volumen" => "45" "paginaInicial" => "575" "paginaFinal" => "583" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0725" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Review article: the modern management of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2036.2010.04241.x" "Revista" => array:6 [ "tituloSerie" => "Aliment Pharmacol Ther" "fecha" => "2010" "volumen" => "31" "paginaInicial" => "771" "paginaFinal" => "787" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0730" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current and novel immunosuppressive therapy for autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2002.30991" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2002" "volumen" => "35" "paginaInicial" => "7" "paginaFinal" => "13" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib0735" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Infliximab as a rescue-treatment in difficult-to-treat autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2013" "volumen" => "58" "paginaInicial" => "529" "paginaFinal" => "534" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0740" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug-induced autoimmune hepatitis caused by anti-tumor necrosis factor alpha agents" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.23834" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2010" "volumen" => "52" "paginaInicial" => "2246" "paginaFinal" => "2247" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0745" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A case of autoimmune hepatitis treated with rituximab" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000322693" "Revista" => array:6 [ "tituloSerie" => "Case Rep Gastroenterol" "fecha" => "2010" "volumen" => "4" "paginaInicial" => "502" "paginaFinal" => "509" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0750" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2010.06.046" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2010" "volumen" => "139" "paginaInicial" => "1198" "paginaFinal" => "1206" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0755" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2003.50266" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2003" "volumen" => "38" "paginaInicial" => "196" "paginaFinal" => "202" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib0760" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver transplantation for autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2000.16666" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2000" "volumen" => "32" "paginaInicial" => "693" "paginaFinal" => "700" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0765" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Transplantation in autoimmune liver diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "World J Gastroenterol" "fecha" => "2008" "volumen" => "14" "paginaInicial" => "3388" "paginaFinal" => "3395" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib0770" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-0029-1233534" "Revista" => array:6 [ "tituloSerie" => "Semin Liver Dis" "fecha" => "2009" "volumen" => "29" "paginaInicial" => "273" "paginaFinal" => "285" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib0775" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22071" "Revista" => array:7 [ "tituloSerie" => "Hepatology" "fecha" => "2008" "volumen" => "47" "paginaInicial" => "581" "paginaFinal" => "591" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0140673600043099" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib0780" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibition of interleukin-17 promotes differentiation of CD25-cells into stable T regulatory cells in patients with autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2012.02.041" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2012" "volumen" => "142" "paginaInicial" => "1526" "paginaFinal" => "1535" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib0785" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.21658" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2007" "volumen" => "46" "paginaInicial" => "472" "paginaFinal" => "484" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib0790" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.24039" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2011" "volumen" => "53" "paginaInicial" => "536" "paginaFinal" => "547" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/00142565/0000021600000007/v1_201609280158/S0014256516300248/v1_201609280158/en/main.assets" "Apartado" => array:4 [ "identificador" => "1067" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Revisiones" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/00142565/0000021600000007/v1_201609280158/S0014256516300248/v1_201609280158/en/main.pdf?idApp=WRCEE&text.app=https://revclinesp.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300248?idApp=WRCEE"]

Estadísticas

Review

Autoimmune hepatitis: From mechanisms to therapy

La hepatitis autoinmune: de los mecanismos al tratamiento

R. Liberala,b, G. Mieli-Vergania,c, D. Vergania,

Autor para correspondencia

diego.vergani@kcl.ac.uk

Corresponding author.

a Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine, London, UK

b Department of Gastroenterology, Centro Hospitalar São João and Faculty of Medicine, University of Porto, Porto, Portugal

c Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK

Leído

103

Veces
se ha leído el artículo

Total PDF

Total HTML

Compartir estadísticas

 array:23 [
  "pii" => "S0014256516300248"
  "issn" => "00142565"
  "doi" => "10.1016/j.rce.2016.04.003"
  "estado" => "S300"
  "fechaPublicacion" => "2016-10-01"
  "aid" => "1260"
  "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and Sociedad Espa&#241;ola de Medicina Interna &#40;SEMI&#41;"
  "copyrightAnyo" => "2016"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "ssu"
  "cita" => "Rev Clin Esp. 2016;216:372-83"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:2 [
    "total" => 96
    "formatos" => array:2 [
      "HTML" => 66
      "PDF" => 30
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S0014256516300315"
    "issn" => "00142565"
    "doi" => "10.1016/j.rce.2016.04.010"
    "estado" => "S300"
    "fechaPublicacion" => "2016-10-01"
    "aid" => "1267"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and Sociedad Espa&#241;ola de Medicina Interna &#40;SEMI&#41;"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "ssu"
    "cita" => "Rev Clin Esp. 2016;216:384-92"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 146
      "formatos" => array:2 [
        "HTML" => 104
        "PDF" => 42
      ]
    ]
    "es" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">REVISI&#211;N</span>"
      "titulo" => "Consideraciones cl&#237;nicas sobre la posolog&#237;a de los anticoagulantes orales de acci&#243;n directa"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "384"
          "paginaFinal" => "392"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Clinical considerations on the posology of direct oral anticoagulants"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "J&#46; S&#225;ez-Pe&#241;ataro, C&#46; Avenda&#241;o-Sol&#225;, J&#46;R&#46; Gonz&#225;lez-Juanatey"
          "autores" => array:3 [
            0 => array:2 [
              "nombre" => "J&#46;"
              "apellidos" => "S&#225;ez-Pe&#241;ataro"
            ]
            1 => array:2 [
              "nombre" => "C&#46;"
              "apellidos" => "Avenda&#241;o-Sol&#225;"
            ]
            2 => array:2 [
              "nombre" => "J&#46;R&#46;"
              "apellidos" => "Gonz&#225;lez-Juanatey"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "Traduccion" => array:1 [
      "en" => array:9 [
        "pii" => "S225488741630042X"
        "doi" => "10.1016/j.rceng.2016.04.003"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => false
          "ES2" => false
          "LATM" => false
        ]
        "gratuito" => false
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "en"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S225488741630042X?idApp=WRCEE"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300315?idApp=WRCEE"
    "url" => "/00142565/0000021600000007/v1_201609280158/S0014256516300315/v1_201609280158/es/main.assets"
  ]
  "itemAnterior" => array:18 [
    "pii" => "S0014256516300789"
    "issn" => "00142565"
    "doi" => "10.1016/j.rce.2016.05.005"
    "estado" => "S300"
    "fechaPublicacion" => "2016-10-01"
    "aid" => "1280"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46; and Sociedad Espa&#241;ola de Medicina Interna &#40;SEMI&#41;"
    "documento" => "simple-article"
    "crossmark" => 1
    "subdocumento" => "edi"
    "cita" => "Rev Clin Esp. 2016;216:370-1"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 47
      "formatos" => array:2 [
        "HTML" => 34
        "PDF" => 13
      ]
    ]
    "es" => array:10 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>"
      "titulo" => "Prote&#237;na C reactiva en l&#237;quido pleural&#46; &#191;Ayuda a predecir los derrames paraneum&#243;nicos complicados&#63;"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "370"
          "paginaFinal" => "371"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "C-reactive protein in pleural fluid&#46; Does it help predict complicated parapneumonic effusions&#63;"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "L&#46; Ferreiro, L&#46; Vald&#233;s"
          "autores" => array:2 [
            0 => array:2 [
              "nombre" => "L&#46;"
              "apellidos" => "Ferreiro"
            ]
            1 => array:2 [
              "nombre" => "L&#46;"
              "apellidos" => "Vald&#233;s"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300789?idApp=WRCEE"
    "url" => "/00142565/0000021600000007/v1_201609280158/S0014256516300789/v1_201609280158/es/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Review</span>"
    "titulo" => "Autoimmune hepatitis&#58; From mechanisms to therapy"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "372"
        "paginaFinal" => "383"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "R&#46; Liberal, G&#46; Mieli-Vergani, D&#46; Vergani"
        "autores" => array:3 [
          0 => array:3 [
            "nombre" => "R&#46;"
            "apellidos" => "Liberal"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "G&#46;"
            "apellidos" => "Mieli-Vergani"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          2 => array:4 [
            "nombre" => "D&#46;"
            "apellidos" => "Vergani"
            "email" => array:1 [
              0 => "diego&#46;vergani&#64;kcl&#46;ac&#46;uk"
            ]
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:3 [
          0 => array:3 [
            "entidad" => "Institute of Liver Studies&#44; King&#39;s College London&#44; Faculty of Life Sciences &#38; Medicine&#44; London&#44; UK"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Department of Gastroenterology&#44; Centro Hospitalar S&#227;o Jo&#227;o and Faculty of Medicine&#44; University of Porto&#44; Porto&#44; Portugal"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Paediatric Liver&#44; GI &#38; Nutrition Centre&#44; King&#39;s College Hospital&#44; London&#44; UK"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "La hepatitis autoinmune&#58; de los mecanismos al tratamiento"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1502
            "Ancho" => 2481
            "Tamanyo" => 170596
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of liver damage&#46; Liver damage is initiated by the presentation of a self-antigenic peptide within a major histocompatibility molecule &#40;MHC&#41; by professional antigen presenting cells &#40;APCs&#41;&#46; The presence of appropriate costimulation alongside exposure to various cytokines drives the differentiation of uncommitted CD4 helper T-cells &#40;Th0&#41;&#46; IL-6 and IL-1&#946; lead to differentiation into pathogenic Th17 cells that secrete the proinflammatory cytokine IL-17&#46; Th17 cells promote hepatocyte secretion of IL-6&#44; which in turn further enhances Th17 development&#46; Exposure to IL-12 leads to the differentiation of Th1 cells secreting IFN-&#947;&#44; which induces monocyte &#40;M&#934;&#41; differentiation&#44; activates cytotoxic CD8 T-cells and promotes NK cell killing&#46; IFN-&#947; also increases MHC class I and induces class II expression by hepatocytes&#44; further exacerbating inflammation&#46; Exposure to IL-4 leads to Th2 differentiation&#46; Th2 cells secrete IL-13&#44; IL-4 and IL-10 that enable B cell maturation into plasma cells with the consequent production of autoantibodies&#46; Autoantibodies are in turn involved in antibody-mediated cellular cytotoxicity and complement activation&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Autoimmune hepatitis &#40;AIH&#41; is an immune-mediated inflammatory liver disease characterised serologically by hypergammaglobulinaemia and the presence of non-organ and liver-specific autoantibodies&#44; and histologically by a dense mononuclear cell infiltrate in the portal tract&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">1</span></a> Two types of AIH are recognised&#58; AIH type 1 &#40;AIH-1&#41;&#44; defined by the presence of anti-smooth muscle &#40;SMA&#41; and&#47;or anti-nuclear &#40;ANA&#41; antibodies&#59; and AIH type 2 &#40;AIH-2&#41;&#44; defined by positivity for anti-liver kidney microsomal type 1 &#40;anti-LKM-1&#41; and&#47;or anti-liver cytosol type 1 &#40;anti-LC-1&#41; antibodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">AIH occurs globally&#44; affecting children and adults of all ages and both sexes&#44; although it is more commonly found in females&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">4</span></a> There are no robust epidemiological data on AIH&#46; Available studies show an incidence of 1&#46;5&#8211;2&#46;0 cases per 100&#44;000 people per year in Northern Europe&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">5&#44;6</span></a> Prevalence estimates range from 16&#46;9 cases per 100&#44;000 people in Northern Europe to 35&#46;9 cases per 100&#44;000 people in Alaskan natives&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">5&#44;7</span></a> While AIH-1 affects both children and adults&#44; AIH-2 is mainly a paediatric condition&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">8</span></a> Female predominance is a feature of both types&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The mechanisms responsible for its development include genetic predisposition to autoimmunity through possession of specific human leucocyte antigen &#40;HLA&#41; alleles&#44; immune reactions to liver cell antigens&#44; possibly triggered by a mechanism of molecular mimicry&#44; and impairment in immune regulation&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">AIH has variable modes of presentation&#58; it can present insidiously&#44; with complications of portal hypertension&#44; or with a clinical picture of acute hepatitis&#44; or more rarely with acute liver failure &#40;ALF&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">4&#44;10</span></a> In addition&#44; variant forms of the disease&#44; presenting with concomitant features of primary biliary cholangitis &#40;PBC&#41; or primary sclerosing cholangitis &#40;PSC&#41; are increasingly recognised&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">11</span></a> AIH should be considered during the diagnostic workup of any increase in liver enzyme levels&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">12</span></a> A set of inclusion and exclusion criteria for the diagnosis of AIH have been established&#44; and meanwhile revised&#44; by the International Autoimmune Hepatitis Group &#40;IAIHG&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">13&#44;14</span></a> Immunosuppressive therapy with steroids&#44; with or without azathioprine&#44; remains the mainstay of treatment&#44; and should be instituted as soon as the diagnosis is made&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">1</span></a> Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil &#40;MMF&#41; or calcineurin inhibitors &#40;CNI&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1&#44;4</span></a> Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease&#46; Patients with end-stage liver disease&#44; and those with ALF at diagnosis&#44; will require liver transplantation &#40;LT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">15</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">This review aims to discuss the recent advances in the understanding of AIH pathogenesis&#44; diagnosis&#44; and treatment&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Genetics</span><p id="par0030" class="elsevierStylePara elsevierViewall">AIH is a &#8220;complex trait&#8221; disease that does not follow a Mendelian pattern of inheritance&#46; The mode of inheritance of a complex trait disorder is unknown&#44; though it involves one or more genes&#44; operating alone or in concert&#44; to increase or reduce the risk of the trait and interacting with environmental factors&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Predisposition to AIH is linked to Major Histocompatibility Complex &#40;MHC&#41; class II genes&#44; more specifically to the Human Leucocyte Antigen &#40;HLA&#41;-DR locus&#44; located on the short arm of chromosome 6 &#8211; which are involved in the presentation of antigenic peptides to T-cells&#44; and are therefore implicated in the initiation of an adaptive immune response&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">16&#44;17</span></a> In Europe and North America&#44; the alleles conferring susceptibility to AIH-1 are <span class="elsevierStyleItalic">DRB1</span>&#42;<span class="elsevierStyleItalic">0301</span> and <span class="elsevierStyleItalic">DRB1</span>&#42;<span class="elsevierStyleItalic">0401</span>&#44; which encode the HLA DR3 and DR4 antigens&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">18</span></a> The first genome wide association study &#40;GWAS&#41; in AIH performed in Dutch AIH-1 patients and replicated in a cohort of German patients confirmed the HLA association&#44; <span class="elsevierStyleItalic">DRB1&#42;0301</span> and <span class="elsevierStyleItalic">DRB1&#42;0401</span> being primary and secondary susceptibility genotypes&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">19</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Susceptibility to AIH-2 is conferred by the possession of HLA DR7 &#40;<span class="elsevierStyleItalic">DRB1&#42;0701</span>&#41; and DR3 &#40;<span class="elsevierStyleItalic">DRB1&#42;0301</span>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">20</span></a> and those patients who are positive for <span class="elsevierStyleItalic">DRB1&#42;0701</span> have a more aggressive form of the disease with worse overall prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">21</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">A number of genes outside the MHC have also been linked to AIH susceptibility&#46; For example&#44; a substitution from A &#40;adenine&#41; to G &#40;guanine&#41; in exon 1 of the <span class="elsevierStyleItalic">CTLA-4</span> gene confers susceptibility to AIH-1 in Caucasians from North America&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">22</span></a> Additionally&#44; a polymorphism at position 308 in the tumour necrosis factor &#945; &#40;<span class="elsevierStyleItalic">TNFA</span>&#41; gene promoter is particularly frequent in patients with AIH-1 from Europe and North America&#44; and is associated with a poorer response to steroids&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">23</span></a> A <span class="elsevierStyleItalic">FAS</span> gene promoter polymorphism at position 670 also enhances susceptibility to AIH and influences progression to a more aggressive form characterised by the early development of cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">24</span></a> Polymorphisms in the vitamin D receptor can also be predisposing factors to the development of autoimmune liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">25</span></a> The first AIH GWAS reported that AIH-1 is associated with variants of <span class="elsevierStyleItalic">CARD10</span> and <span class="elsevierStyleItalic">SH2B3</span> genes&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">A form of AIH resembling AIH-2 has been described in some 20&#37; of patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy &#40;APECED&#41;&#44; an autosomal recessive condition due to homozygous mutations in the <span class="elsevierStyleItalic">AIRE1</span> gene and characterised by a variety of organ-specific autoimmune diseases&#46; Additionally&#44; <span class="elsevierStyleItalic">AIRE1</span> mutations have been reported in three children with severe AIH-2 with extra-hepatic autoimmune manifestations&#44; as well as in four children with AIH-1 with a family history of autoimmune disease&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Potential triggers</span><p id="par0055" class="elsevierStylePara elsevierViewall">In patients with increased genetic susceptibility&#44; a potential trigger for AIH development is an immune response to exogenous pathogens that cross-reacts with structurally similar liver autoantigens&#44; a phenomenon known as molecular mimicry&#46; The strongest support for this model is in the context of viral hepatitis&#44; where autoimmunity is a common feature during chronic infection&#46; Indeed&#44; 50&#37; of patients with chronic hepatitis B or C &#40;HCV&#41; eventually develop autoantibody seropositivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">27&#44;28</span></a> In chronic HCV&#44; some 10&#37; of patients are anti-LKM-1 positive&#44; the autoantibody titre correlating with disease severity and being associated with adverse reactions to interferon treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">29</span></a> The molecular target of anti-LKM-1 is cytochrome P4502D6 &#40;CYP2D6&#41; and within anti-LKM-1 positive chronic HCV patients&#44; reactivity against the key autoantigenic epitope CYP2D6<span class="elsevierStyleInf">193&#8211;212</span> can be seen in 50&#37; of cases&#46; There is direct evidence of cross-reactivity between anti-LKM-1 and antibodies directed against homologous regions of HCV &#40;NS5B HCV<span class="elsevierStyleInf">2985&#8211;2990</span>&#41; and cytomegalovirus &#40;exon CMV<span class="elsevierStyleInf">130&#8211;135</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">30</span></a> There is also sequence homology between CYP2D6<span class="elsevierStyleInf">254&#8211;271</span> and amino acids present in the E1 HCV and the IE1 75 of the Herpes Simplex Virus 1 &#40;HSV-1&#41;&#46; As anti-LKM-1 antibodies cross-react with homologous regions of CYP2D6&#44; HCV&#44; CMV and HSV&#44; a &#8220;multi-hit&#8221; mechanism for the generation of autoantibody seropositivity and possibly for the development AIH-2 can be envisaged&#46; In this model&#44; on a background of genetic susceptibility&#44; sequential exposure to common viral pathogens favours the development of cross-reactive T cells&#46; It is therefore conceivable that as yet unidentified single or repeated viral infections could contribute to the initiation of the autoimmune attack in AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">9</span></a> One case-report describes a 10-year-old girl who acquired HCV infection following liver transplant for end-stage liver disease caused by &#945;1-anti-trypsin deficiency&#46; Two weeks after HCV infection IgM anti-LKM-1 antibodies appeared&#44; followed by IgG anti-LKM-1 antibodies&#46; This finding is suggestive of HCV as a trigger of a primary anti-LKM-1&#47;anti-CYP2D6 autoimmune response&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">31</span></a> Interestingly&#44; 10 years later&#44; the patient developed florid AIH type 2&#44; which responded satisfactorily to immunosuppressive treatment&#59; by this time there was no trace of the previous HCV infection &#40;unpublished data&#41;&#46; Moreover&#44; in a recent report&#44; up to 8&#46;7&#37; of patients with autoimmune disease&#44; including cryoglobulinaemia&#44; Hashimoto thyroiditis and inflammatory bowel disease &#40;IBD&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">32</span></a> had serum HCV antibody-positivity&#44; linking HCV infection with a breakdown of immune tolerance&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The antibiotics nitrofurantoin and minocycline&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">33</span></a> as well as the statins and the anti-TNF agents adalimumab and infliximab have been reported as non-viral environmental triggers of AIH&#46; However&#44; because drug-induced liver injury with features of AIH does not usually require long-term immunosuppressive treatment&#44; these triggers should be considered independently&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">33</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Though the evidence for molecular mimicry is convincing&#44; a universal trigger has not yet been discovered&#46; Moreover&#44; other non-mutually exclusive mechanisms that may contribute to the initiation and perpetuation of AIH&#44; such as epitope spreading or exposure to previously hidden autoantigens during hepatocellular injury&#44; should also be explored&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Effector immune mechanisms</span><p id="par0070" class="elsevierStylePara elsevierViewall">The dense infiltrate of lymphocytes&#44; plasma cells&#44; and macrophages characteristic of the histological picture of AIH suggests that an autoaggressive cellular immune attack is the basis of this condition&#46; Over the past four decades&#44; intense investigations have begun to uncover the mechanisms by which this inflammatory infiltration mediates liver damage&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The predominant population within the cellular infiltrate is composed of &#945;&#47;&#946; T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">34</span></a> Amongst these cells&#44; the majority are CD4<span class="elsevierStyleSup">pos</span> T helper &#40;Th&#41; cells&#44; with a sizable minority of cytotoxic CD8<span class="elsevierStyleSup">pos</span> T-cells&#46; Immunohistochemically&#44; lymphocytes of a non-T-cell lineage are seen relatively rarely&#44; and include natural killer &#40;NK&#41;-cells&#44; macrophages&#44; B-cells and plasma cells&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">34</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Regardless of the nature of the initial trigger&#44; the immune response in AIH is believed to stem from the recognition by na&#239;ve CD4<span class="elsevierStyleSup">pos</span> lymphocytes of a self-antigenic peptide contained within an HLA class II molecule on an antigen presenting cell &#40;APC&#41;&#46; In the presence of the appropriate co-stimulatory signals &#8211; provided by the interaction of CD28 expressed by the na&#239;ve CD4<span class="elsevierStyleSup">pos</span> T-cell and CD80&#47;CD86 expressed by the APC &#8211; the na&#239;ve cell differentiates into an effector cell subtype depending on the cytokines present in the microenvironment and the nature of the antigen&#46; The liver is home to several specialised APC populations&#44; and antigen presentation can occur <span class="elsevierStyleItalic">in situ</span> without the need of trafficking to the regional lymphoid tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">35</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The effector T-cell subsets are largely defined by the cytokines they produce&#59; Th1-cells produce IL-2 as well as the main mediator of the tissue damage in AIH&#44; IFN-&#947;&#46; IFN-&#947; stimulates CD8<span class="elsevierStyleSup">pos</span> T-cells&#44; enhances the expression of HLA class I molecules by hepatocytes&#44; while inducing the aberrant expression of HLA class II molecules and activating monocytes&#47;macrophages&#44; which in turn release IL-1 and tumour necrosis factor alpha &#40;TNF-&#945;&#41;&#46; On the other hand&#44; Th2-cells produce IL-4&#44; IL-10 and IL-13&#44; cytokines that induce the maturation of B-cells into plasma cells&#44; with consequent production of autoantibodies&#46; Autoantibodies themselves can contribute to liver damage by triggering antibody-mediated cellular cytotoxicity and complement activation&#46; Th17-cells produce IL-17&#44; IL-22&#44; and TNF-&#945;&#44;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">9</span></a> while inducing hepatocytes to secrete IL-6&#44; which further enhances Th17 activation&#46; Although Th17-cells have been shown to be elevated in the circulation and liver of AIH patients&#44; their precise contribution to the pathogenesis of AIH is unknown and currently under investigation&#46; Mechanisms leading to and&#47;or perpetuating the autoimmune liver attack in AIH are depicted in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Regulatory immune mechanisms</span><p id="par0090" class="elsevierStylePara elsevierViewall">The development of autoimmune diseases is favoured by the breakdown of self-tolerance mechanisms that&#44; in health&#44; prevent the majority of autoreactive T cell clones from entering the periphery&#46; As circulating autoreactive T cells are&#44; however&#44; present in health&#44; there are both intrinsic and extrinsic peripheral tolerance mechanisms to limit autoimmune tissue damage&#46; Key to this is the dominant form of immune suppression exerted by professional regulatory T cells &#40;Tregs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">36</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Several studies have reported that regulatory T-cells are numerically defective in patients with AIH&#46; A lower circulating frequency of CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">pos</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">37&#44;38</span></a> CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">high</span><a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">39</span></a> or CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">high</span>CD127<span class="elsevierStyleSup">neg</span><a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">40</span></a> Tregs has been reported in AIH patients compared to healthy subjects&#44; and this defect is associated with lower FOXP3 expression&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">39&#44;41</span></a> Moreover&#44; during immunosuppressive therapy&#44; the circulating Treg frequency has been shown to increase to some extent&#44; although not reaching the levels seen in health&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">37&#44;39</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">When co-cultured with CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">neg</span> cells&#44; magnetically isolated CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">pos</span> Tregs from AIH patients have impaired ability to generate an anti-inflammatory cytokine milieu rich in TGF-&#946;&#44; suggesting that they are ineffective promoters of linked-suppression&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">41</span></a> Magnetically isolated CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">pos</span> Tregs from AIH patients have impaired ability to suppress the proliferation of CD8<span class="elsevierStyleSup">pos38</span> and of CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">neg</span><a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">39&#44;42</span></a> cell populations compared to normal controls&#46; CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">pos</span> Tregs from AIH patients are also ineffective suppressors of IFN-&#947; production by CD8 T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">38</span></a> Additionally&#44; Tregs from AIH patients&#44; but not healthy subjects&#44; effectively enhance the activation of pro-inflammatory monocytes&#44; by elevating the level of spontaneous migration and by increasing the production of TNF-&#945; and the expression of TLR-4&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">43</span></a> Magnetically isolated CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">pos</span>CD127<span class="elsevierStyleSup">neg</span> Tregs from AIH patients are also less able to suppress CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">neg</span> cell proliferation in AIH compared to health&#44;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">42</span></a> although this defect has not been observed in flow cytometrically isolated CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">high</span>CD127<span class="elsevierStyleSup">neg</span> cells&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">44</span></a> Tregs from AIH patients express lower levels of galectin-9 compared to health&#44; and this defect is mirrored by reduced expression of the galectin-9 ligand&#44; T-cell immunoglobulin and mucin domain-3 &#40;TIM-3&#41;&#44; by CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">neg</span> cells&#44; suggesting that AIH may also be associated with effector cell resistance to Treg control&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">42</span></a> We have recently observed that in AIH there is a lower frequency of CD39<span class="elsevierStyleSup">pos</span> Tregs&#44; these cells failing to hydrolyse adequately pro-inflammatory nucleotides and to suppress the production of IL-17 by effector CD4 T-cells&#46; CD39<span class="elsevierStyleSup">pos</span> Tregs from AIH patients are also unstable upon pro-inflammatory challenge&#44;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">45</span></a> suggesting that defective immuno-regulation in AIH might result not only from reduced Treg number and function but also from increased conversion of Tregs into effector cells&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical presentation</span><p id="par0105" class="elsevierStylePara elsevierViewall">AIH can present with diverse clinical manifestations&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">46</span></a> There are basically three patterns of disease presentation&#58; an acute onset&#44; characterised by non-specific symptoms such as malaise&#44; nausea&#47;vomiting&#44; anorexia and abdominal pain&#44; followed by jaundice&#44; dark urine and pale stools&#59; an insidious onset&#44; with an illness characterised by progressive fatigue&#44; relapsing jaundice&#44; headache&#44; anorexia&#44; amenorrhoea and weight loss&#59; and finally a presentation with complications of portal hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">17</span></a> The mode of presentation of AIH is therefore variable&#44; and the disease should be suspected and excluded in all patients complaining of symptoms and signs of prolonged or severe liver disease&#46; Some patients&#44; however&#44; are completely asymptomatic and are diagnosed after incidental discovery of abnormal liver function tests&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Histological evidence of cirrhosis is described in at least 30&#37; of patients&#44; regardless of the mode of presentation&#44; suggesting that subclinical disease has been present for some time&#46; Indeed&#44; advanced fibrosis or cirrhosis can often be found in patients presenting acutely&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">10</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">AIH can develop occasionally during pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">47</span></a> Post-partum development of AIH and exacerbation of existing disease in patients whose condition improved during pregnancy has also been described&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">48</span></a> Approximately 40&#37; of AIH patients have a family history of autoimmune disease and at least 20&#37; have concomitant autoimmune diseases or will develop them during follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">49</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The complications associated with AIH mirror those found in other progressive liver diseases&#46; Thus&#44; chronic hepatitis can progress to cirrhosis and to hepatocellular carcinoma &#40;HCC&#41; despite the use of immunosuppressive therapy&#46; HCC is relatively rare in AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">10</span></a> Yeoman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">50</span></a> reported 15 cases of HCC&#44; all with underlying cirrhosis&#44; among 243 patients with AIH who were followed up for 16 years&#46; Wong et al&#46; reported 6 cases of HCC&#44; also all with underlying cirrhosis&#44; among 322 patients followed up for 10 years&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">51</span></a> Surveillance for HCC is therefore warranted&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Diagnosis</span><p id="par0125" class="elsevierStylePara elsevierViewall">The diagnosis of AIH is based on the presence of elevated serum transaminase and IgG levels&#44; autoantibody seropositivity and histological evidence of interface hepatitis&#46; This tenet has been factored into the IAIHG diagnostic criteria for AIH&#44;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">13&#44;14</span></a> which were originally developed for use in the research setting&#46; This scoring system incorporates a number of positive and negative scores &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; enabling the researcher to grade clinical&#44; laboratory and histological features of AIH&#46; The score has also proved useful in the clinical context when assessing patients with few or atypical features of the disease&#46; The distinction between a definite and probable diagnosis of AIH predominantly relates to the extent of the increase in serum gamma-globulin&#47;IgG levels or autoantibody titre&#44; as well as exposure to alcohol&#44; hepatotoxic medication or infection&#46; Laboratory and histological features associated with cholestasis carry a negative score&#46; In the rare instances where conventional autoantibodies are not detected&#44; the presence of anti-asialoglycoprotein receptor &#40;anti-ASGPR&#41;&#44; anti-soluble liver antigen&#47;liver pancreas &#40;anti-SLA&#47;LP&#41; or atypical perinuclear anti-neutrophil cytoplasmic antibodies &#40;atypical pANCA&#44; currently better referred to as pANNA&#41; weigh towards a probable diagnosis of AIH&#46; The scoring system also incorporates response to corticosteroids&#44; with a definite diagnosis before steroid treatment requiring a score higher than 15&#44; and a definite diagnosis after treatment institution requiring a score greater than 17&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">14</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">It is important to note that because healthy children are very rarely autoantibody positive&#44; in the paediatric setting&#44; lower autoantibody titres contribute to the diagnoses of AIH&#46; These titres are 1&#58;20 for ANA and SMA and 1&#58;10 for anti-LKM-1&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">2&#44;12</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">A simplified scoring system &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; for use in clinical practice&#44; has recently been proposed by the IAIHG&#46; This system is based on only four criteria&#58; positivity for autoantibodies&#44; elevated IgG levels&#44; histological evidence of interface hepatitis and the exclusion of viral hepatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">52</span></a> Neither scoring system is immediately applicable to the diagnosis of the juvenile form of AIH&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Autoantibodies</span><p id="par0140" class="elsevierStylePara elsevierViewall">Autoantibody seropositivity is a key criterion for the diagnosis and classification of AIH&#46; The IAIHG includes positivity for ANA&#44; SMA&#44; anti-LKM-1&#44; anti-LC-1&#44; anti-SLA&#47;LP and ANCAs autoantibodies in their original and revised diagnostic scoring systems&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">13&#44;14</span></a></p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Anti-nuclear antibodies</span><p id="par0145" class="elsevierStylePara elsevierViewall">The target antigens of ANA in AIH are heterogeneous and incompletely defined&#46; Though ANA have been shown to react with single- and double-stranded deoxyribonucleic acid &#40;DNA&#41;&#44; small nuclear ribonucleoproteins &#40;sn-RNPs&#41;&#44; centromeres&#44; histones&#44; chromatin and cyclin A&#44; all these reactivities can be negative despite positivity of ANA by immunofluorescence &#40;IFL&#41;&#46; A better definition of the ANA target antigens will be followed by the development of new techniques using recombinant nuclear antigens and immunoassays&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">3</span></a> In terms of IFL&#44; ANA gives a readily detectable nuclear staining of kidney&#44; stomach and liver sections&#46; In AIH&#44; a homogenous pattern of staining is commonly observed&#44; particularly in the liver&#44; with coarsely or finely speckled patterns visualised less frequently&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">2</span></a> A clearer definition of the nuclear pattern should be sought using human epithelial type 2 &#40;HEp2&#41; cells&#44; which are characterised by prominent nuclei&#46; These&#44; however&#44; should not be used for screening purposes due to a high positivity rate in healthy subjects&#46; A clinically relevant titre of ANA in AIH is considered 1&#47;40 in adults and 1&#47;20 in children&#44; in whom titres correlate with disease activity&#46; ANA can also be identified in up to 52&#37; of patients with PBC&#46; However&#44; in contrast to AIH&#44; in which no disease-specific ANA has been reported&#44; the PBC-specific ANA showing multiple nuclear dot or rim-like membranous patterns are highly diagnostic for this condition&#46; They are recognised by IFL when HEp-2 or HeLa cells are used as substrate&#46; Of note&#44; ANA are present in other autoimmune disorders&#44; such as systemic lupus erythematosus&#44; Sj&#246;gren syndrome and systemic sclerosis&#44; as well as non-autoimmune conditions&#44; like viral hepatitis&#44; drug-induced hepatitis&#44; and alcoholic and non-alcoholic fatty liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">53</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Anti-smooth muscle antibodies</span><p id="par0150" class="elsevierStylePara elsevierViewall">The first targets of AIH-specific SMA to be recognised &#8211; following preincubation of serum with thrombosthenin &#40;platelet actomyosin&#41; or purified thrombosthenin-A &#40;the actin fraction of thrombosthenin&#41; &#8211; were constituents of actin&#46; Later&#44; SMA were also shown to be directed against other components of the cytoskeleton such as tubulin&#44; vimentin&#44; desmin&#44; and skeletin&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">54</span></a> SMA IFL patterns can be visualised on kidney&#44; stomach and liver sections&#44; where they stain the artery walls&#46; In the stomach substrate they also bind the muscularis mucosa and the lamina propria&#46; In the kidney&#44; the SMA typical of AIH stains the smooth muscle of the vessels&#44; glomeruli and tubules &#40;VGT pattern&#41;&#46; The VG and VGT IFL patterns are much more specific for AIH than the isolated V pattern&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">2</span></a> The AIH-1-specific target of SMA responsible for the VGT pattern remains elusive&#46; However&#44; when vinblastine-arrested cultured fibroblasts were used as a substrate&#44; AIH-1-specific SMA VGT-positive sera predominantly stained the microfilaments&#46; In contrast&#44; non-AIH-1 SMA V-positive sera reacted with non-actin-containing intermediate filaments&#46; Several studies point to actin in its filamentous form as the target of the SMA giving the VGT pattern&#46; However&#44; while this pattern is highly specific for AIH-1&#44; some 20&#37; of SMA-positive AIH patients do not have it&#46; Moreover&#44; when molecular assays using purified F-actin are employed&#44; some AIH VGT positive cases are negative&#44; while anti-F-actin positivity is reported in diseases distinct from AIH-1&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">2&#44;54</span></a> SMA titres by IFL are usually equal or above 1&#47;80 in AIH&#44; although very young patients may have titres as low as 1&#47;20&#46; SMA giving the V pattern have been reported in advanced liver disease of other aetiologies&#44; infectious diseases and rheumatic disorders&#59; hence&#44; like ANA&#44; these antibodies are not specific for AIH&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Anti-liver-kidney-microsomal type 1 antibodies</span><p id="par0155" class="elsevierStylePara elsevierViewall">The molecular target of anti-LKM-1&#44; the hallmark of AIH-2&#44; is CYP2D6&#46; This autoantibody stains the hepatocellular cytoplasm and the P3 portion of the renal tubules&#46; Some confusion can occur between the IFL patterns of anti-LKM-1 and AMA because both autoantibodies stain the liver as well as the kidney&#46; However&#44; AMA stain the liver more faintly than anti-LKM-1&#44; and mark the renal tubules more diffusely&#44; while accentuating the mitochondrial-reach distal tubules&#46; Importantly&#44; AMA stain gastric parietal cells while anti-LKM-1 do not&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">2&#44;54</span></a> Since the molecular targets of anti-LKM-1 &#8211; CYP2D6 &#8211; and of AMA &#8211; enzymes of the 2-oxo-acid dehydrogenase complexes &#8211; are known&#44; immune-assays based on the use of recombinant or purified antigens have been developed&#46; Commercially available enzyme-linked immunosorbent assays &#40;ELISAs&#41; accurately detect anti-LKM-1&#44; at least in the context of AIH-2&#44; and detect AMA reasonably accurately&#46; These assays can therefore be utilised when there is doubt about IFL patterns&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">2</span></a> A clinically relevant anti-LKM-1 titre is considered equal or above 1&#47;40 in adults and 1&#47;10 in patients under 18 years of age&#59; the titre of this autoantibody is associated with disease activity&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">2</span></a> Interestingly&#44; as mentioned above&#44; anti-LKM-1 are also detected in some 5&#8211;10&#37; of patients with chronic hepatitis C virus infection&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Anti-liver cytosol type 1 antibodies</span><p id="par0160" class="elsevierStylePara elsevierViewall">Anti-LC-1 react with the folate-metabolising enzyme formiminotransferase cyclodeaminase &#40;FTCD&#41;&#44; which is found at high levels within the liver&#46; This autoantibody stains the liver cell cytoplasm with relative sparing of the centrilobular area&#46; Importantly&#44; anti-LC-1 frequently occurs together with anti-LKM-1&#44; which obscure the anti-LC-1 staining&#46; Thus&#44; in the presence of anti-LKM-1&#44; anti-LC-1 can be detected by the use of liver cytosol in double-dimension immunodiffusion or counterimmunoelectrophoresis&#44; with the use of a positive reference serum&#44; or by ELISA detecting reactivity to its target FTCD&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">2</span></a> This autoantibody was originally described&#44; alone or in combination with anti-LKM-1&#44; to define a clinical entity indistinguishable from AIH-2&#46; Although anti-LC-1 was subsequently detected also in patients positive for serological markers associated with AIH-1&#44; and in patients with chronic HCV infection&#44; anti-LC-1 in isolation scores positively towards a diagnosis of AIH-2&#44; allowing prompt initiation of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">14</span></a> The presence and titre of anti-LC-1 antibodies correlate with disease activity&#44; and represent a potentially useful marker of residual hepatocellular inflammation in AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Anti-soluble liver antigen&#47;liver-pancreas antibodies</span><p id="par0165" class="elsevierStylePara elsevierViewall">Anti-SLA and anti-LP were originally believed to be distinct antibodies but they were subsequently shown to bind the same target&#44; a UGA tRNA suppressor-associated antigenic protein &#40;tRNP<span class="elsevierStyleSup">&#40;ser&#41;sec</span>&#41;&#44; more precisely O-Phosphoseryl-tRNA&#58;selenocysteinyl-tRNA synthase &#40;SepSecS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">55</span></a> They can&#44; therefore&#44; be considered one and the same&#46; Since anti-SLA&#47;LP cannot be detected by IFL&#44; this antibody is detected by radioimmunoassay and ELISA&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">2</span></a> Anti-SLA&#47;LP have been reported in the absence of seropositivity for conventional autoantibodies&#44; suggesting the existence of a third group of AIH patients&#46; However&#44; these early reports used a particularly high cut-off point for conventional autoantibody detection &#8211; higher than those currently used for the diagnosis of AIH &#8211; therefore the nosological entity of AIH-3 has not been accepted by the IAIHG&#46; Though anti-SLA have been reported in occasional HCV infected anti-LKM-1 positive patients&#44; their presence is highly specific for the diagnosis of AIH&#44; and its detection at the time of diagnosis identifies patients with a more severe disease and a worse prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Anti-neutrophil cytoplasmic antibodies</span><p id="par0170" class="elsevierStylePara elsevierViewall">ANCAs react to constituents of the cytoplasm of neutrophils to give a perinuclear &#40;pANCA&#41; or cytoplasmic &#40;cANCA&#41; IFL pattern&#46; The predominant target of c-ANCA is proteinase 3 and this autoantibody is frequently detected in Wegener granulomatosis&#46; On the other hand&#44; p-ANCA binds myeloperoxidase and is most commonly found in microscopic polyangiitis&#46; Similar to what observed in PSC and IBD&#44; pANCAs are frequently detected in AIH-1&#44; although the IFL pattern is somewhat atypical&#46; Staining is associated with peripheral nuclear membrane components&#44; hence the name of peripheral anti-nuclear neutrophil antibody &#40;pANNA&#41;&#46; The proposed target of pANNA is a 50<span class="elsevierStyleHsp" style=""></span>kDa neutrophil-specific nuclear protein belonging to the nuclear pore complex&#44; potentially the tubulin &#946; chain 5&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">54</span></a> Positivity for pANNA is very rare in AIH-2&#46; In AIH-1&#44; however&#44; its detection can aid in the diagnosis&#44; particularly when other autoantibodies are absent&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Histology</span><p id="par0175" class="elsevierStylePara elsevierViewall">Since transaminases and IgG levels do not reflect the extent of histological inflammatory activity&#44; or the presence or absence of cirrhosis&#44; liver biopsy is mandatory not only to confirm the diagnosis but also to evaluate the severity of liver damage&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Hepatitis at the portal-parenchymal interface&#44; known as interface hepatitis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; is typical&#44; but is not exclusively observed in AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">56</span></a> This picture is characterised by a lymphoplasmacytic infiltrate crossing the limiting plate and invading the liver parenchyma&#46; Lymphocytes&#44; plasma cells and histiocytes surround individual dying hepatocytes at the portal-parenchymal interface and in the lobule&#46; Though plasma cells are usually abundant at the interface and throughout the lobule&#44; their presence in low number does not exclude the diagnosis of AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">17</span></a> Other lesions that may be present include hepatocyte swelling and pycnotic necrosis&#46; Fibrosis is present in all but the mildest forms of the disease&#46; In contrast to patients with an insidious course&#44; those presenting with acute liver failure show tissue damage predominantly in the centrilobular area&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">57</span></a> However&#44; many patients presenting with fulminant hepatic failure tend to have massive necrosis and multilobular collapse&#59; importantly&#44; they have less fibrosis than those presenting with a more insidious course&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">10</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">Despite the fact that sampling variation may occur in needle biopsy specimens&#44; especially in the presence of cirrhosis&#44; the severity of the histological appearance is usually of prognostic value&#46; However&#44; even patients with cirrhosis at presentation respond well to immunosuppressive treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Treatment</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Standard treatment</span><p id="par0190" class="elsevierStylePara elsevierViewall">In the early 70s&#44; three randomised clinical trials in adults with AIH provided the basis for the current immunosuppressive regimens&#44; collectively suggesting that treatment with prednisolone improves liver function tests&#44; ameliorates symptoms and prolongs survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0690"><span class="elsevierStyleSup">59&#8211;61</span></a> Although azathioprine was not able to induce remission when used on its own&#44; it did allow the maintenance of remission in association with a significantly reduced dose of steroids&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">62</span></a> Initial treatment with prednisone &#40;or prednisolone&#41;&#44; with or without azathioprine&#44; should be instituted as soon as the diagnosis is made&#44; and not delayed for 6 months as suggested in the early studies&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">63</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">The initial approach to therapy depends upon the histologic findings&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">10</span></a> Transaminase and IgG levels do not always correlate with histological damage and consequently provide limited help in respect to treatment initiation&#46; Prompt treatment is indicated in patients with aggressive disease&#44; usually children or young adults&#44; and in any patient with evidence of interface hepatitis&#44; with or without fibrosis or cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">4</span></a> In older patients with isolated portal inflammation &#40;without interface hepatitis&#41;&#44; institution of therapy is guided by AST and IgG levels&#44; and&#47;or by the presence of symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">46</span></a> The therapeutic approach in patients with a milder form of the disease &#8211; who may be asymptomatic or pauci-symptomatic&#44; and are detected incidentally after discovery of abnormal liver function tests &#8211; is less clear&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">64</span></a> In these cases&#44; the benefit of therapy is undefined and may be so low that the risk of corticosteroid side effects might outweigh its possible benefits&#59; this is particularly relevant when starting therapy in post-menopausal women and elderly patients&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">65</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Although some patients may remain in remission after drug treatment is withdrawn&#44; most require long-term maintenance therapy&#46; Despite the absence of firm guidelines&#44; it is cautious not to attempt withdrawal of immunosuppression within 2 years of diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">4</span></a> During withdrawal attempts&#44; it is essential to closely monitor the liver function tests&#44; as relapse may be severe and even fatal&#46; Patients who have successfully stopped immunosuppression should undergo long-term follow-up&#44; as relapse can occur even 10 years later&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">64</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Alternative treatments</span><p id="par0205" class="elsevierStylePara elsevierViewall">In the group of patients that show failure to standard therapy and intolerance or low compliance to standard immunosuppression&#44; alternative immunosuppressive treatments have been proposed&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">66</span></a> Decisions regarding the use of such regimens have to be based&#44; however&#44; on the scarce data available&#44; mainly on the basis of small series or case reports&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Mycophenolate mofetil &#40;MMF&#41; is a purine antagonist that selectively inhibits proliferation of activated lymphocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">67</span></a> It has been reported to be effective in AIH patients intolerant to azathioprine&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">64</span></a> Therefore&#44; in patients for whom standard immunosuppression fails to induce stable remission&#44; or who are intolerant to azathioprine&#44; MMF&#44; together with prednisolone&#44; is currently the treatment of choice&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">4</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Calcineurin inhibitors&#44; cyclosporine and tacrolimus&#44; have been used as a rescue treatment for difficult-to-treat cases of AIH&#46; As no large study in this subgroup of patients has been published&#44; they should be used with caution&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">64</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Anti-TNF-&#945; agents&#44; such as infliximab&#44; are commonly used to treat immune-mediated diseases such as rheumatoid arthritis&#44; psoriasis and IBD&#46; There is anecdotal evidence that infliximab is efficacious in the management of difficult-to-treat cases of AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">68</span></a> In the largest published retrospective series&#44; treatment with infliximab led to a decrease in transaminase and IgG levels in 11 difficult-to-treat adult patients with AIH&#44; but infectious complications occurred in seven of them&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">68</span></a> Moreover&#44; and worryingly&#44; infliximab therapy for other diseases has been associated with the induction of severe <span class="elsevierStyleItalic">de novo</span> AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">69</span></a> Anecdotal evidence also suggests some benefit with the use of the anti B-cell monoclonal antibody rituximab in difficult-to-treat patients&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">70</span></a> However&#44; the occurrence of severe infections is an important risk-factor associated with these biological treatments&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Budesonide is a corticosteroid with very high affinity for the glucocorticoid receptor and high first pass liver metabolism&#59; hence&#44; it is presently receiving considerable attention as an alternative to prednisone or prednisolone as primary treatment of AIH&#46; Although initial reports were somewhat contradictory&#44; a recent large European study found that a combination of budesonide and azathioprine could induce remission in 60&#37; of non-cirrhotic patients&#44; while medium-dose standard steroids and azathioprine could only induce remission in 39&#37; of patients&#46; The budesonide group had also fewer adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">71</span></a> It should be noted&#44; however&#44; that this reported rate of remission is much lower than that seen in both adults and children &#40;&#8764;80&#37;&#41; when a higher starting dose of prednisone is used&#46; Moreover&#44; because budesonide cannot be used in cirrhotic patients &#8211; representing at least a third of the AIH population &#8211; its clinical utility has limitations&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">72</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Liver transplantation</span><p id="par0230" class="elsevierStylePara elsevierViewall">AIH accounts for 2&#8211;3&#37; of paediatric and 4&#8211;6&#37; of adult liver transplants &#40;LT&#41; performed in Europe and the United States&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">4</span></a> LT is indicated for AIH patients who present with acute liver failure and do not respond to immunosuppressive treatment&#44; or with end-stage chronic liver disease and for those with hepatocellular carcinoma that meet the transplant criteria&#46;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">73&#44;74</span></a> Although patients with a chronic presentation of AIH typically respond well to immunosuppressive treatment&#44; approximately 10&#37; will eventually require LT&#46; Patients who fail to reach remission after 4 years of therapy are the most common candidates for LT&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">75</span></a> The indications for LT for end-stage chronic AIH are similar to those for other end-stage liver diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">1&#44;15</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Novel treatment approaches</span><p id="par0235" class="elsevierStylePara elsevierViewall">Given that loss of immunoregulation is central to the pathogenesis of AIH&#44; Treg cell therapy &#8211; aimed at reconstituting self-tolerance &#8211; is a highly promising candidate for alternative and effective immune intervention in AIH&#46; To date&#44; this approach has been hindered by the limited ability of Tregs to expand and by their propensity to apoptosis&#46; However&#44; because corticosteroid therapy can partially restore the potency of the Treg population&#44; Tregs in AIH do have the potential to expand and regain their function&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">37&#44;38</span></a> Using a polyclonal T cell stimulation strategy &#40;that engages the T cell receptor <span class="elsevierStyleItalic">via</span> CD3 and the co-stimulatory molecule CD28&#44; while providing exogenous IL-2&#44; a key cytokine for Treg survival and growth&#41;&#44; Tregs can be expanded from circulating CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">pos</span> Tregs&#44; and also generated <span class="elsevierStyleItalic">de novo</span> from non-regulatory CD4<span class="elsevierStyleSup">pos</span>CD25<span class="elsevierStyleSup">neg</span> T cells in both healthy subjects and patients with AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">76</span></a> Interestingly&#44; expanded Tregs express higher levels of FOXP3 and are more effective suppressors compared to freshly isolated Tregs&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">76</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Although FOXP3 is the most specific marker of human Tregs&#44; its intracellular location limits its use in the laboratory setting&#46; In addition to the lack of specific cell-surface markers for Tregs&#44; the human CD4<span class="elsevierStyleSup">pos</span> CD25<span class="elsevierStyleSup">high</span> population contains a proportion of activated effector T cells&#46; Furthermore&#44; Tregs and effector Th17 cells share a common progenitor&#44; though their developmental pathways differ&#46; Since <span class="elsevierStyleItalic">de novo</span> generation of Tregs relies on strong T cell receptor &#40;TCR&#41; signalling&#44; the risk of concomitant expansion of effector Th17 cells needs to be addressed when considering Treg therapy for AIH&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">9</span></a> The physical removal of IL17<span class="elsevierStyleSup">pos</span> cells&#44; or the use of small interfering RNAs specific for the Th17-associated transcription factor RORC&#44; leads to elevated FOXP3 expression and increased suppressive function by expanded Tregs from AIH patients&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">77</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">The potential for successful Treg therapy is particularly strong in AIH-2&#44; given that the antigenic regions &#40;CYP2D6<span class="elsevierStyleInf">217&#8211;260</span> and CYP2D6<span class="elsevierStyleInf">305&#8211;348</span>&#41;&#44; targeted by B&#44; CD4 and CD8 T cells&#44; are well characterised&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">78</span></a> Several lines of evidence demonstrate that autoantigen-specific Tregs suppress more efficiently than their non-antigen-specific counterparts&#46; In this regard&#44; antigen-specific Tregs generated from AIH-2 patients are able to suppress CD4 and CD8 T cell responses more potently than polyclonally expanded T-regs&#46; The most efficient suppression of autoreactive T cells has been achieved by Treg co-culture with semi-mature dendritic cells loaded with the CYP2D6 peptides&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">79</span></a></p></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0250" class="elsevierStylePara elsevierViewall">R&#46; Liberal&#44; D&#46; Vergani and G&#46; Mieli-Vergani are supported by grants from the Rosetree Foundation&#44; UK&#44; and PSC Partners Seeking a Cure&#44; USA&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:16 [
        0 => array:3 [
          "identificador" => "xres734853"
          "titulo" => "Abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0005"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec738661"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres734852"
          "titulo" => "Resumen"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0010"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec738660"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Genetics"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Potential triggers"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Effector immune mechanisms"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Regulatory immune mechanisms"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Clinical presentation"
        ]
        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Diagnosis"
        ]
        11 => array:3 [
          "identificador" => "sec0040"
          "titulo" => "Autoantibodies"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Anti-nuclear antibodies"
            ]
            1 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Anti-smooth muscle antibodies"
            ]
            2 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Anti-liver-kidney-microsomal type 1 antibodies"
            ]
            3 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Anti-liver cytosol type 1 antibodies"
            ]
            4 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Anti-soluble liver antigen&#47;liver-pancreas antibodies"
            ]
            5 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Anti-neutrophil cytoplasmic antibodies"
            ]
          ]
        ]
        12 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "Histology"
        ]
        13 => array:3 [
          "identificador" => "sec0080"
          "titulo" => "Treatment"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Standard treatment"
            ]
            1 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Alternative treatments"
            ]
            2 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Liver transplantation"
            ]
            3 => array:2 [
              "identificador" => "sec0100"
              "titulo" => "Novel treatment approaches"
            ]
          ]
        ]
        14 => array:2 [
          "identificador" => "sec0105"
          "titulo" => "Conflict of interest"
        ]
        15 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-04-01"
    "fechaAceptado" => "2016-04-02"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec738661"
          "palabras" => array:5 [
            0 => "Autoimmune hepatitis"
            1 => "Pathogenesis"
            2 => "Autoantibodies"
            3 => "Diagnosis"
            4 => "Immunosuppressive treatment"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec738660"
          "palabras" => array:5 [
            0 => "Hepatitis autoinmune"
            1 => "Patogenia"
            2 => "Autoanticuerpos"
            3 => "Diagn&#243;stico"
            4 => "Tratamiento inmunosupresor"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Autoimmune hepatitis &#40;AIH&#41; is a progressive inflammatory hepatopathy and an important cause of end-stage liver disease&#46; Its aetiology remains unknown&#44; though both genetic and environmental factors are involved in its development&#46; The major mechanism of autoimmune liver damage involves immune reactions against host liver antigens&#46; Numerical and functional defects of regulatory T-cells play a permissive role enabling autoimmune liver injury to occur and persist&#46; The most typical features of AIH are female preponderance&#44; hypergammaglobulinaemia&#44; seropositivity for circulating autoantibodies and a picture of interface hepatitis on histology&#46; Two types of AIH are distinguished according to serological profile&#58; AIH type 1 patients are positive for anti-nuclear and&#47;or anti-smooth muscle antibodies&#44; whereas AIH type 2 patients are defined by the positivity for anti-liver kidney microsomal type 1 antibody and&#47;or for anti-liver cytosol type 1 antibody&#46; Clinical manifestations are variable&#44; and AIH onset is often ill-defined&#44; frequently mimicking acute hepatitis&#59; its course may be fluctuating&#46; AIH responds to immunosuppressive treatment in the majority of cases&#46; Steroids with or without azathioprine should be instituted promptly upon diagnosis&#46; Remission is achieved in some 80&#37; of patients&#46; For the remaining 20&#37; of patients&#44; alternative immunosuppressive agents such as mycophenolate mofetil and calcineurin inhibitors are an option&#46; Liver transplantation should be considered for those patients who progress to cirrhosis and develop complications of end-stage liver disease&#44; as well as for those presenting with acute liver failure&#59; outcomes are excellent&#44; although the disease may recur in the allograft&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La hepatitis autoinmune &#40;HAI&#41; es una hepatopat&#237;a inflamatoria progresiva y una causa importante de insuficiencia hep&#225;tica terminal&#46; Su origen contin&#250;a siendo una inc&#243;gnita&#44; si bien influyen en su evoluci&#243;n factores tanto gen&#233;ticos como ambientales&#46; El principal mecanismo de da&#241;o hep&#225;tico autoinmune son las reacciones inmunitarias contra los ant&#237;genos hep&#225;ticos del receptor&#46; Los defectos num&#233;ricos y funcionales de los linfocitos T reguladores desempe&#241;an un permisivo papel a la hora de propiciar que la enfermedad hep&#225;tica autoinmune se produzca y perdure&#46; Las particularidades m&#225;s t&#237;picas de la HAI son el predominio femenino&#44; hipergammaglobulinemia&#44; seropositividad para autoanticuerpos circulantes e imagen de hepatitis de interfase en la histolog&#237;a&#46; Se distinguen 2 tipos de HAI conforme a su perfil serol&#243;gico&#58; los pacientes con HAI tipo 1 dan positivo para anticuerpos antinucleares y&#47;o antim&#250;sculo liso&#44; mientras que los pacientes con HAI tipo 2 dan positivo para el anticuerpo antimicrosomal de h&#237;gado tipo 1 y&#47;o para el anticuerpo contra el citosol hep&#225;tico 1&#46; Los signos cl&#237;nicos var&#237;an&#44; y el inicio de la HAI suele estar mal definido&#44; imitando hepatitis aguda&#59; su evoluci&#243;n puede fluctuar&#46; La HAI remite con tratamiento inmunodepresor en la mayor&#237;a de los casos&#46; Los corticosteroides con o sin azatioprina deber&#237;an iniciarse inmediatamente despu&#233;s del diagn&#243;stico&#46; La remisi&#243;n se consigue en alrededor del 80&#37; de los pacientes&#46; Para el 20&#37; restante&#44; una opci&#243;n son los f&#225;rmacos inmunodepresores&#44; como el micofenolato de mofetilo o inhibidores de calcineurina&#46; El trasplante hep&#225;tico debe ser tenido en cuenta para aquellos pacientes que cursen con cirrosis y padezcan complicaciones de insuficiencia hep&#225;tica terminal&#44; as&#237; como para los que experimenten insuficiencia hep&#225;tica aguda&#59; los resultados son excelentes&#44; si bien la enfermedad podr&#237;a recidivar en el alotransplante&#46;</p></span>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1502
            "Ancho" => 2481
            "Tamanyo" => 170596
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of liver damage&#46; Liver damage is initiated by the presentation of a self-antigenic peptide within a major histocompatibility molecule &#40;MHC&#41; by professional antigen presenting cells &#40;APCs&#41;&#46; The presence of appropriate costimulation alongside exposure to various cytokines drives the differentiation of uncommitted CD4 helper T-cells &#40;Th0&#41;&#46; IL-6 and IL-1&#946; lead to differentiation into pathogenic Th17 cells that secrete the proinflammatory cytokine IL-17&#46; Th17 cells promote hepatocyte secretion of IL-6&#44; which in turn further enhances Th17 development&#46; Exposure to IL-12 leads to the differentiation of Th1 cells secreting IFN-&#947;&#44; which induces monocyte &#40;M&#934;&#41; differentiation&#44; activates cytotoxic CD8 T-cells and promotes NK cell killing&#46; IFN-&#947; also increases MHC class I and induces class II expression by hepatocytes&#44; further exacerbating inflammation&#46; Exposure to IL-4 leads to Th2 differentiation&#46; Th2 cells secrete IL-13&#44; IL-4 and IL-10 that enable B cell maturation into plasma cells with the consequent production of autoantibodies&#46; Autoantibodies are in turn involved in antibody-mediated cellular cytotoxicity and complement activation&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 709
            "Ancho" => 950
            "Tamanyo" => 315240
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Histology of autoimmune hepatitis&#46; The portal and periportal inflammatory infiltrate characteristic of autoimmune hepatitis is composed of lymphocytes&#44; monocytes&#47;macrophages and plasma cells &#40;interface hepatitis&#44; arrows&#41;&#46; Haematoxilin and eosin staining &#40;picture kindly provided by Dr&#46; Alberto Quaglia&#44; Institute of Liver Studies&#44; King&#39;s College Hospital&#41;&#46;</p>"
        ]
      ]
      2 => array:9 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Alvarez F&#44; Berg PA et al&#46; J Hepatol 1999&#59;31&#58;929&#8211;938&#46;"
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Pre-treatment score &#62;15&#58; definite AIH&#59; 10&#8211;15&#58; probable AIH&#59; Post-treatment score &#62;17&#58; definite AIH&#59; 12&#8211;17&#58; probable AIH&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">ALP&#44; alkaline phosphatase&#59; AST&#44; aspartate aminotransferase&#59; ALT&#44; alanine aminotransferase&#59; IgG&#44; immunoglobulin G&#59; ANA&#44; anti-nuclear antibody&#59; SMA&#44; anti-smooth muscle antibody&#59; anti-LKM-1&#44; anti-liver kidney microsomal type 1 antibodies&#59; AMA&#44; anti-mitochondrial antibodies&#59; SLA&#47;LP&#44; soluble liver antigen&#47;liver pancreas&#59; ASGPR&#44; asialoglycoprotein receptor&#59; p-ANNA&#44; peripheral anti-nuclear neutrophil antibody &#40;also known as atypical pANCA&#41;&#59; HLA&#44; human leucocyte antigen&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Feature&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ALP&#58; AST &#40;or ALT&#41; ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;5&#8211;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serum globulins or IgG &#40;times above normal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;5&#8211;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;0&#8211;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA&#44; SMA or anti-LKM-1 titres&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;1&#58;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#58;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Viral markers of active infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hepatotoxic drug history&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Average alcohol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;25<span class="elsevierStyleHsp" style=""></span>g&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;60<span class="elsevierStyleHsp" style=""></span>g&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Histological features&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Interface hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Plasma cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rosettes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None of the above&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Biliary changes<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Atypical changes<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immune diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Thyroiditis&#44; colitis&#44; other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DR3 or DR4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Seropositivity for other autoantibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-SLA&#47;LP&#44; actin&#44; ASGPR&#44; pANNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Response to therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Remission&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1212842.png"
              ]
            ]
          ]
          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Including granulomatous cholangitis&#44; concentric periductal fibrosis&#44; ductopenia&#44; marginal bile duct proliferation and cholangiolitis&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Any other prominent feature suggesting a different aetiology&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">International autoimmune hepatitis group revised diagnostic scoring system&#46;</p>"
        ]
      ]
      3 => array:9 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Hennes EM&#44; Zeniya M et al&#46; Hepatology 2008&#59;48&#58;169&#8211;176&#46;"
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Score &#8805;6&#58; probable AIH&#59; &#8805;7&#58; definite AIH&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">ANA&#44; anti-nuclear antibody&#59; SMA&#44; anti-smooth muscle antibody&#59; anti-LKM-1&#44; anti-liver kidney microsomal antibody type 1&#59; SLA&#44; soluble liver antigen&#59; IgG&#44; immunoglobulin G&#59; AIH&#44; autoimmune hepatitis&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cut-off&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA or SMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;1&#58;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">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="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA or SMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;1&#58;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Or anti-LKM-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;1&#58;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Or SLA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IgG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;Upper limit of normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;1&#46;10 times upper limit of normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liver histology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Compatible with AIH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Typical of AIH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Absence of viral hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1212843.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Addition of points achieved for all autoantibodies cannot exceed a maximum of 2 points&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Simplified criteria for the diagnosis of autoimmune hepatitis&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:79 [
            0 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis&#58; a comprehensive review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46; Liberal"
                            1 => "C&#46;R&#46; Grant"
                            2 => "G&#46; Mieli-Vergani"
                            3 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaut.2012.11.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Autoimmun"
                        "fecha" => "2013"
                        "volumen" => "41"
                        "paginaInicial" => "126"
                        "paginaFinal" => "139"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23218932"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver autoimmune serology&#58; a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Vergani"
                            1 => "F&#46; Alvarez"
                            2 => "F&#46;B&#46; Bianchi"
                            3 => "E&#46;L&#46; Can&#231;ado"
                            4 => "I&#46;R&#46; Mackay"
                            5 => "M&#46;P&#46; Manns"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2004.08.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2004"
                        "volumen" => "41"
                        "paginaInicial" => "677"
                        "paginaFinal" => "683"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15464251"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical significance of autoantibodies in autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Liberal"
                            1 => "G&#46; Mieli-Vergani"
                            2 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaut.2013.08.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Autoimmun"
                        "fecha" => "2013"
                        "volumen" => "46"
                        "paginaInicial" => "17"
                        "paginaFinal" => "24"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24016388"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnosis and management of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;P&#46; Manns"
                            1 => "A&#46;J&#46; Czaja"
                            2 => "J&#46;D&#46; Gorham"
                            3 => "E&#46;L&#46; Krawitt"
                            4 => "G&#46; Mieli-Vergani"
                            5 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.23584"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2010"
                        "volumen" => "51"
                        "paginaInicial" => "2193"
                        "paginaFinal" => "2213"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20513004"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S1873994614001482"
                          "estado" => "S300"
                          "issn" => "18739946"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidence and prevalence of primary biliary cirrhosis&#44; primary sclerosing cholangitis&#44; and autoimmune hepatitis in a Norwegian population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46;M&#46; Boberg"
                            1 => "E&#46; Aadland"
                            2 => "J&#46; Jahnsen"
                            3 => "N&#46; Raknerud"
                            4 => "M&#46; Stiris"
                            5 => "H&#46; Bell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Scand J Gastroenterol"
                        "fecha" => "1998"
                        "volumen" => "33"
                        "paginaInicial" => "99"
                        "paginaFinal" => "103"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9489916"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis in Denmark&#58; incidence&#44; prevalence&#44; prognosis&#44; and causes of death&#46; A nationwide registry-based cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46; Gronbaek"
                            1 => "H&#46; Vilstrup"
                            2 => "P&#46; Jepsen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2013.10.020"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2014"
                        "volumen" => "60"
                        "paginaInicial" => "612"
                        "paginaFinal" => "617"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24326217"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of autoimmune liver disease in Alaska Natives"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46;J&#46; Hurlburt"
                            1 => "B&#46;J&#46; McMahon"
                            2 => "H&#46; Deubner"
                            3 => "B&#46; Hsu-Trawinski"
                            4 => "J&#46;L&#46; Williams"
                            5 => "K&#46;V&#46; Kowdley"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2002.06019.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Gastroenterol"
                        "fecha" => "2002"
                        "volumen" => "97"
                        "paginaInicial" => "2402"
                        "paginaFinal" => "2407"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12358264"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0435"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis&#58; contrasts and comparisons in children and adults &#8211; a comprehensive review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Floreani"
                            1 => "R&#46; Liberal"
                            2 => "D&#46; Vergani"
                            3 => "G&#46; Mieli-Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaut.2013.08.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Autoimmun"
                        "fecha" => "2013"
                        "volumen" => "46"
                        "paginaInicial" => "7"
                        "paginaFinal" => "16"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24035197"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0440"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathogenesis of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46; Liberal"
                            1 => "M&#46;S&#46; Longhi"
                            2 => "G&#46; Mieli-Vergani"
                            3 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bpg.2011.09.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Best Pract Res Clin Gastroenterol"
                        "fecha" => "2011"
                        "volumen" => "25"
                        "paginaInicial" => "653"
                        "paginaFinal" => "664"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22117632"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0445"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E&#46;L&#46; Krawitt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra050408"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2006"
                        "volumen" => "354"
                        "paginaInicial" => "54"
                        "paginaFinal" => "66"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16394302"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0450"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The variant forms of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "A&#46;J&#46; Czaja"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Intern Med"
                        "fecha" => "1996"
                        "volumen" => "125"
                        "paginaInicial" => "588"
                        "paginaFinal" => "598"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8815758"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0455"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnostic criteria of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "R&#46; Liberal"
                            1 => "C&#46;R&#46; Grant"
                            2 => "M&#46;S&#46; Longhi"
                            3 => "G&#46; Mieli-Vergani"
                            4 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.autrev.2013.11.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Autoimmun Rev"
                        "fecha" => "2014"
                        "volumen" => "13"
                        "paginaInicial" => "435"
                        "paginaFinal" => "440"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24418295"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0460"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Meeting report&#58; International Autoimmune Hepatitis Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46;J&#46; Johnson"
                            1 => "I&#46;G&#46; McFarlane"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1993"
                        "volumen" => "18"
                        "paginaInicial" => "998"
                        "paginaFinal" => "1005"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8406375"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0465"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "International Autoimmune Hepatitis Group Report&#58; review of criteria for diagnosis of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Alvarez"
                            1 => "P&#46;A&#46; Berg"
                            2 => "F&#46;B&#46; Bianchi"
                            3 => "L&#46; Bianchi"
                            4 => "A&#46;K&#46; Burroughs"
                            5 => "E&#46;L&#46; Cancado"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "1999"
                        "volumen" => "31"
                        "paginaInicial" => "929"
                        "paginaFinal" => "938"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10580593"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0470"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver transplantation and autoimmune liver diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46; Liberal"
                            1 => "Y&#46; Zen"
                            2 => "G&#46; Mieli-Vergani"
                            3 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/lt.23704"
                      "Revista" => array:6 [
                        "tituloSerie" => "Liver Transpl"
                        "fecha" => "2013"
                        "volumen" => "19"
                        "paginaInicial" => "1065"
                        "paginaFinal" => "1077"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23873751"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0475"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetics of liver disease&#58; immunogenetics and disease pathogenesis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46;T&#46; Donaldson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gut"
                        "fecha" => "2004"
                        "volumen" => "53"
                        "paginaInicial" => "599"
                        "paginaFinal" => "608"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15016758"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0480"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46; Vergani"
                            1 => "M&#46;S&#46; Longhi"
                            2 => "D&#46;P&#46; Bogdanos"
                            3 => "Y&#46; Ma"
                            4 => "G&#46; Mieli-Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00281-009-0170-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Immunopathol"
                        "fecha" => "2009"
                        "volumen" => "31"
                        "paginaInicial" => "421"
                        "paginaFinal" => "435"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19533129"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0485"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;D&#46; Strettell"
                            1 => "P&#46;T&#46; Donaldson"
                            2 => "L&#46;J&#46; Thomson"
                            3 => "P&#46;J&#46; Santrach"
                            4 => "S&#46;B&#46; Moore"
                            5 => "A&#46;J&#46; Czaja"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "1997"
                        "volumen" => "112"
                        "paginaInicial" => "2028"
                        "paginaFinal" => "2035"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9178696"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0490"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genome-wide association study identifies variants associated with autoimmune hepatitis type 1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46;S&#46; de Boer"
                            1 => "N&#46;M&#46; van Gerven"
                            2 => "A&#46; Zwiers"
                            3 => "B&#46;I&#46; Witte"
                            4 => "H&#46; Bontkes"
                            5 => "C&#46;M&#46; van Nieuwkerk"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2014.04.022"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2014"
                        "volumen" => "147"
                        "paginaInicial" => "443"
                        "paginaFinal" => "452"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24768677"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0495"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "I&#46; Djilali-Saiah"
                            1 => "A&#46; Fakhfakh"
                            2 => "H&#46; Louafi"
                            3 => "S&#46; Caillat-Zucman"
                            4 => "D&#46; Debray"
                            5 => "F&#46; Alvarez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2006.07.034"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2006"
                        "volumen" => "45"
                        "paginaInicial" => "844"
                        "paginaFinal" => "850"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17050030"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0500"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Ma"
                            1 => "M&#46; Okamoto"
                            2 => "M&#46;G&#46; Thomas"
                            3 => "D&#46;P&#46; Bogdanos"
                            4 => "A&#46;R&#46; Lopes"
                            5 => "B&#46; Portmann"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2002.32092"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2002"
                        "volumen" => "35"
                        "paginaInicial" => "658"
                        "paginaFinal" => "664"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11870381"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0505"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cytotoxic T lymphocyte antigen-4 &#40;CTLA-4&#41; gene polymorphisms and susceptibility to type 1 autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "K&#46; Agarwal"
                            1 => "A&#46;J&#46; Czaja"
                            2 => "D&#46;E&#46; Jones"
                            3 => "P&#46;T&#46; Donaldson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510310110"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2000"
                        "volumen" => "31"
                        "paginaInicial" => "49"
                        "paginaFinal" => "53"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10613727"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0510"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46;J&#46; Czaja"
                            1 => "S&#46; Cookson"
                            2 => "P&#46;K&#46; Constantini"
                            3 => "M&#46; Clare"
                            4 => "J&#46;A&#46; Underhill"
                            5 => "P&#46;T&#46; Donaldson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "1999"
                        "volumen" => "117"
                        "paginaInicial" => "645"
                        "paginaFinal" => "652"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10464141"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0515"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "K&#46; Agarwal"
                            1 => "A&#46;J&#46; Czaja"
                            2 => "P&#46;T&#46; Donaldson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1399-0039.2006.00794.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Tissue Antigens"
                        "fecha" => "2007"
                        "volumen" => "69"
                        "paginaInicial" => "227"
                        "paginaFinal" => "235"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17493146"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0520"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46; Vogel"
                            1 => "C&#46;P&#46; Strassburg"
                            2 => "M&#46;P&#46; Manns"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2002.30084"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2002"
                        "volumen" => "35"
                        "paginaInicial" => "126"
                        "paginaFinal" => "131"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11786968"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0525"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "AIRE gene analysis in children with autoimmune hepatitis type I or II"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46;O&#46; Lankisch"
                            1 => "O&#46; Mourier"
                            2 => "E&#46;M&#46; Sokal"
                            3 => "D&#46; Habes"
                            4 => "F&#46; Lacaille"
                            5 => "L&#46; Bridoux-Henno"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MPG.0b013e31818550de"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Gastroenterol Nutr"
                        "fecha" => "2009"
                        "volumen" => "48"
                        "paginaInicial" => "498"
                        "paginaFinal" => "500"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19322061"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0530"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mimicry between the hepatitis B virus DNA polymerase and the antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis B virus infection"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "G&#46;V&#46; Gregorio"
                            1 => "K&#46; Choudhuri"
                            2 => "Y&#46; Ma"
                            3 => "A&#46; Vegnente"
                            4 => "G&#46; Mieli-Vergani"
                            5 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
                        "fecha" => "1999"
                        "volumen" => "162"
                        "paginaInicial" => "1802"
                        "paginaFinal" => "1810"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9973445"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0535"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mimicry between the hepatitis C virus polyprotein and antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis C virus infection"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46;V&#46; Gregorio"
                            1 => "K&#46; Choudhuri"
                            2 => "Y&#46; Ma"
                            3 => "P&#46; Pensati"
                            4 => "R&#46; Iorio"
                            5 => "P&#46; Grant"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Immunol"
                        "fecha" => "2003"
                        "volumen" => "133"
                        "paginaInicial" => "404"
                        "paginaFinal" => "413"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12930368"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0540"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of non-organ-specific autoantibodies and chronic liver disease in the general population&#58; a nested case&#8211;control study of the Dionysos cohort"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Lenzi"
                            1 => "S&#46; Bellentani"
                            2 => "G&#46; Saccoccio"
                            3 => "P&#46; Muratori"
                            4 => "F&#46; Masutti"
                            5 => "L&#46; Muratori"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gut"
                        "fecha" => "1999"
                        "volumen" => "45"
                        "paginaInicial" => "435"
                        "paginaFinal" => "441"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10446115"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0545"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cytochrome P4502D6&#40;193&#8211;212&#41;&#58; a new immunodominant epitope and target of virus&#47;self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Kerkar"
                            1 => "K&#46; Choudhuri"
                            2 => "Y&#46; Ma"
                            3 => "A&#46; Mahmoud"
                            4 => "D&#46;P&#46; Bogdanos"
                            5 => "L&#46; Muratori"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
                        "fecha" => "2003"
                        "volumen" => "170"
                        "paginaInicial" => "1481"
                        "paginaFinal" => "1489"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12538711"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0550"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Primary and secondary liver&#47;kidney microsomal autoantibody response following infection with hepatitis C virus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46;D&#46; Mackie"
                            1 => "M&#46; Peakman"
                            2 => "M&#46; Yun"
                            3 => "R&#46; Sallie"
                            4 => "H&#46; Smith"
                            5 => "E&#46;T&#46; Davies"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "1994"
                        "volumen" => "106"
                        "paginaInicial" => "1672"
                        "paginaFinal" => "1675"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8194716"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0555"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of hepatitis C serum antibody in autoimmune diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Agmon-Levin"
                            1 => "M&#46; Ram"
                            2 => "O&#46; Barzilai"
                            3 => "B&#46;S&#46; Porat-Katz"
                            4 => "R&#46; Parikman"
                            5 => "C&#46; Selmi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaut.2009.02.017"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Autoimmun"
                        "fecha" => "2009"
                        "volumen" => "32"
                        "paginaInicial" => "261"
                        "paginaFinal" => "266"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19356903"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0560"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug-induced autoimmune hepatitis&#58; clinical characteristics and prognosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Bjornsson"
                            1 => "J&#46; Talwalkar"
                            2 => "S&#46; Treeprasertsuk"
                            3 => "P&#46;S&#46; Kamath"
                            4 => "N&#46; Takahashi"
                            5 => "S&#46; Sanderson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.23588"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2010"
                        "volumen" => "51"
                        "paginaInicial" => "2040"
                        "paginaFinal" => "2048"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20512992"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0565"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "G&#46; Senaldi"
                            1 => "B&#46; Portmann"
                            2 => "A&#46;P&#46; Mowat"
                            3 => "G&#46; Mieli-Vergani"
                            4 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dis Child"
                        "fecha" => "1992"
                        "volumen" => "67"
                        "paginaInicial" => "1447"
                        "paginaFinal" => "1453"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1489223"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0570"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The liver as a lymphoid organ"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "I&#46;N&#46; Crispe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1146/annurev.immunol.021908.132629"
                      "Revista" => array:6 [
                        "tituloSerie" => "Annu Rev Immunol"
                        "fecha" => "2009"
                        "volumen" => "27"
                        "paginaInicial" => "147"
                        "paginaFinal" => "163"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19302037"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0575"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulatory T cells&#58; mechanisms of suppression and impairment in autoimmune liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "R&#46; Liberal"
                            1 => "C&#46;R&#46; Grant"
                            2 => "M&#46;S&#46; Longhi"
                            3 => "G&#46; Mieli-Vergani"
                            4 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/iub.1349"
                      "Revista" => array:6 [
                        "tituloSerie" => "IUBMB Life"
                        "fecha" => "2015"
                        "volumen" => "67"
                        "paginaInicial" => "88"
                        "paginaFinal" => "97"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25850692"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0580"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impairment of CD4&#40;&#43;&#41;CD25&#40;&#43;&#41; regulatory T-cells in autoimmune liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;S&#46; Longhi"
                            1 => "Y&#46; Ma"
                            2 => "D&#46;P&#46; Bogdanos"
                            3 => "P&#46; Cheeseman"
                            4 => "G&#46; Mieli-Vergani"
                            5 => "D&#46; Vergani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2004.03.008"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2004"
                        "volumen" => "41"
                        "paginaInicial" => "31"
                        "paginaFinal" => "37"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15246204"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0585"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of CD4&#43; CD25&#43; regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;S&#46; Longhi"
                            1 => "Y&#46; Ma"
                             …4
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaut.2005.10.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Autoimmun"
                        "fecha" => "2005"
                        "volumen" => "25"
                        "paginaInicial" => "63"
                        "paginaFinal" => "71"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0590"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.23792"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2010"
                        "volumen" => "52"
                        "paginaInicial" => "999"
                        "paginaFinal" => "1007"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0595"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.27884"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2015"
                        "volumen" => "62"
                        "paginaInicial" => "863"
                        "paginaFinal" => "875"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0600"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Functional study of CD4&#43;CD25&#43; regulatory T cells in health and autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
                        "fecha" => "2006"
                        "volumen" => "176"
                        "paginaInicial" => "4484"
                        "paginaFinal" => "4491"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0605"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9&#47;tim-3 pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.25682"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2012"
                        "volumen" => "56"
                        "paginaInicial" => "677"
                        "paginaFinal" => "686"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0610"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22914"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2009"
                        "volumen" => "50"
                        "paginaInicial" => "130"
                        "paginaFinal" => "142"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0615"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "FOXP3&#43; regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2012.02.029"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2012"
                        "volumen" => "57"
                        "paginaInicial" => "125"
                        "paginaFinal" => "132"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0620"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dysfunctional CD39 regulatory T cells and aberrant control of T helper type 17 cells in autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.26583"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2014"
                        "volumen" => "59"
                        "paginaInicial" => "1007"
                        "paginaFinal" => "1015"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0625"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical features and management of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Gastroenterol"
                        "fecha" => "2008"
                        "volumen" => "14"
                        "paginaInicial" => "3301"
                        "paginaFinal" => "3305"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0630"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severe autoimmune hepatitis first presenting in the early post partum period"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Gastroenterol Hepatol"
                        "fecha" => "2004"
                        "volumen" => "2"
                        "paginaInicial" => "622"
                        "paginaFinal" => "624"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0635"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management and outcome of pregnancy in autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gut"
                        "fecha" => "2001"
                        "volumen" => "48"
                        "paginaInicial" => "97"
                        "paginaFinal" => "102"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0640"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis in childhood&#58; a 20-year experience"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510250308"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1997"
                        "volumen" => "25"
                        "paginaInicial" => "541"
                        "paginaFinal" => "547"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0016508506002617"
                          "estado" => "S300"
                          "issn" => "00165085"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0645"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis&#58; implications for follow-up and screening"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22432"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2008"
                        "volumen" => "48"
                        "paginaInicial" => "863"
                        "paginaFinal" => "870"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0650"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Development of hepatocellular carcinoma in autoimmune hepatitis patients&#58; a case series"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10620-010-1444-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Dig Dis Sci"
                        "fecha" => "2011"
                        "volumen" => "56"
                        "paginaInicial" => "578"
                        "paginaFinal" => "585"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0655"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Simplified criteria for the diagnosis of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22322"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2008"
                        "volumen" => "48"
                        "paginaInicial" => "169"
                        "paginaFinal" => "176"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0660"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune liver serology&#58; current diagnostic and clinical challenges"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Gastroenterol"
                        "fecha" => "2008"
                        "volumen" => "14"
                        "paginaInicial" => "3374"
                        "paginaFinal" => "3387"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0665"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoantibodies and their antigens in autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-0029-1233533"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Liver Dis"
                        "fecha" => "2009"
                        "volumen" => "29"
                        "paginaInicial" => "241"
                        "paginaFinal" => "253"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0670"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification of target antigen for SLA&#47;LP autoantibodies in autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2000"
                        "volumen" => "355"
                        "paginaInicial" => "1510"
                        "paginaFinal" => "1515"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0675"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Histological findings in chronic hepatitis C with autoimmune features"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510260229"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1997"
                        "volumen" => "26"
                        "paginaInicial" => "459"
                        "paginaFinal" => "466"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0680"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune acute liver failure&#58; proposed clinical and histological criteria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.24080"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2011"
                        "volumen" => "53"
                        "paginaInicial" => "517"
                        "paginaFinal" => "526"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0685"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis in children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Liver Dis"
                        "fecha" => "2002"
                        "volumen" => "6"
                        "paginaInicial" => "623"
                        "paginaFinal" => "634"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0016508514008002"
                          "estado" => "S300"
                          "issn" => "00165085"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0690"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Controlled prospective trial of corticosteroid therapy in active chronic hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Q J Med"
                        "fecha" => "1971"
                        "volumen" => "40"
                        "paginaInicial" => "159"
                        "paginaFinal" => "185"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0695"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical&#44; biochemical&#44; and histological remission of severe chronic active liver disease&#58; a controlled study of treatments and early prognosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "1972"
                        "volumen" => "63"
                        "paginaInicial" => "820"
                        "paginaFinal" => "833"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0700"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Controlled trial of prednisone and azathioprine in active chronic hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1973"
                        "volumen" => "1"
                        "paginaInicial" => "735"
                        "paginaFinal" => "737"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0705"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Azathioprine for long-term maintenance of remission in autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199510123331502"
                      "Revista" => array:7 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1995"
                        "volumen" => "333"
                        "paginaInicial" => "958"
                        "paginaFinal" => "963"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S187399461200133X"
                          "estado" => "S300"
                          "issn" => "18739946"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0710"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2010.12.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2011"
                        "volumen" => "55"
                        "paginaInicial" => "171"
                        "paginaFinal" => "182"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0715"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacological management of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1517/14656566.2011.524206"
                      "Revista" => array:7 [
                        "tituloSerie" => "Expert Opin Pharmacother"
                        "fecha" => "2011"
                        "volumen" => "12"
                        "paginaInicial" => "607"
                        "paginaFinal" => "613"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0016508508011992"
                          "estado" => "S300"
                          "issn" => "00165085"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0720"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune hepatitis &#40;AIH&#41; in the elderly&#58; a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2006.04.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2006"
                        "volumen" => "45"
                        "paginaInicial" => "575"
                        "paginaFinal" => "583"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib0725"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Review article&#58; the modern management of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2036.2010.04241.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Aliment Pharmacol Ther"
                        "fecha" => "2010"
                        "volumen" => "31"
                        "paginaInicial" => "771"
                        "paginaFinal" => "787"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib0730"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Current and novel immunosuppressive therapy for autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2002.30991"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2002"
                        "volumen" => "35"
                        "paginaInicial" => "7"
                        "paginaFinal" => "13"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib0735"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Infliximab as a rescue-treatment in difficult-to-treat autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2013"
                        "volumen" => "58"
                        "paginaInicial" => "529"
                        "paginaFinal" => "534"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib0740"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug-induced autoimmune hepatitis caused by anti-tumor necrosis factor alpha agents"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.23834"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2010"
                        "volumen" => "52"
                        "paginaInicial" => "2246"
                        "paginaFinal" => "2247"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib0745"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A case of autoimmune hepatitis treated with rituximab"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000322693"
                      "Revista" => array:6 [
                        "tituloSerie" => "Case Rep Gastroenterol"
                        "fecha" => "2010"
                        "volumen" => "4"
                        "paginaInicial" => "502"
                        "paginaFinal" => "509"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib0750"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2010.06.046"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2010"
                        "volumen" => "139"
                        "paginaInicial" => "1198"
                        "paginaFinal" => "1206"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib0755"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2003.50266"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2003"
                        "volumen" => "38"
                        "paginaInicial" => "196"
                        "paginaFinal" => "202"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib0760"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver transplantation for autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2000.16666"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2000"
                        "volumen" => "32"
                        "paginaInicial" => "693"
                        "paginaFinal" => "700"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib0765"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Transplantation in autoimmune liver diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Gastroenterol"
                        "fecha" => "2008"
                        "volumen" => "14"
                        "paginaInicial" => "3388"
                        "paginaFinal" => "3395"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib0770"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-0029-1233534"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Liver Dis"
                        "fecha" => "2009"
                        "volumen" => "29"
                        "paginaInicial" => "273"
                        "paginaFinal" => "285"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib0775"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22071"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2008"
                        "volumen" => "47"
                        "paginaInicial" => "581"
                        "paginaFinal" => "591"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0140673600043099"
                          "estado" => "S300"
                          "issn" => "01406736"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib0780"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibition of interleukin-17 promotes differentiation of CD25-cells into stable T regulatory cells in patients with autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2012.02.041"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2012"
                        "volumen" => "142"
                        "paginaInicial" => "1526"
                        "paginaFinal" => "1535"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib0785"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.21658"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2007"
                        "volumen" => "46"
                        "paginaInicial" => "472"
                        "paginaFinal" => "484"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib0790"
              "etiqueta" => "79"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoantigen-specific regulatory T cells&#44; a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.24039"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2011"
                        "volumen" => "53"
                        "paginaInicial" => "536"
                        "paginaFinal" => "547"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/00142565/0000021600000007/v1_201609280158/S0014256516300248/v1_201609280158/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "1067"
    "tipo" => "SECCION"
    "es" => array:2 [
      "titulo" => "Revisiones"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "es"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/00142565/0000021600000007/v1_201609280158/S0014256516300248/v1_201609280158/en/main.pdf?idApp=WRCEE&text.app=https://revclinesp.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300248?idApp=WRCEE"
]

Información del artículo

ISSN: 00142565
Idioma original: Inglés

DOI:10.1016/j.rce.2016.04.003

Datos actualizados diariamente

año/Mes	Html	Pdf	Total

2023 Marzo	1	3	4
2021 Junio	1	2	3
2019 Marzo	1	0	1
2018 Octubre	1	0	1
2018 Enero	1	0	1
2017 Noviembre	2	0	2
2017 Junio	1	0	1
2017 Mayo	3	1	4
2017 Abril	0	2	2
2017 Marzo	2	0	2
2017 Febrero	3	1	4
2017 Enero	5	3	8
2016 Diciembre	5	2	7
2016 Noviembre	11	5	16
2016 Octubre	28	11	39
2016 Septiembre	3	5	8

Mostrar todo

Indexada en:

Síguenos:

Suscribirse:

Estadísticas

Indexada en:

Síguenos:

Suscribirse:

Estadísticas

Suscríbase a la newsletter