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          "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>"
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    "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>"
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          "titulo" => "Introduction"
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          "titulo" => "Genetics"
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          "titulo" => "Potential triggers"
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          "titulo" => "Effector immune mechanisms"
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              "titulo" => "Anti-smooth muscle antibodies"
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              "titulo" => "Anti-liver-kidney-microsomal type 1 antibodies"
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              "titulo" => "Anti-liver cytosol type 1 antibodies"
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              "titulo" => "Anti-soluble liver antigen&#47;liver-pancreas antibodies"
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              "titulo" => "Liver transplantation"
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              "titulo" => "Novel treatment approaches"
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            0 => "Autoimmune hepatitis"
            1 => "Pathogenesis"
            2 => "Autoantibodies"
            3 => "Diagnosis"
            4 => "Immunosuppressive treatment"
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            0 => "Hepatitis autoinmune"
            1 => "Patogenia"
            2 => "Autoanticuerpos"
            3 => "Diagn&#243;stico"
            4 => "Tratamiento inmunosupresor"
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        "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>"
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      "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>"
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        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "mostrarDisplay" => false
        "figura" => array:1 [
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        "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>"
        ]
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      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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            "imagen" => "gr2.jpeg"
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          "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"
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          "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>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">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
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Review
Autoimmune hepatitis: From mechanisms to therapy
La hepatitis autoinmune: de los mecanismos al tratamiento
R. Liberala,b, G. Mieli-Vergania,c, D. Vergania,
Corresponding author
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
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          "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>"
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    "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>"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Genetics"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Potential triggers"
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          "titulo" => "Effector immune mechanisms"
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              "titulo" => "Anti-smooth muscle antibodies"
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              "titulo" => "Anti-liver-kidney-microsomal type 1 antibodies"
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              "titulo" => "Anti-liver cytosol type 1 antibodies"
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        ]
        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" => "xpalclavsec820421"
          "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" => "xpalclavsec820420"
          "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
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        ]
        "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
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                  \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
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                  \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
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                  \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
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        "fuente" => "Adapted from Hennes EM&#44; Zeniya M et al&#46; Hepatology 2008&#59;48&#58;169&#8211;176&#46;"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Simplified criteria for the diagnosis of autoimmune hepatitis&#46;</p>"
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      "titulo" => "References"
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        0 => array:2 [
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          "bibliografiaReferencia" => array:79 [
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                  "host" => array:1 [
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                  "contribucion" => array:1 [
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Original language: English
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