Autoimmune-liver-disease-autoimmunity-and-liver-transplantation_2014_Journal-of-Hepatology

Autoimmune liver disease,autoimmunity and liver transplantation

Marco Carbone 1,3,James M.Neuberger 2,3,?

1Division of Gastroenterology and Hepatology,Department of Medicine,Addenbrooke’s Hospital,Cambridge,United Kingdom;2Liver Unit,Queen Elizabeth Hospital,Birmingham,United Kingdom;3Organ Donation and Transplantation,National Health Service Blood and

Transplant (NHSBT),Bristol,United Kingdom

Summary Primary biliary cirrhosis (PBC),primary sclerosing cholangitis (PSC)and autoimmune hepatitis (AIH)represent the three major autoim-mune liver diseases (AILD).PBC,PSC,and AIH are all complex disor-ders in that they result from the effects of multiple genes in combination with as yet unidenti?ed environmental factors.Recent genome-wide association studies have identi?ed numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses.These loci may provide a clue as to the immune-based pathogenesis of AILD.Moreover,many signi?cant risk loci for PBC and PSC are also risk loci for other autoimmune dis-orders,such type I diabetes,multiple sclerosis and rheumatoid arthritis,suggesting a shared genetic basis and possibly similar molecular pathways for diverse autoimmune conditions.There is no curative treatment for all three disorders,and a signi?cant num-ber of patients eventually progress to end-stage liver disease requir-ing liver transplantation (LT).LT in this context has a favourable overall outcome with current patient and graft survival exceeding 80%at 5years.Indications are as for other chronic liver disease although recent data suggest that while lethargy improves after transplantation,the effect is modest and variable so lethargy alone is not an indication.In contrast,pruritus rapidly responds.Cholangi-ocarcinoma,except under rigorous selection criteria,excludes LT because of the high risk of recurrence.All three conditions may recur after transplantation and are associated with a greater risk of both acute cellular and chronic ductopenic rejection.It is possible that a crosstalk between alloimmune and autoimmune response perpetu-ate each other.An immunological response toward self-or allo-antigens is well recognised after LT in patients transplanted for non-autoimmune indications and sometimes termed ‘‘de novo auto-immune hepatitis’’.Whether this is part of the spectrum of rejection or an autoimmune process is not clear.In this manuscript,we review novel ?ndings about disease processes and mechanisms that lead to autoimmunity in the liver and their possible involvement in the immune response vs.the graft after LT.ó2013European Association for the Study of the Liver.Published by Elsevier B.V.All rights reserved.Introduction

Autoimmune hepatitis (AIH),primary biliary cirrhosis (PBC)and primary sclerosing cholangitis (PSC)are the tree major forms of autoimmune liver disease,which differ according to the focus of autoimmune injury,the pattern of in?ammation and the clin-ical phenotype.

In AIH,the autoimmune injury affects the hepatocytes,lead-ing to the histological picture of interface hepatitis.In PBC,the autoimmune injury affects the small,interlobular bile ducts,causing the typical appearance of non-suppurative,destructive cholangitis.In PSC,autoimmune or immune-mediated injury affects the medium-sized intra-and extrahepatic bile ducts,caus-ing concentric and obliterative ?brosis and multifocal bile duct stricturing.

AIH,PBC,and PSC represent complex disorders,in that they result from the interaction between genetic and environmental factors (Fig.1).In recent years,there have been major efforts to delineate the genetic architecture of these conditions.Recent genome-wide association studies (GWAS)and iCHIP-association studies [1–8]identi?ed numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses.These ?ndings have resulted in a better understanding of the pathogenic mechanisms underlying these immune-mediated conditions,highlighting common immune pathways between clinically associated disorders and explaining the tendency for patients and their families to suffer from multiple autoimmune conditions.This translates in the possibility of unique immuno-logic pathways for therapeutic intervention.The implication is that biological processes involved in loss of immune tolerance to one self-antigen (such as CYP2D6in the case of some models of AIH or PDC-E2in PBC)might be the same for other self-anti-gens (such as thyroid peroxidase in thyroid disease).All three disorders have a progressive course that,if untreated,develop into liver failure requiring liver transplanta-tion (LT).The aim of treatment is to abolish or reduce in?amma-tion,cholestasis and progression of ?brosis.Standard therapy in AIH consists of a combination of corticosteroids and azathioprine,

which is effective in 80%of patients;however progression may

occur despite seemingly effective treatment.Other immunosup-pressive agents such as mycophenolate mofetil,d-penicillamine,sirolimus and anti-T cell therapies have been tried in refractory cases with limited success [9].The only licensed therapy for PBC and PSC is ursodeoxycholic acid (UDCA)[10].In PBC,response to UDCA has a favourable effect on long-term

survival

Journal of Hepatology 2014vol.60j

210–223

Keywords:Autoimmunity;Primary biliary cirrhosis;Primary sclerosing cholan-gitis;Autoimmune hepatitis;Genome-wide association studies;Recurrence;

Rejection;De novo autoimmune hepatitis.Received 25June 2013;received in revised form 13August 2013;accepted 22September 2013?Corresponding author.Address:Organ Donation and Transplantation,NHSBT,Bristol,United Kingdom.

E-mail address:James.Neuberger@https://www.wendangku.net/doc/5617853206.html, (J.M.

Neuberger).Frontiers in Liver

Transplantation

and progression of?brosis;those who do not respond to UDCA have a poor survival(10-year survival is>95%and<80%in responders and non-responders to UDCA,respectively)[11]. Other drugs including methotrexate,colchicine and?brates,have been tested in combination with UDCA but none has been found to be of bene?t[12–18].A promising agent,under investigation is Obeticholic acid(OCA);this is a novel bile acid,which is an ago-nist of the Farsenoid X receptor implicated in the metabolism and enterohepatic circulation of bile acids[19].

In PSC,treatment with UDCA improves serum liver tests but does not improve survival;indeed,higher doses(17–23mg/kg/ day)are associated with high rates of serious adverse events [20].Although some units no longer routinely advise their patients with PSC to take UDCA,recent data from the analysis of the UK-PSC cohort[21]of around700patients,have shown a dose dependent effect of UDCA on LT-free survival(UK-PSC–unpublished data).Thus,for these autoimmune liver diseases there is a subgroup of patients who are non-responders to cur-rent treatments and have a poor prognosis,for whom new ther-apeutic options are warranted.However,development of novel agents is currently hindered by inadequate understanding of the aetiology and pathogenesis of these autoimmune conditions. Clinical phenotypes of autoimmune liver disease

Clinical and immunological features suggest that AIH is an arche-typal autoimmune condition.It is characterized by a strong female preponderance(F:M ratio7:1);hypergammaglobulina-emia;seropositivity for autoantibodies and a good clinical,sero-logical and histological response to corticosteroids.Furthermore, in AIH concurrent autoimmune disorders occur in approximately 40%of patients,particularly autoimmune thyroid disorder(AITD). Two types of AIH are recognised:type1(AIH-1),characterised by antinuclear antibodies(ANA)and/or anti-smooth muscle antibody(SMA),and type2(AIH-2),characterised by anti-liver kidney microsomal type1antibody(anti-LKM-1)or for anti-liver cytosol type1antibody(anti-LC-1)[22].

PBC also exhibits a number of autoimmune features,including the presence of autoreactive T cell and B cell responses against mitochondrial self-antigens,in particular the E2-domain of pyru-vate dehydrogenase complex(PDC-E2);the almost universal presence of auto-antibodies reactive with mitochondrial self-antigens;a strong female predominance(F:M ratio,10:1)and an association with other autoimmune diseases in the same indi-vidual and their close family.A concurrent autoimmune disorder occurs in between32%and53%of patients,most notably AITD, systemic lupus erythematosus(SLE)or systemic sclerosis(SSc) [23,24].Autoimmunity is also common in families of PBC patients,with an estimated14–20%of?rst degree relatives of PBC probands having an autoimmune disease other than PBC [25,26].However,unlike AIH,no immunosuppressive agent to date has been shown to be effective in PBC.

PSC is considered an‘autoimmune disease with atypical fea-tures’because it displays several differences when compared with the classical autoimmune diseases:these include male pre-dominance(M:F ratio,2:1),the absence of disease-speci?c auto-antibodies,and the poor response to immunosuppression. However,features that suggest an immune-mediated origin include the major contribution of risk variants within the human leukocyte antigen(HLA)complex,the presence of non-speci?c autoantibodies,including atypical anti-neutrophil cytoplasmic antibodies(ANCA)[27],the preferential usage of speci?c T cell receptor variable chains implying the presence of a speci?c (self)-antigen[28],and a strong association with other autoim-mune or immune-mediated disorders which occur in approxi-mately70%of patients.Most notable is a form of in?ammatory bowel disease(IBD),sometimes termed IBD-PSC,which affects up to90%of patients[29,30].IBD without any sign of PSC occurs more frequently among?rst degree relatives of patients with

PSC.

JOURNAL OF HEPATOLOGY Journal of Hepatology2014vol.60j210–223211

IBD in those with PSC tends to have a different phenotype com-pared with IBD alone.Approximately25%of PSC patients have an autoimmune condition outside of the gastrointestinal tract, most commonly type I diabetes mellitus(T1DM)or AITD[31].

Shared serological,immunological and histological patterns exist across the spectrum of AIH,PBC,and PSC.Conditions exhib-iting features of two different autoimmune liver diseases are commonly designated‘overlap syndromes’.These are repre-sented by variant forms of AIH,in which there are characteristics of both AIH and PBC(‘AIH/PBC overlap’)or AIH and PSC(‘AIH/PSC overlap’).Whether these represent distinct entities or part of a disease spectrum ranging from pure PBC’/‘pure PSC at one extreme to‘pure AIH’at the other,is not clear.Despite genetic susceptibility loci for these diseases being strongly linked to the HLA region,these are generally distinct across all three disease entities.Intriguingly,there is barely any signi?cant genetic over-lap between PBC and PSC.Indeed,clinical overlap of PBC and PSC is not a well-recognized entity.

Recent highlights from high-throughput genetic studies of autoimmune liver disease

In the last decade,there have been major efforts in Europe,North America and Japan to establish large,well-characterised patient cohorts for high-throughput genetic studies of PBC and PSC, and to a lesser extent,AIH.Four GWAS[1–4]and two iCHIP-asso-ciation[5,6]studies of PBC have been published;and two GWAS of PSC followed by a number of replication studies,and a recent iCHIP association study of PSC[7,8,21,32–35].High-throughput genetic studies have revolutionized the study of complex dis-eases,changed the genetic landscape of autoimmune liver dis-ease and highlight the shared genetic basis of diverse autoimmune conditions.Risk loci for PBC and PSC appear to be enriched for gene products involved in innate or acquired immune responses,consistent with an autoimmune component to pathogenesis.However,more work is required to con?rm can-didate genes,to evaluate the functional consequences of risk vari-ants and to understand how functional changes contribute to disease-speci?c pathologies.

GWAS have clearly demonstrated that the major component of the genetic architecture of PBC and PSC is within the HLA region.As expected in a genetically complex disease,GWAS also identi?ed several novel non-HLA variants,but all lie in immuno-related genes.In PBC,candidate genes are potentially involved in regulation of the immune system,from the development and dif-ferentiation of the myeloid cell compartment(SPIB,IRF5,IRF8, and IL-7R)to antigen presentation and T cell differentiation(class II HLA,CD80,IL12,IL12R,TYK2,STAT4,SOCS1)up to B cell function (SPIB,IRF8,PLC-L2,SPIB,PLC-L2,IKZF3,CXCR5).In PSC,there is an overwhelming contribution to disease risk by the HLA(in partic-ular HLA class I genes HLA-B and HLA-C).The immunological implications of the PSC associated HLA variants are not entirely clear.It is possible there is a protective effect of the HLA-C2killer immunoglobulin receptors(KIRs)ligand variant on PSC develop-ment[36].The non-HLA?ndings in PSC to some extent indicate that the proposed hypotheses on PSC pathogenesis related to autoimmune mechanisms(IL2and IL2RA),bile acid toxicity (GPBAR1),and mechanisms related to the concomitant IBD(IL2/ IL21,IL2RA,REL etc.)might operate in concert to cause the disease.

However,more work is required to con?rm candidate genes, to evaluate the functional consequences of risk variants and to understand how functional changes contribute to disease-speci?c pathologies.

A GWAS of AIH in European and Japanese cohorts are under-way and results from these studies will be reported by2014.

GWAS typically identify common genetic variants with small effect sizes,leading to incomplete tagging of rarer variants with a potentially higher phenotypic impact.Also,GWAS have identi?ed only a small number of the causal variants for recently identi?ed genetic loci(mainly intronic and intergenic)which,in turn,inter-pret only a small part of the genetic contribution to these dis-eases(i.e.,‘missing heritability’).To identify the rare genetic variants and explain the missing heritability sequencing the use of emerging platform is required.Whole-genome and whole-exome sequencing(which focuses on the protein-coding exons and exon/intron boundaries containing splicing signals)are becoming increasingly available but present signi?cant chal-lenges with respect to data analysis,interpretation,and display. Integration of the other comprehensive‘‘-omics’’methodologies into the analysis of genetic variants may help to explain their potential effects.Transcriptomics aims to elucidate the tran-scripts of the genome or gene expression levels on the RNA level under varying conditions;genomics/transcriptomics screens can yield information on both gene expression and alternative splic-ing and can help to identify previously unknown genes.Finally, proteomics studies the proteome in a cell compartment,tissue or organism comprising all proteins that are encoded in the gen-ome and represents the next step in the study of biological sys-tems[37,38].Studying the genome/proteome in AILD will shed light on common and distinct pathological pathways leading to AILD.

As with translation of many genomic discoveries,translating this work into direct health bene?ts will require interaction among a wide array of biomedical disciplines,including genom-ics,molecular biology,clinical medicine,pharmacology and bioinformatics.

Shared genetic basis of different autoimmune diseases

An emerging theme in the genetics of complex disorders is the considerable overlap of genetic susceptibility factors between related diseases.The recent PSC iCHIP study[8]has revealed strong positive correlation of44non-HLA loci identi?ed in GWAS of seven clinically associated autoimmune disorders,including ulcerative colitis(UC),Crohn’s disease(CD),T1DM,coeliac dis-ease(CeD),psoriasis,rheumatoid arthritis(RA)and sarcoidosis, suggesting close similarity in the genetic architecture of PSC and each of these conditions.Of these loci,11achieved gen-ome-wide signi?cance and33loci achieved suggestive signi?-cance(p<5?10à5)in the standard test of association. Functional network analysis showed that candidate genes at pleiotropic loci were related in terms of their function,highlight-ing common pathways involved in the pathogenesis of PSC and clinically associated disorders.These observations suggest there might be distinct mechanisms by which autoimmunity occurs, each mechanism predisposing to a particular phenotype or set of phenotypes.This might also suggest that there might be unique immunologic pathways that we have to focus on for ther-apeutic intervention(Fig.2

). Frontiers in Liver Transplantation

212Journal of Hepatology2014vol.60j210–223

An alternative interpretation is that the pervasive sharing of risk variants of genes across a wide range of autoimmune dis-eases implies that the common variants identi?ed through GWAS are not particularly helpful in explaining the organ-speci?c man-ifestation of a given autoimmune trait.The most likely explana-tion for the ambiguity of the genetic ?ndings is that phenotypes might be the result of gene-gene interaction (epista-sis)or gene-environment interaction.From this perspective,the study of the ‘exposome’,which represents the environmental fac-tors which we are exposed to in a lifetime,represents a cutting-edge tool in the study of autoimmunity [39];the study of the exposome needs to address exogenous factors,such as tobacco smoke,diet,drugs,occupational exposures,environmental pollu-tants,ultraviolet radiation,heavy metal,and endogenous factors related to the environment,including by-products of in?amma-tion,lipid peroxidation and oxidative stress [40].Some of these components may act as nucleophiles or electrophiles,and as such,would be capable of DNA and protein modi?cation [41].Recent studies in T2DM have shown that the exposome can indeed be measured and characterized using environmental-wide association studies (EWAS),where epidemiological data are comprehensively interpreted in a manner similar to GWAS [42].Growing interest in the ?eld of autoimmune diseases is in the exploration of the ‘infectome’,which is the part of the expo-some referring to the collection of an individual’s infectious expo-sures,which are associated with the disease.An autoimmune disease can be induced or triggered by infectious agents.In many cases,it is not a single infection but rather the ‘burden of infec-tions’from childhood that is responsible for the induction of autoimmunity.In contrast,the hygiene hypothesis underlines the protective role played by infections [39].Further hints regarding infective factors potentially involved in the develop-ment of or protection against autoimmunity can be provided by the study of the ‘microbiome’,de?ned as the community of com-mensal,symbiotic,and pathogenic microorganisms that share our body space.For example,in the case of PBC,it may

be

https://www.wendangku.net/doc/5617853206.html,work map showing complexity of shared genetic effects.Some shared risk loci are involved in the pathogenesis of several autoimmune disorders.These loci are clustered in the centre of the ?gure.Other shared risk loci are associated with only two conditions.Numerous risk loci are associated with a single disorder.It is plausible that the central loci associated with numerous conditions are those involved in autoimmunity in general,whereas risk loci speci?c to a given disease determine the particular phenotype.AITD,autoimmune thyroid disease;AS,ankylosing spondylitis;CeD,coeliac disease;CD,Crohn’s disease;PSC,primary sclerosing cholangitis;MS,multiple sclerosis;PBC,primary biliary cirrhosis;RA,rheumatoid arthritis;SLE,Systemic lupus erythematosus;SS,systemic sclerosis;T1DM,type 1diabetes mellitus;UC,ulcerative colitis.Reproduced from [156].With permission from the Editor in Chief Prof.Eric M.Gershwin.

JOURNAL OF HEPATOLOGY

Journal of Hepatology 2014vol.60j 210–223213

pertinent to understand the normal microbiome of the urinary bladder and vagina,as infections in these sites have been associ-ated with PBC[43].

Studying the role of the different aspects of the exposome in the development of autoimmune diseases could complement classical immunological research tools and GWAS.Several factors suggest that PBC may represent an ideal model disease for the investigation of the role of the exposome:its relatively high prevalence com-pared to other immunologic diseases;the well-known evidence in support of a combination of genetic,environmental,and infec-tious factors involved in the pathogenesis of the disease;the variability of its natural history,which suggests the presence of high-risk and low-risk patients;the association with other autoim-mune diseases;and the lack of need of immunosuppression,which might impair the immunological assessment of the‘infectome’(the infective component of the exposome).More recently,there is indicative evidence that in addition to genetics,other comple-mentary mechanisms are involved in the pathogenesis of autoim-munity,in particular,epigenetics–de?ned as stable and heritable patterns of gene expression caused by mechanisms other than changes in the underlying DNA sequence.Epigenetic mechanisms primarily consist of DNA methylation,histone modi?cations and small non-coding RNA transcripts.Epigenetic marks can be affected by age and other environmental triggers,and can there-fore provide a plausible link between environmental factors and the onset and development of autoimmune liver disease[44].

Below,we review the basis of the autoimmune response toward the graft in patients with and without previous autoimmune disease and examine the current evidence on mechanisms that lead to the autoimmunity and their link to transplant rejection.

Liver transplantation for autoimmune liver disease

AIH,PBC,and PSC represent three major indications for liver transplantation(LT)in Western countries[45].Paradoxically, the rise in the documented prevalence of PBC[46]contrasts with the fall in the transplant rate(Table1).Reasons for this decline are not clear but may relate to a changing pattern of disease, increased rates of diagnosis,more effective treatment or other causes.The proportion LTs for AIH and PSC has remained stable (2%and4%,respectively);in some areas,such as in the Scandina-vian countries,which have a relatively low prevalence of hepati-tis C and alcoholic liver disease(ALD),PSC is the leading indication accounting for16%of the LT[47].LT in AILD is indi-cated when liver failure occurs with complications similar to those for end-stage liver disease caused by other aetiologies.An unacceptable quality of life because of severe,treatment-resis-tant pruritus or severe hepatic encephalopathy may also merit consideration for transplantation.Fatigue in PBC and other chole-static liver diseases is often severe and disabling.Cross-sectional studies have shown no evidence of improved fatigue after LT [48,49].We have recently shown,in a single-centre,prospective, longitudinal cohort that fatigue improves after LT.However,44% of the31patients had moderate to severe fatigue at two years after LT.Whether this improvement is enough to justify organ allocation in patient with fatigue alone,without liver failure, remains still an open issue[50].

Recurrent cholangitis related to dominant strictures or intra-hepatic strictures not amenable to dilatation and stenting in PSC rarely represent indication for LT.Cholangiocarcinoma (CCA)may complicate PSC,with a10-year incidence of7–9% [51].Risk factors for CCA include advanced disease(elevated bil-irubin,variceal bleeding),proctocolectomy,chronic ulcerative colitis with colorectal cancer or dysplasia,long history of in?am-matory bowel disease,and polymorphisms of the NKG2D gene [52–54].Historically,the presence of such a tumour contra-indi-cates LT because of the high rate of recurrence.However,studies from the Mayo Clinic suggest that in highly selected cases, aggressive treatment with chemo-and radiotherapy may allow some patients to have a good outcome(54).Hepatocellular carci-noma(HCC)occurs in patients with AILD with cirrhosis,with a variable incidence(AIH:1.9%per year[55];PBC4%–12.3at 10years[56–58];PSC:2%per year[59,60])and represents an indication for LT.The prioritization of these patients for LT is the same as for other liver diseases associated with HCC.

Outcomes after LT for AILD are generally excellent(Table1). Speci?c post-transplant issues in patients transplanted for AILD are recurrence of the original disease and a higher rate of rejec-tion,which may both impact on survival.Furthermore,PSC trans-plant recipients with concomitant IBD are more likely to develop colon cancer,with a cumulative incidence at10years after LT of 8.2%[61].Routine surveillance colonoscopy is therefore usually recommended.

Recurrence of autoimmune liver disease after liver transplantation

Autoimmune liver disease might be expected not to recur after LT as the grafts should be protected from such injury from the outset by levels of immunosuppression that prevents allograft rejection. However,AIH,PBC,and PSC recur in many recipients and recur-rence may be more aggressive than the original disease(Table2).

Table1.Transplant activity and survival for autoimmune liver diseases in two different eras(1988–2001and2000–2009)in Europe.The number of LT for AIH and PSC has remained stable over the time while the number of LT for PBC,despite the rise in the prevalence of the disease,has declined.

European Liver Transplant Registry report[45,145].

Frontiers in Liver Transplantation

214Journal of Hepatology2014vol.60j210–223

Recurrent AIH(rAIH)is reported in about23%and is diagnosed at a median interval of26months,but recurrence after more than 10years after transplant and in those taking17.5–20mg of prednis-olone per day,has been reported.rAIH may be seen with normal liver tests so the use of protocol biopsy may identify those with clin-ically silent recurrence[62].Histological features of rAIH include a mononuclear in?ltrate of lymphocytes and plasma cells extending from portal tracts to lobular parenchyma and an absence of features of acute rejection such as endothelialitis and ductulitis.There is some evidence that corticosteroid withdrawal does not precipitate rAIH[63],although recurrence is often responsive to an introduc-tion of,or an increase in the dose of corticosteroids.

The diagnosis of recurrent PBC(rPBC)is made on histological criteria since liver tests are nonspeci?c and AMA persist irrespec-tive of evidence of graft histology.The reported prevalence rate of rPBC ranges from0%to35%.The reported incidence rate is21–37%at10years and43%at15years[62].The median time to rPBC ranges between3and5.5years.The reported recurrence fre-quency rate increases with time and varies in part because of dif-ferent diagnostic criteria as well as different policies for protocol biopsies,since recurrence may be present with normal liver tests. Because of the bene?cial effect of UDCA in slowing the progression of PBC in the native liver,this is commonly offered to those with evidence of rPBC.However,the assessment of drug ef?cacy is chal-lenging as many patients have normal or near normal liver tests at diagnosis;the current data,which are limited,suggest that UDCA does not seem to in?uence patient and graft survival[64].

PSC has been shown to recur between10%and27%,with a mean interval between LT and onset of6months to5years [62].Recurrent PSC(rPSC)needs to be distinguished from sec-ondary sclerosing cholangitis.There are several causes of second-ary sclerosing cholangitis,including hepatic artery thrombosis, ischemic and ischemia/reperfusion injury,infection with CMV or HIV,ABO incompatibility and rejection;the diagnosis is made on showing multiple non-anastomotic strictures with no other risk factors.There is no established medical therapy for rPSC. UDCA may be of bene?t in those with coexisting UC,as some sug-gest it reduces the risk of colon cancer[65].Interventional chol-angiographic treatment of biliary strictures should be considered when dominant strictures are present;however,such approaches are rarely feasible since most strictures are multiple and most recipients have a Roux loop(since the disease affects both the intra-and extra-hepatic bile ducts).Therefore,magnetic resonance imaging(MRI)is often used to diagnose or exclude rPBC although percutaneous transhepatic cholangiography(PTC)allows both diag-nostic and,in some cases,therapeutic intervention.Recent series report the successful use of single and double balloon enteros-copy in patients with roux loop[66,67].

Immunosuppressive strategies to reduce the risk of recur-rence of AILD are dif?cult to be evaluated since majority of stud-ies are retrospective and detailed information,including changes in immunosuppression and disease stage where the change of medication took place,are missing.

Graft loss due to recurrent disease is not a major issue in PBC, but it is in AIH and PSC(percentage of graft lost due to recurrent disease:1.3%in PBC;6.2%in AIH;and8.4%in PSC)[68];the rate of graft loss from rAIH may be falling because of increasing long-term use of corticosteroids in these patients.

LT provides a unique setting to help understand the patho-physiology of autoimmune liver https://www.wendangku.net/doc/5617853206.html,ing protocol fol-low-up and liver biopsies to pinpoint the onset of disease,it might be possible to elucidate the innate and adaptive immune processes active at the earliest stage of disease.In practical terms, this is not easily achieved since the majority of centres have dis-continued the practice of protocol liver biopsies in allograft recip-ients other than HCV.

Risk factors for recurrent AILD

Assessment of risk factors for recurrence of AILD requires not only comparison between patients with and without recurrence (which is problematic because some patients without recurrence at the time of analysis will subsequently develop recurrence)but also a consistent approach to the diagnostic criteria,and in the use of protocol biopsies.

AIH:The pathogenesis of recurrent AIH is unclear;recent data sug-gest that recipient memory T cells might be driving the auto-immune process,which means that auto-antigenic peptides are being recog-nized on mismatched donor HLA class1and2molecules in the graft [69].rAIH can occur on the background of immunosuppression that is adequate to prevent rejection[70].This might be interpreted as meaning that such levels of immunosuppression inhibit auto-antigen speci?c T regs leading to subsequent in?ammation and hepatocyte injury[71].Risk factors for recurrence of AIH after OLT have been assessed in several studies,but most remain unvalidated and contro-versial.Donor and recipient matching for HLA-DR3or DR4is a contro-versial risk factor[62,72,73].The analysis of HLA matching from the National Institute of Health(NIH)Liver Transplantation Database showed that HLA-DR locus mismatching was a signi?cant risk factor for recurrence of AIH[74].A recent study reports that elevated IgG before LT and moderate to severe in?ammation in the explant are asso-ciated with an increased risk of recurrent autoimmune hepatitis.These ?ndings suggest that recurrence of autoimmune hepatitis may re?ect incomplete suppression of disease activity prior to LT[75].

PBC:Several studies have shown that tacrolimus-based immu-nosuppression is associated with an increased risk of recurrence of PBC,with a reduced time to recurrence compared with ciclosporin [76,77].Whether tacrolimus is truly associated with recurrence or represents a surrogate of another time-dependent variable is unknown.The role of genetic factors has not been investigated thoroughly.The human leukocyte antigen(HLA)pro?le and HLA donor-recipient mismatch have controversial association in rPBC [78–82].We have recently identi?ed the association between rPBC and a non-HLA locus(rs62270414)in position3q25,which hosts the IL12A gene.We found an additive effect between this SNP and the choice of calcineurin inhibitor at one year with the risk of rPBC;this is greatest with a combination of tacrolimus at one year and rs62270414genotype AG or GG,and least with a combi-nation of ciclosporin at1-year and rs62270414genotype AA[77]. Although these?ndings are preliminary and require con?rmation, they are intriguing in that they suggest mechanisms causing PBC in the allograft and native liver might be similar.

PSC:An intriguing risk factor well documented for rPSC is the link with IBD.Speci?cally,the absence of in?ammation in the intestine,either due to absence of concurrent IBD or colectomy before or during LT has a protective effect against rPSC[83];this is in keeping with the hypothesis of aberrant homing of mucosal lymphocytes to the liver in the development of PSC[84].How-ever these?ndings were not consistent in all studies.rPSC has also been associated with acute cellular rejection(ACR),particu-larly steroid resistant ACR[85–87].It is currently unknown whether rPSC results from a response to an

immunogenic JOURNAL OF HEPATOLOGY

Journal of Hepatology2014vol.60j210–223215

damaged biliary system due to ACR,or common factors predis-pose to both ACR and recurrent disease.Genetic factors that have been associated with biliary strictures after LT include metallo-proteinase-2genotype [88]and CCR5-D 32[89].A recent series of 114PSC living donor LT (LDLT)from Japan [90]has shown that grafts from ?rst-degree-relatives,especially par-ents,carried the greatest risk of rPSC.A partial explanation may be that ?rst-degree relatives and siblings have a prevalence of PSC about 100-fold that of nonrelatives [91].The incidence of recurrence in recipients with grafts from related donors other than parents as well as nonrelated donors was similar to those reported for deceased donors LT [87].Another possible mechanism contrib-uting to the effect of ?rst-degree-related donors might be linked to the effect of a shared genetic disposition in a blood-related recipi-ent and donor pair including the HLA system.Rejection after liver transplantation in autoimmune liver disease The reported incidence of ACR after LT generally shows a large variation between different centres and time periods (Table 3),and this is partially related to evolving immunosuppressive strat-egies,different policy on protocol biopsies and to a lesser extent,discrepancies in the diagnostic criteria for rejection.There are rel-atively few published studies with speci?c focus on the incidence of rejection after LT according to underlying disease,and there are no studies focused on characterizing histopathological differ-ences in the in?ammatory in?ltrates of ACR in different liver dis-ease.Based on available data,and the variation in reporting rejection rates,it is hard to state with certainty that patients transplanted for autoimmune condition carry a higher risk of acute cellular rejection (ACR)compared to other patient groups.However,there is some evidence that patients transplanted for AILD are more likely to experience ACR compared to those transplanted for non-autoimmune liver disease.It is of interest that indications for which there is no evidence of immune involvement in the pathogenesis of the original liver disease,such as alcoholic hepatitis and fulminant hepatic failure from paracet-

amol overdose,are associated with the lowest incidence of ACR

[92,93].AIH :A few series reported that patients transplanted for AIH were more likely to develop both early acute rejection and late

acute rejection (LAR,acute rejection after 90days post LT)[94–98].One study showed a higher incidence of ACR requiring T cell depleting antibodies,such as OKT3treatment,in the ?rst 12months post-OLT [98].However a higher rate of ACR does not seem to affect the graft survival.We have recently shown

Table 2.Published series of recurrent autoimmune liver disease after liver

transplantation.

ACR,acute cellular rejection;AIH,autoimmune hepatitis;Aza,Azathioprine;CCA,cholangiocarcinoma;CyA,Ciclosporin;CIT,cold ischemic time;ECD,extended criteria donor;HLA,human leukocyte antigen;IBD,in?ammatory bowel disease;IMS,immunosuppression;LT,liver transplantation;MMF,Mycophenolate Mofetil;n.d.,not determined;Pred,prednisolone;PBC,primary biliary cirrhosis;PSC,primary sclerosing cholangitis;Tac,

tacrolimus.

Frontiers in Liver Transplantation

216Journal of Hepatology 2014vol.60j 210–223

in the Birmingham cohort(period2000–2010)that the risk of developing LAR was not increased in those transplanted for AIH.This might be explained by the policy of long-term steroid treatment in patients transplanted for AIH introduced in Birming-ham after2000[92].Unfortunately,patients transplanted for AIH have been shown to have a higher frequency of chronic ductope-nic rejection(CR)or‘ductopenia’,which affects more than50%of portal tracts and an obliterative arteriopathy affecting large-and medium-sized arteries,which occur generally after the?rst year post-LT[93,98].Data from an older cohort in Birmingham(period 1982–1998)showed that patients transplanted for AIH,who developed CR were younger than other AIH patients at LT and more often had histological features of moderate to severe acute rejection on early post-LT biopsies[98].Risk factors for CR in AIH have not been reported in other series.The impact of improve-ments in immunosuppression on the risk of CR remains uncertain.

PBC:There are reports showing patients transplanted for PBC suffer more frequently from ACR[98,95,98–101].We recently reported that PBC recipients have one of the highest risks of LAR,with an odds ratio of2.1,compared to those with hepatitis C that had the lowest risk of LAR.A pre-LT diagnosis of PBC and a young recipient age were the only independent predictors of LAR in the Cox logistic regression model.In this study,graft survival was worse in those with LAR,but we have not speci?cally assessed the outcome of those transplanted for PBC[92].

PSC:Many older series have reported a higher incidence of ACR in patients transplanted for PSC[100,102].Again,the num-ber of ACR episodes had no impact on patient or graft survival but such an effect may be masked by relatively small numbers and the heterogeneity of patients.In our recent Birmingham cohort those transplanted for PSC had one of the highest risks of LAR with an OR of1.8[92].There are con?icting data about whether the presence of IBD has an adverse impact on the risk of rejection of PSC after the transplantation.Some groups have reported a higher incidence of ACR in PSC patients with ulcer-ative colitis(UC)compared with PSC patients without UC [96,103–105].These data were not con?rmed in other cohorts [106].

The reason why patients with AILD might have an increased frequency of rejection is not clear.There are recent data from the lung transplantation?eld suggesting that pre-existing immune response to self-antigens might augment the risk of developing alloimmune response to mismatched donor antigens [107–109].

Table3.Published series of acute and chronic rejection in autoimmune liver

disease.

ACR,acute cellular rejection;ALD,alcoholic liver disease;CMV,cytomegalovirus;HCV,hepatitis C virus;IBD,in?ammatory bowel disease;n.d.,not

determined.

JOURNAL OF HEPATOLOGY Journal of Hepatology2014vol.60j210–223217

NK cells may be important because of their ability to recog-nize allogeneic MHC antigens and their potent cytolytic activ-ity;they have emerged as a focus of interest in the transplant ?eld as they might participate in the immune response in both acute and chronic rejection of solid organ allografts [110].They possess a variety of inhibitory and acti-vating receptors,such as the KIRs,which recognize MHC class I molecules and kill target cells that display reduced levels of MHC class I antigens.There is evidence that KIR interaction with donor HLA-C ligands leads to a differential degree of NK cell inhibition and this might in?uence the development and degree of CR,subsequent ?brosis and outcome of the allograft [111].However,the effect of NK epitope mismatching on ACR after LT is uncertain.Modulation of KIR and donor HLA (partic-ularly HLA-C)interactions might represent an important novel approach to promote long-term graft and patient survival after organ transplantation.This is of interest since particular combi-nations of KIRs and HLA class I ligands that reduce NK cell inhibition have been shown to increase the susceptibility to autoimmune diseases in general [112];speci?cally,particular

genetic variants of ligands for NK cell receptors might increase

the risk of PSC [113].Consistent with this,an increase in NK cells in the liver in PSC,compared with other liver diseases

has been described [114].NK cells have been called into ques-tion in PBC,since they have been shown to be involved in the destruction of cholangiocytes,and NK-T cells are partly responsible for the exacerbation of disease in PBC [115–117].Furthermore,a marked suppression of anti-mitochondrial auto-antibodies (AMA)and cytokine production from autoreactive T cells has been shown in a murine model of PBC following in-vivo depletion of NK and NK-T cells [118].These data overall imply a major role for NK cells effector mechanisms in the pathogenesis of AILD.These might represent some of the effec-tors of a ‘crosstalk’between alloimmune response and autoim-mune response after organ transplant that perpetuate each other,and could in part explain why those transplanted for AILD are more likely to experience rejection (Fig.3).While early ACR does not seem to impact on long-term out-come,CR is much more closely associated with graft failure.It was previously assumed that mainly alloimmune responses con-tribute to the pathogenesis of CR.However,more recent ?ndings,

particularly in the ?eld of lung transplantation,demonstrate that autoimmunity to tissue-restricted self-antigens may contribute to the immunopathogenesis of CR following transplantation [109].Some authors have therefore proposed that the autoim-mune component should be recognized in the pathogenesis of CR and be considered in developing new strategies for preventing and/or treating CR following transplantation.

De novo autoimmune hepatitis after liver transplantation A clinical entity sharing the biochemical,immunological,and his-tological characteristics of AIH,called de novo AIH (dn-AIH),has been well described in adults and children undergoing LT for a range of diseases unrelated to autoimmunity [119](Table 4).The clinical manifestations of dn-AIH are similar to those of recur-rent AIH including a prominent plasma cell in?ltrate with interface Table 4.Published series of de novo autoimmune

hepatitis.

?Age at presentation;age at transplant not reported in the original paper.

AIH,autoimmune hepatitis.

Frontiers in Liver Transplantation

218Journal of Hepatology 2014vol.60j 210–223

hepatitis,hypergammaglobulinaemia,increased serum IgG levels, and autoantibodies.Dn-AIH has also been diagnosed in the absence of autoantibodies[120]and in some patients without increased serum IgG levels or autoantibodies[121].Such varia-tions in diagnoses makes assessment of the literature challenging. Dn-AIH generally presents after one year post-LT and usually responds well to increased immunosuppression,but some cases progress to cirrhosis or graft failure[122].As in recurrent autoim-mune hepatitis,the HLA status of the recipient[123],the duration after LT[124],and the number of rejection episodes[125,126]have been proposed as contributing factors,but none of these has been consistently recognized as predictive of its occurrence.However, weaning from corticosteroid therapy does not seem to be a trigger.

The immune response in dn-AIH may be directed against allo-antigens,neo-antigens,or self-antigens.An alloantigen in dnAIH has been identi?ed in the glutathione-S-transferase T1(GSTT1), which is an alloantigen present in some individuals and that gener-ates alloantibodies in those who lack it[127].The gene that encodes GSTT1is absent in20%of the white population,and GSTT1donor/ recipient genotype mismatch has been suggested as a necessary con-dition for the appearance of autoantibodies and de novo AIH[127]. However,dn-AIH has also been described in the absence of a GSTT1 mismatch[128].There is evidence that the choice of calcineurin inhibitor may in?uence the development of de novo AIH mediated by anti-GSTT1antibodies,with patients treated with tacrolimus hav-ing a lower occurrence[129].These observations support the concept that dn-AIH may represent an alloimmune response(i.e.,a form of rejection),in which immune-mediated injury is directed towards hepatocytes rather than bile ducts or vascular endothelium;and GSTT1might represent not the only alloantigen that can trigger an autoimmune response.Further support for an alloimmune mecha-nism in dn-AIH is the strong correlation with previous rejection his-tory and steroid dependence[130].

Alternatively,the in?ammatory response within the donor liver may also unmask neo-antigens and intensify the co-stimu-latory signals that activate lymphocytes[131–133].

Some argue that the immune response in de-AIH may be direc-ted against self-antigens.It has been shown that bronchial administration of anti-MHC class I antibodies in the native lungs of HLA-mismatched mice induced bronchiolar scarring,a manifes-tation of chronic allograft rejection in the lung;this is accompanied by up-regulation of IL17and de novo antibody formation to the self-antigens,such as K-a1-tubulin,and collagen V,also seen in chronic human lung rejection[134].Authors have hypothesised that chronic alloimmune injury may release protected self-anti-gens,which elicit autoantibody formation,and that the cycle may be perpetuated by ongoing IL17signaling,a known facilitator of alloimmunity and autoimmunity.Further supporting the auto-immune hypothesis is the presence of a plasma cell in?ammatory in?ltrates,hallmark of autoimmune injury,and the fact that anti-MHC class I antibodies fail to induce bronchiolar scarring in B cell de?cient mice[135].

Some experts argue that rejection and dn-AIH are part of the same spectrum[136];rejection during the early stage post-trans-plant is driven by an MHC-restricted and epitope speci?c process; the resultant graft damage may lead to T cell responses to other graft antigens and breaks tolerance to self-antigens leading to dn-AIH.

An autoimmune-like hepatitis has also been described in LT recipients treated with PegIFN and RBV for recurrent hepatitis C,with no history of AILD[137].

Histological?ndings are an essential element in the differential diagnosis between dn-AIH,ACR,LAR,and CR.The higher propor-tion of plasma cells and the severity of the interface activity(more typical in AIH)and the prevalence of bile duct damage(character-istic of rejection)are currently used as markers,albeit imprecise ones.However,no accurate limit for the percentage of plasma cells has been established,and none of these criteria have been tested prospectively for reproducibility,predictive value,or an associa-tion with serological evidence of autoimmunity.The time interval between disease occurrence and LT is another important diagnos-tic clue[138].Diagnostic dif?culties arise when ACR,CR or AIH develop at uncharacteristic intervals after LT[139,140]or when histological manifestations of graft dysfunction are atypical [141,142]or inexplicable[138,143,144].Future studies aimed at investigating the role of autoantibody and the antigenic speci?city of the liver-in?ltrating lymphocytes in patients with autoimmune disorder after LT are therefore

warranted.

JOURNAL OF HEPATOLOGY

Journal of Hepatology2014vol.60j210–223219

Conclusions

AILD remains a good indication for LT with excellent patient and graft outcomes.Recurrence of the original disease,particularly of PSC,represents a signi?cant cause of graft loss after LT.Preven-tive or therapeutic strategies are limited by the lack of a full understanding of the disease pathogenesis in the native liver. LT provides a unique setting to help understand the pathophysi-ology of AILD.However,variations in clinical practice and the use of protocol liver biopsies means that the understanding of the severity and risk factors for recurrent disease and evaluation of therapeutic interventions is,at best,limited.

A higher risk of both acute cellular and ductopenic rejection is a further challenge in patients transplanted for autoimmune con-ditions.Early ACR does not impact negatively on long-term out-come and may promote tolerance,while CR is a rare but important cause of late graft dysfunction and graft loss.Immuno-logical factors responsible for the original liver disease may be active post-transplant and potentially act as a predisposing con-dition for acute and chronic rejection.

Con?ict of interest

The authors declared that they do not have anything to disclose regarding funding or con?ict of interest with respect to this manuscript.

Acknowledgment

Authors gratefully acknowledge Kelly Spiess for support in proofreading.

References

[1]Hirsch?eld GM,Liu X,Xu C,Lu Y,Xie G,Lu Y,et al.Primary biliary cirrhosis

associated with HLA,IL12A,and IL12RB2variants.N Engl J Med 2009;360:2544–2555.

[2]Liu X,Invernizzi P,Lu Y,Kosoy R,Lu Y,Bianchi I,et al.Genome-wide meta-

analyses identify three loci associated with primary biliary cirrhosis.Nat Genet2010;42:658–660.

[3]Mells GF,Floyd JA,Morley KI,Cordell HJ,Franklin CS,Shin SY,et al.

Genome-wide association study identi?es12new susceptibility loci for primary biliary cirrhosis.Nat Genet2011;43:329–332.

[4]Nakamura M,Nishida N,Kawashima M,Aiba Y,Tanaka A,Yasunami M,

et al.Genome-wide association study identi?es TNFSF15and POU2AF1as susceptibility loci for primary biliary cirrhosis in the Japanese population.

Am J Hum Gen2012;91:721–728.

[5]Juran BD,Hirsch?eld GM,Invernizzi P,Atkinson EJ,Li Y,Xie G,et al.

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at13q14,multiple independent associations at four established risk loci and epistasis between1p31and7q32risk variants.Hum Mol Genet2012;21:5209–5221.

[6]Liu JZ,Almarri MA,Gaffney DJ,Mells GF,Jostins L,Cordell HJ,et al.Dense

?ne-mapping study identi?es new susceptibility loci for primary biliary cirrhosis.Nat Genet2012;44:1137–1141.

[7]Karlsen TH,Franke A,Melum E,Kaser A,Hov JR,Balschun T,et al.Genome-

wide association analysis in primary sclerosing cholangitis.Gastroenterol-ogy2010;138:1102–1111.

[8]Liu JZ,Hov JR,Folseraas T,Ellinghaus E,Rushbrook SM,Doncheva NT,et al.

Dense genotyping of immune-related disease regions identi?es nine new risk loci for primary sclerosing cholangitis.Nat Genet2013;45:670–675.

[9]Manns MP,Czaja AJ,Gorham JD,Krawitt EL,Mieli-Vergani G,Vergani D,

et al.Diagnosis and management of autoimmune hepatitis.American Association for the Study of Liver Diseases.Hepatology 2010;51:2193–2213.[10]European Association for the Study of the Liver.EASL clinical practice

guidelines:management of cholestatic liver diseases.J Hepatol 2009;51:237–267.

[11]Carbone M,Mells GF,Pells G,Dawwas MF,Newton JL,Heneghan MA,et al.

Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid.Gastroenterology 2013;144:560–569.

[12]Gong Y,Gluud C.Methotrexate for primary biliary cirrhosis.Cochrane

Database Syst Rev2005;20:CD004385.

[13]Combes B,Emerson SS,Flye NL,Munoz SJ,Luketic VA,Mayo MJ,et al.

Methotrexate(MTX)plus ursodeoxycholic acid(UDCA)in the treatment of primary biliary cirrhosis.Hepatology2005;42:1184–1193.

[14]Leung J,Bonis PA,Kaplan MM.Colchicine or methotrexate,with ursodiol,

are effective after20years in a subset of patients with primary biliary cirrhosis.Clin Gastroenterol Hepatol2011;9:776–780.

[15]Lee YM,Kaplan MM.Ef?cacy of colchicine in patients with primary biliary

cirrhosis poorly responsive to ursodiol and methotrexate.Am J Gastroen-terol2003;98:205–208.

[16]Honda A,Ikegami T,Nakamuta M,Miyazaki T,Iwamoto J,Hirayama T,et al.

Anticholestatic effects of beza?brate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid.Hepatology 2013;57:1931–1941.

[17]Ohira H,Sato Y,Ueno T,Sata M.Feno?brate treatment in patients with

primary biliary cirrhosis.Am J Gastroenterol2002;97:2147–2149.

[18]Iwasaki S,Ohira H,Nishiguchi S,Zeniya M,Kaneko S,Onji M,et al.The

ef?cacy of ursodeoxycholic acid and beza?brate combination therapy for primary biliary cirrhosis:a prospective,multicenter study.Hepatol Res 2008;38:557–564.

[19].

[20]Lindor KD,Kowdley KV,Luketic VA,Harrison ME,McCashland T,Befeler AS,

et al.High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.Hepatology2009;50:808–814.

[21]Srivastava B,Mells GF,Cordell HJ,Muriithi A,Brown M,Ellinghaus E,et al.

Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis.Scand J Gastroenterol2012;47:820–826.

[22]Bogdanos DP,Mieli-Vergani G,Vergani D.Autoantibodies and their

antigens in autoimmune hepatitis.Semin Liver Dis2009;29:241–253. [23]Gershwin ME,Selmi C,Worman HJ,Gold EB,Watnik M,Utts J,et al.Risk

factors and comorbidities in primary biliary cirrhosis:a controlled inter-view-based study of1032patients.Hepatology2005;42:1194–1202. [24]Corpechot C,Chretien Y,Chazouilleres O,Poupon R.Demographic,lifestyle,

medical and familial factors associated with primary biliary cirrhosis.J Hepatol2010;53:162–169.

[25]Watt FE,James OF,Jones DE.Patterns of autoimmunity in primary biliary

cirrhosis patients and their families:a population-based cohort study.QJM 2004;97:397–406.

[26]Feizi T,Naccarato R,Sherlock S,Doniach D.Mitochondrial and other tissue

antibodies in relatives of patients with primary biliary cirrhosis.Clin Exp Immunol1972;10:609–622.

[27]Angulo P,Peter JB,Gershwin ME,DeSotel CK,Shoenfeld Y,Ahmed AE,et al.

Serum autoantibodies in patients with primary sclerosing cholangitis.J Hepatol2000;32:182–187.

[28]Broome U,Grunewald J,Scheynius A,Olerup O,Hultcrantz R.Preferential V

beta3usage by hepatic T lymphocytes in patients with primary sclerosing cholangitis.J Hepatol1997;26:527–534.

[29]Loftus Jr EV,Harewood GC,Loftus CG,Tremaine WJ,Harmsen WS,

Zinsmeister AR,et al.PSC-IBD:a unique form of in?ammatory bowel disease associated with primary sclerosing cholangitis.Gut2005;54:91–96.

[30]Lamberts LE,Janse M,Haagsma EB,van den Berg AP,Weersma RK.

Immune-mediated diseases in primary sclerosing cholangitis.Dig Liv Dis 2011;43:802–806.

[31]Saarinen S,Olerup O,Broome U.Increased frequency of autoimmune

diseases in patients with primary sclerosing cholangitis.Am J Gastroenterol 2000;95:3195–3199.

[32]Melum E,Franke A,Schramm C,Weismüller TJ,Gotthardt DN,Offner FA,

et al.Genome-wide association analysis in primary sclerosing cholangitis identi?es two non-HLA susceptibility loci.Nat Genet2011;43:17–19. [33]Janse M,Lamberts LE,Franke L,Raychaudhuri S,Ellinghaus E,Muri Boberg

K,et al.Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2,REL,and CARD9.

Hepatology2011;53:1977–1985.

[34]Folseraas T,Melum E,Rausch P,Juran BD,Ellinghaus E,Shiryaev A,et al.

Extended analysis of a genome-wide association study in primary scleros-ing cholangitis detects multiple novel risk loci.J Hepatol2012;57:366–375

. Frontiers in Liver Transplantation

220Journal of Hepatology2014vol.60j210–223

[35]Ellinghaus D,Folseraas T,Holm K,Ellinghaus E,Melum E,Balschun T,et al.

Genome-wide association analysis in sclerosing cholangitis and ulcerative colitis identi?es risk loci at GPR35and TCF4.Hepatology2012,[Epub ahead of print].

[36]Hov JR,Lleo A,Selmi C,Woldseth B,Fabris L,Strazzabosco M,et al.Genetic

associations in Italian primary sclerosing cholangitis:heterogeneity across Europe de?nes a critical role for HLA-C.J Hepatol2010;52:712–717. [37]Manolio TA,Chisholm RL,Ozenberger B,Roden DM,Williams MS,Wilson R,

et al.Implementing genomic medicine in the clinic:the future is here.

Genet Med2013;15:258–267.

[38]Hannivoort RA,Hernandez-Gea V,Friedman SL.Genomics and proteomics

in liver?brosis and cirrhosis.Fibrogenesis Tissue Repair2012;5:1.

[39]Bogdanos DP,Smyk DS,Invernizzi P,Rigopoulou EI,Blank M,Pouria S,et al.

Infectome:a platform to trace infectious triggers of autoimmunity.

Autoimmun Rev2013;12:726–740.

[40]Rappaport SM.Implications of the exposome for exposure science.J Expo

Sci Environ Epidemiol2011;21:5–9.

[41]Smith MT,Zhang L,McHale CM,Skibola CF,Rappaport SM.Benzene,the

exposome and future investigations of leukemia etiology.Chem Biol Interact2011;192:155–159.

[42]Patel CJ,Bhattacharya J,Butte AJ.An Environment-Wide Association Study

(EWAS)on type2diabetes mellitus.PLoS One2010;5:e10746.

[43]Prince MI,Ducker SJ,James OF.Case–control studies of risk factors for

primary biliary cirrhosis in two United Kingdom populations.Gut 2010;59:508–512.

[44]Lu Q.The critical importance of epigenetics in autoimmunity.J Autoimmun

2013;41:1–5.

[45]Adam R,Karam V,Delvart V,O’Grady J,Mirza D,Klempnauer J,et al.

Evolution of indications and results of liver transplantation in Europe.A report from the European Liver Transplant Registry(ELTR).J Hepatol 2012;57:675–688.

[46]Prince MI,James OF.The epidemiology of primary biliary cirrhosis.Clin

Liver Dis2003;7:795–819.

[47]Nordic Liver Transplant Registry.Available at:

.

[48]Gross CR,Malinchoc M,Kim WR,Evans RW,Wiesner RH,Petz JL,et al.

Quality of life before and after liver transplantation for cholestatic liver disease.Hepatology1999;29:356–364.

[49]Pells G,Mells GF,Carbone M,Newton JL,Bathgate AJ,Burroughs AK,et al.

The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort.J Hepatol2013;59:67–73.

[50]Carbone M,Bufton S,Monaco A,Grif?ths L,Jones DE,Neuberger JM.The

Effect of Liver Transplantation on Fatigue in Patients with Primary Biliary Cirrhosis–A Prospective Study.J Hepatol2013,[Epub ahead of print]. [51]Claessen MM,Vleggaar FP,Tytgat KM,Siersema PD,van Buuren HR.High

lifetime risk of cancer in primary sclerosing cholangitis.J Hepatol 2009;50:158–164.

[52]Melum E,Karlsen TH,Schrumpf E,Bergquist A,Thorsby E,Boberg KM,et al.

Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms.Hepatology2008;47:90–96.

[53]Boberg KM,Bergquist A,Mitchell S,Pares A,Rosina F,Broome U,et al.

Cholangiocarcinoma in primary sclerosing cholangitis:risk factors and clinical presentation.Scand J Gastroenterol2002;37:1205–1211.

[54]Darwish Murad S,Kim WR,Harnois DM,Douglas DD,Burton J,Kulik LM,

et al.Ef?cacy of neoadjuvant chemoradiation,followed by liver transplan-tation,for perihilar cholangiocarcinoma at12US centers.Gastroenterology 2012;143:88–98,e3.

[55]Wong RJ,Gish R,Frederick T,Bzowej N,Frenette C.Development of

hepatocellular carcinoma in autoimmune hepatitis patients:a case series.

Dig Dis Sci2011;56:578–585.

[56]Harada K,Hirohara J,Ueno Y,Nakano T,Kakuda Y,Tsubouchi H,et al.

Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis:national data from Japan.Hepatology2013;57:1942–1949. [57]Shibuya A,Tanaka K,Miyakawa H,Shibata M,Takatori M,Sekiyama K,et al.

Hepatocellular carcinoma and survival in patients with primary biliary cirrhosis.Hepatology2002;35:1172–1178.

[58]Deutsch M,Papatheodoridis GV,Tzakou A,Hadziyannis SJ.Risk of

hepatocellular carcinoma and extrahepatic malignancies in primary biliary cirrhosis.Eur J Gastroenterol Hepatol2008;20:5–9.

[59]Demarchi B,Bresso F,Novero D,Palestro G,Sapone N,Pellicano R,et al.

Hepatocellular carcinoma complicating primary sclerosing cholangitis in Crohn’s disease.A case report.Minerva Gastroenterol Dietol 2007;53:279–283.[60]Harnois DM,Gores JG,Ludwig J,Steers JL,LaRusso NE,Wiesner RH.Are

patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer?J Hepatol1997;27:512–516. [61]Watt KD,Pedersen RA,Kremers WK,Heimbach JK,Sanchez W,Gores GJ.

Long-term probability of and mortality from de novo malignancy after liver transplantation.Gastroenterology2009;137:2010–2017.

[62]Duclos-Vallee JC,Sebagh M.Recurrence of autoimmune disease,primary

sclerosing cholangitis,primary biliary cirrhosis,and autoimmune hepatitis after liver transplantation.Liver Transpl2009;15:S25–S34.

[63]Campsen J,Zimmerman MA,Trotter JF,Wachs M,Bak T,Steinberg T,et al.

Liver transplantation for autoimmune hepatitis and the success of aggres-sive corticosteroid withdrawal.Liver Transpl2008;14:1281–1286.

[64]Charatcharoenwitthaya P,Pimentel S,Talwalkar JA,Enders FT,Lindor KD,

Krom RA,et al.Long-term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation.

Liver Transpl2007;13:1236–1245.

[65]Pardi DS,Loftus EV,Kremers WK,Keach J,Lindor KD.Ursodeoxycholic acid

as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis.Gastroenterology2003;124:889–893.

[66]Saleem A,Baron TH,Gostout CJ,Topazian MD,Levy MJ,Petersen BT,et al.

Endoscopic retrograde cholangiopancreatography using a single-balloon enteroscope in patients with altered Roux-en-Y anatomy.Endoscopy 2010;42:656–660.

[67]Koornstra JJ.Double balloon enteroscopy for endoscopic retrograde

cholangiopancreaticography after Roux-en-Y reconstruction:case series and review of the https://www.wendangku.net/doc/5617853206.html,h J Med2008;66:275–279.

[68]Rowe IA,Webb K,Gunson BK,Mehta N,Haque S,Neuberger J.The impact of

disease recurrence on graft survival following liver transplantation:a single centre experience.Transpl Int2008;21:459–465.

[69]Ilyas JA,O’Mahony CA,Vierling JM.Liver transplantation in autoimmune

liver diseases.Best Pract Res Clin Gastroenterol2011;25:765–782.

[70]O’Grady JG.Phenotypic expression of recurrent disease after liver trans-

plantation.Am J Transplant2010;10:1149–1154.

[71]Longhi MS,Ma Y,Mieli-Vergani G,Vergani D.Aetiopathogenesis of

autoimmune hepatitis.J Autoimmun2010;34:7–14.

[72]Ayata G,Gordon FD,Lewis WD,Pomfret E,Pomposelli JJ,Jenkins RL,et al.

Liver transplantation for autoimmune hepatitis:a long-term pathologic study.Hepatology2000;32:185–192.

[73]Milkiewicz P,Hubscher SG,Skiba G,Hathaway M,Elias E.Recurrence of

autoimmune hepatitis after liver transplantation.Transplantation 1999;68:253–256.

[74]Balan V,Ruppert K,Demetris AJ,Ledneva T,Duquesnoy RJ,Detre KM,et al.

Long-term outcome of human leukocyte antigen mismatching in liver transplantation:results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database.Hepatology 2008;48:878–888.

[75]Montano-Loza AJ,Mason AL,Ma M,Bastiampillai RJ,Bain VG,Tandon P.

Risk factors for recurrence of autoimmune hepatitis after liver transplan-tation.Liver Transpl2009;15:1254–1261.

[76]Neuberger J,Gunson B,Hubscher S,Nightingale P.Immunosuppression

affects the rate of recurrent primary biliary cirrhosis after liver transplan-tation.Liver Transpl2004;10:488–491.

[77]Carbone M,Mells GF,Alexander GJ,Westbrook RH,Heneghan MA,Sandford

RN,et al.Calcineurin inhibitors and the IL12A locus in?uence risk of recurrent primary biliary cirrhosis after liver transplantation.Am J Transplant2013;13:1110–1111.

[78]Morioka D,Egawa H,Kasahara M,Jo T,Sakamoto S,Ogura Y,et al.Impact of

human leukocyte antigen mismatching on outcomes of living donor liver transplantation for primary biliary cirrhosis.Liver Transpl2007;13:80–90.

[79]Charatcharoenwitthaya P,Pimentel S,Talwalkar JA,et al.Long-term

survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation.Liver Transpl 2007;13:1236–1245.

[80]Sanchez EQ,Levy MF,Goldstein RM,Fasola CG,Tillery GW,Netto GJ,et al.

The changing clinical presentation of recurrent primary biliary cirrhosis after liver transplantation.Transplantation2003;76:1583–1588.

[81]Khettry U,Anand N,Faul PN,Lewis WD,Pomfret EA,Pomposelli J,et al.

Liver transplantation for primary biliary cirrhosis:a long-term pathologic study.Liver Transpl2003;9:87–96.

[82]Manousou P,Arvaniti V,Tsochatzis E,Isgro G,Jones K,Shirling G,et al.

Primary biliary cirrhosis after liver transplantation:in?uence of immuno-suppression and human leukocyte antigen locus disparity.Liver Transpl 2010;16:64–73

.

JOURNAL OF HEPATOLOGY

Journal of Hepatology2014vol.60j210–223221

[83]Alabraba E,Nightingale P,Gunson B,Hubscher S,Olliff S,Mirza D,et al.A

re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts.Liver Transpl2009;15:330–340.

[84]Grant AJ,Lalor PF,Salmi M,Jalkanen S,Adams DH.Homing of mucosal

lymphocytes to the liver in the pathogenesis of hepatic complications of in?ammatory bowel https://www.wendangku.net/doc/5617853206.html,ncet2002;359:150–157.

[85]Alexander J,Lord JD,Yeh MM,Cuevas C,Bakthavatsalam R,Kowdley KV.

Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl2008;14:245–251.

[86]Campsen J,Zimmerman MA,Trotter JF,Wachs M,Bak T,Steinberg T.

Clinically recurrent primary sclerosing cholangitis following liver trans-plantation:a time course.Liver Transpl2008;14:181–185.

[87]Cholongitas E,Shusang V,Papatheodoridis GV,Marelli L,Manousou P,

Rolando N.Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl2008;14:138–143.

[88]Ten Hove WR,Korkmaz KS,Op den Dries S,de Rooij BJ,van Hoek B,Porte RJ,

et al.Matrix metalloproteinase2genotype is associated with nonanasto-motic biliary strictures after orthotopic liver transplantation.Liver Int 2011;31:1110–1117.

[89]op den Dries S,Buis CI,Adelmeijer J,Van der Jagt EJ,Haagsma EB,Lisman T,

et al.The combination of primary sclerosing cholangitis and CCR5-D32in recipients is strongly associated with the development of nonanastomotic biliary strictures after liver transplantation.Liver Int2011;31:1102–1109.

[90]Egawa H,Ueda Y,Ichida T,Teramukai S,Nakanuma Y,Onishi S,et al.Risk

factors for recurrence of primary sclerosing cholangitis after living donor liver transplantation in Japanese registry.Am J Transplant 2011;11:518–527.

[91]Bergquist A,Lindberg G,Saarinen S,BrooméU.Increased prevalence of

primary sclerosing cholangitis among?rst-degree relatives.J Hepatol 2005;42:252–256.

[92]Thurairajah PH,Carbone M,Bridgestock H,Thomas P,Hebbar S,Gunson BK,

et https://www.wendangku.net/doc/5617853206.html,te acute liver allograft rejection;a study of its natural history and graft survival in the current era.Transplantation2013;95:955–959. [93]Farges O,Saliba F,Farhamant H,Samuel D,Bismuth A,Reynes M,et al.

Incidence of rejection and infection after liver transplantation as a function of the primary disease:possible in?uence of alcohol and polyclonal immunoglobulins.Hepatology1996;23:240–248.

[94]Vogel A,Heinrich E,Bahr MJ,Rifai K,Flemming P,Melter M,et al.Long-term

outcome of liver transplantation for autoimmune hepatitis.Clin Transplant 2004;18:62–69.

[95]Seiler CA,Dufour JF,Renner EL,Schilling M,Büchler MW,Bischoff P,et al.

Primary liver disease as a determinant for acute rejection after liver https://www.wendangku.net/doc/5617853206.html,ngenbecks Arch Surg1999;384:259–263.

[96]Wiesner RH,Demetris AJ,Belle SH,Seaberg EC,Lake JR,Zetterman RK,et al.

Acute hepatic allograft rejection:incidence,risk factors,and impact on outcome.Hepatology1998;28:638–645.

[97]Molmenti EP,Netto GJ,Murray NG,Smith DM,Molmenti H,Crippin JS,et al.

Incidence and recurrence of autoimmune/alloimmune hepatitis in liver transplant recipients.Liver Transpl2002;8:519–526.

[98]Milkiewicz P,Gunson B,Saksena S,Hathaway M,Hubscher SG,Elias E.

Increased incidence of chronic rejection in adult patients transplanted for autoimmune hepatitis:assessment of risk factors.Transplantation 2000;70:477–480.

[99]Berlakovich GA,Imhof M,Karner-Hanusch J,Gotzinger P,Gollackner B,

Gnant M,et al.The importance of the effect of underlying disease on rejection outcomes following orthotopic liver transplantation.Transplan-tation1996;61:554–560.

[100]Uemura T,Ikegami T,Sanchez EQ,Jennings LW,Narasimhan G,McKenna GJ,et https://www.wendangku.net/doc/5617853206.html,te acute rejection after liver transplantation impacts patient survival.Clin Transplant2008;22:316–323.

[101]Hayashi M,Keeffe EB,Krams SM,Martinez OM,Ojogho ON,So SK,et al.

Allograft rejection after liver transplantation for autoimmune liver dis-eases.Liver Transpl Surg1998;4:208–214.

[102]Graziadei IW,Wiesner RH,Marotta PJ,Porayko MK,Hay JE,Charlton MR, et al.Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.Hepatology1999;30:1121–1127.

[103]Vera A,Moledina S,Gunson B,Hubscher S,Mirza D,Olliff S,et al.Risk factors for recurrence of primary sclerosing cholangitis of liver allograft.

Lancet2002;360:1943–1944.

[104]Narumi S,Roberts JP,Emond JC,Lake J,Ascher NL.Liver transplantation for sclerosing cholangitis.Hepatology1995;22:451–457.

[105]Miki C,Harrison JD,Gunson BK,Buckels JA,McMaster P,Mayer AD.

In?ammatory bowel disease in primary sclerosing cholangitis:an analysis of patients undergoing liver transplantation.Br J Surg 1995;82:1114–1117.[106]Jeyarajah DR,Netto GJ,Lee SP,Testa G,Abbasoglu O,Husberg BS,et al.

Recurrent primary sclerosing cholangitis after orthotopic liver transplan-tation:is chronic rejection part of the disease process?Transplantation 1998;66:1300–1306.

[107]Bharat A,Kuo E,Steward N,Aloush A,Hachem R,Trulock EP,et al.

Immunological link between primary graft dysfunction and chronic lung allograft rejection.Ann Thorac Surg2008;86:189–195,[discussion196–7]. [108]Daud SA,Yusen RD,Meyers BF,Chakinala MM,Walter MJ,Aloush AA.

Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome.Am J Respir Crit Care Med2007;175:507–513. [109]Subramanian V,Mohanakumar T.Chronic rejection:a signi?cant role for Th17-mediated autoimmune responses to self-antigens.Expert Rev Clin Immunol2012;8:663–672.

[110]Pratschke J,Stauch D,Kotsch K.Role of NK and NKT cells in solid organ transplantation.Transpl Int2009;22:859–868.

[111]Hanvesakul R,Spencer N,Cook M,Gunson B,Hathaway M,Brown R,et al.

Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation.Am J Transplant2008;8:1931–1941. [112]Parham P.MHC class I molecules and KIRs in human history,health and survival.Nat Rev Immunol2005;5:201–214.

[113]Karlsen TH,Boberg KM,Olsson M,Sun JY,Senitzer D,Bergquist A,et al.

Particular genetic variants of ligands for natural killer cell receptors may contribute to the HLA associated risk of primary sclerosing cholangitis.J Hepatol2007;46:899–906.

[114]Hashimoto E,Lindor KD,Homburger HA,Dickson ER,Czaja AJ,Wiesner RH.

Immunohistochemical characterization of hepatic lymphocytes in primary biliary cirrhosis in comparison with primary sclerosing cholangitis and autoimmune chronic active hepatitis.Mayo Clin Proc1993;68:1049–1055. [115]Kita H,Naidenko OV,Kronenberg M,Ansari AA,Rogers P,He XS,et al.

Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer.Gastroenterology 2002;123:1031–1043.

[116]Wu SJ,Yang YH,Tsuneyama K,Leung PS,Illarionov P,Gershwin ME,et al.

Innate immunity and primary biliary cirrhosis:activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and?brosis.

Hepatology2011;53:915–925.

[117]Chuang YH,Lian ZX,Yang GX,Shu SA,Moritoki Y,Ridgway WM,et al.

Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis.Hepatology2008;47:571–580.

[118]Shimoda S,Tsuneyama K,Kikuchi K,Harada K,Nakanuma Y,Nakamura M, et al.The role of natural killer(NK)and NK T cells in the loss of tolerance in murine primary biliary cirrhosis.Clin Exp Immunol2012;168:279–284. [119]Mieli-Vergani G,Vergani D.De novo autoimmune hepatitis after liver transplantation.J Hepatol2004;40:3–7.

[120]Richter A,Grabhorn E,Helmke K,Manns MP,Ganschow R,Burdelski M.

Clinical relevance of autoantibodies after pediatric liver transplantation.

Clin Transplant2007;21:427–432.

[121]Cho JM,Kim KM,Oh SH,Lee YJ,Rhee KW,Yu E.De novo autoimmune hepatitis in Korean children after liver transplantation:a single institu-tion’s experience.Transpl Proc2011;43:2394–2396.

[122]Czaja AJ.Diagnosis,pathogenesis,and treatment of autoimmune hepatitis after liver transplantation.Dig Dis Sci2012;57:2248–2266.

[123]Salcedo M,Vaquero J,Ba?ares R,Rodríguez-Mahou M,Alvarez E,Vicario JL, et al.Response to steroids in de novo autoimmune hepatitis after liver transplantation.Hepatology2002;35:349–356.

[124]Salcedo M,Rodríguez-Mahou M,Rodríguez-Sainz C,Rincón D,Alvarez E, Vicario JL,et al.Risk factors for developing de novo autoimmune hepatitis associate with anti-glutathione S-transferase T1antibodies after liver transplantation.Liver Transpl2009;15:530–539.

[125]Miyagawa-Hayashino A,Haga H,Egawa H,Hayashino Y,Sakurai T, Minamiguchi S,et al.Outcome and risk factors of de novo autoimmune hepatitis in living-donor liver transplantation.Transplantation 2004;78:128–135.

[126]Venick RS,McDiarmid SV,Farmer DG,Gornbein J,Martin MG,Vargas JH, et al.Rejection and steroid dependence:unique risk factors in the development of pediatric posttransplant de novo autoimmune hepatitis.

Am J Transpl2007;7:955–963.

[127]Aguilera I,Sousa JM,Gavilan F,Bernardos A,Wichmann I,Nu?ez-Roldan A.

Glutathione S-transferase T1genetic mismatch is a risk factor for de novo immune hepatitis in liver transplantation.Transpl Proc 2005;37:3968–3969.

[128]Yoshizawa K,Shirakawa H,Ichijo T,Umemura T,Tanaka E,Kiyosawa K, et al.De novo autoimmune hepatitis following living-donor liver trans-plantation for primary biliary cirrhosis.Clin Transpl2008;22:385–390

. Frontiers in Liver Transplantation

222Journal of Hepatology2014vol.60j210–223

[129]Aguilera I,Sousa JM,Praena JM,Gómez-Bravo MA,Nú?ez-Roldan A.Choice of calcineurin inhibitor may in?uence the development of de novo immune hepatitis associated with anti-GSTT1antibodies after liver transplantation.

Clin Transplant2011;25:207–212.

[130]Neil DA,Hübscher SG.Current views on rejection pathology in liver transplantation.Transpl Int2010;23:971–983.

[131]Czaja AJ.Autoimmune hepatitis Part A:pathogenesis.Expert Rev Gastro-enterol Hepatol2007;1:113–128.

[132]Lohse AW,Weiler-Norman C,Burdelski M.De novo autoimmune hepatitis after liver transplantation.Hepatol Res2007;37:S462.

[133]Czaja AJ.Understanding the pathogenesis of autoimmune hepatitis.Am J Gastroenterol2001;96:1224–1231.

[134]Fukami N,Ramachandran S,Saini D,Walter M,Chapman W,Patterson GA.

Antibodies to MHC class I induce autoimmunity:role in the pathogenesis of chronic rejection.J Immunol2009;182:309–318.

[135]Fukami N,Ramachandran S,Takenaka M,Weber J,Subramanian V, Mohanakumar T.An obligatory role for lung in?ltrating B cells in the immunopathogenesis of obliterative airway disease induced by antibodies to MHC class I molecules.Am J Transplant2012;12:867–876.

[136]Demetris AJ,Sebagh M.Plasma cell hepatitis in liver allografts:variant of rejection or autoimmune hepatitis?Liver Transpl2008;14:750–755. [137]Selzner N,Guindi M,Renner EL,Berenguer M.Immune-mediated compli-cations of the graft in interferon-treated hepatitis C positive liver trans-plant recipients.J Hepatol2011;55:207–217.

[138]Banff Working Group,Demetris AJ,Adeyi O,Bellamy CO,Clouston A, Charlotte F,et al.Liver biopsy interpretation for causes of late liver allograft dysfunction.Hepatology2006;44:489–501.

[139]Pappo O,Ramos H,Starzl TE,Fung JJ,Demetris AJ.Structural integrity and identi?cation of causes of liver allograft dysfunction occurring more than5 years after transplantation.Am J Surg Pathol1995;19:192–206.

[140]B?ckman L,Gibbs J,Levy M,McMillan R,Holman M,Husberg B.Causes of late graft loss after liver transplantation.Transplantation 1993;55:1078–1082.

[141]Krasinskas AM,Demetris AJ,Poterucha JJ,Abraham SC.The prevalence and natural history of untreated isolated central perivenulitis in adult allograft livers.Liver Transpl2008;14:625–632.

[142]Tsamandas AC,Jain AB,Felekouras ES,Fung JJ,Demetris AJ,Lee RG,et al.

Central venulitis in the allograft liver:a clinicopathologic study.Trans-plantation1997;64:252–257.

[143]Hubscher SG.Recurrent autoimmune hepatitis after liver transplantation: diagnostic criteria,risk factors,and outcome.Liver Transpl 2001;7:285–291.

[144]Demetris A,Adams D,Bellamy C,Blakolmer K,Clouston A,Dhillon AP,et al.

Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection.An International panel.Hepatology2000;31:792–799. [145]Adam R,McMaster P,O’Grady JG,Castaing D,Klempnauer JL,Jamieson N, et al.Evolution of liver transplantation in Europe:report of the European Liver Transplant Registry.Liver Transpl2003;9:1231–1243.

[146]Prados E,Cuervas-Mons V,de la Mata M,Fraga E,Rimola A,Prieto M,et al.

Outcome of autoimmune hepatitis after liver transplantation.Transplan-tation1998;66:1645–1650.

[147]Ratziu V,Samuel D,Sebagh M,Farges O,Saliba F,Ichai P,et al.Long-term follow-up after liver transplantation for autoimmune hepatitis:evidence of recurrence of primary disease.J Hepatol1999;30:131–141.

[148]Reich DJ,Fiel I,Guarrera JV,Emre S,Guy SR,Schwartz ME,et al.

Liver transplantation for autoimmune hepatitis.Hepatology 2000;32:693–700.[149]González-Koch A,Czaja AJ,Carpenter HA,Roberts SK,Charlton MR,Porayko MK,et al.Recurrent autoimmune hepatitis after orthotopic liver trans-plantation.Liver Transpl2001;7:302–310.

[150]Abu-Elmagd K,Demetris J,Rakela J,et al.Transplantation for primary biliary cirrhosis:disease recurrence and outcome in421patients.Hepa-tology1997;26:176A.

[151]Sanchez EQ,Levy MF,Goldstein RM,et al.The changing clinical presen-tation of recurrent primary biliary cirrhosis after liver transplantation.

Transplantation2003;76:1583–1588.

[152]Jacob DA,Bahra M,Schmidt SC,et al.Mayo risk score for primary biliary cirrhosis:a useful tool for the prediction of course after liver transplan-tation?Ann Transpl2008;13:35–42.

[153]Goss JA,Shackleton CR,Farmer DG,Arnaout WS,Seu P,Markowitz JS,et al.

Orthotopic liver transplantation for primary sclerosing cholangitis.A12-year single center experience.Ann Surg1997;225:472–481,[discussion 481–3].

[154]Jeyarajah DR,Netto GJ,Lee SP,Testa G,Abbasoglu O,Husberg BS,et al.

Recurrent primary sclerosing cholangitis after orthotopic liver transplan-tation:is chronic rejection part of the disease process?Transplantation 1998;66:1300–1306.

[155]Graziadei IW,Wiesner RH,Batts KP,Marotta PJ,LaRusso NF,Porayko MK, et al.Recurrence of primary sclerosing cholangitis following liver trans-plantation.Hepatology1999;29:1050–1056.

[156]Mells GF,Kaser A,Karlsen TH.Novel insights into autoimmune liver diseases provided by genome-wide association studies.J Autoimmun 2013;46:41–54.

[157]McEntee G,Wiesner RH,Rosen C,Cooper J,Wahlstrom E.A comparative study of patients undergoing liver transplantation for primary sclerosing cholangitis and primary biliary cirrhosis.Transplant Proc 1991;23:1563–1564.

[158]Shaked A,Colonna JO,Goldstein L,Busuttil RW.The interrelation between sclerosing cholangitis and ulcerative colitis in patients undergoing liver transplantation.Ann Surg1992;215:598–603,[discussion604–605]. [159]Bathgate AJ,Pravica V,Perrey C,Therapondos G,Plevris JN,Hayes PC,et al.

The effect of polymorphisms in tumor necrosis factor-alpha,interleukin-10,and transforming growth factor-beta1genes in acute hepatic allograft rejection.Transplantation2000;69:1514–1517.

[160]Brandsaeter B,Schrumpf E,Bentdal O,Brabrand K,Smith HJ,Abildgaard A, et al.Recurrent primary sclerosing cholangitis after liver transplantation:a magnetic resonance cholangiography study with analyses of predictive factors.Liver Transpl2005;11:1361–1369.

[161]Kerkar N,Hadzic′N,Davies ET,Portmann B,Donaldson PT,Rela M,et al.De novo autoimmune hepatitis after liver https://www.wendangku.net/doc/5617853206.html,ncet 1998;351:409–413.

[162]Gupta P,Hart J,Millis JM,Cronin D,Brady L.De novo hepatitis with autoimmune antibodies and atypical histology:a rare cause of late graft dysfunction after pediatric liver transplantation.Transplantation 2001;71:664–668.

[163]Eguchi S,Takatsuki M,Hidaka M,Tajima Y,Zen Y,Nakanuma Y,et al.De novo autoimmune hepatitis after living donor liver transplantation is unlikely to be related to immunoglobulin subtype4-related immune disease.J Gastroenterol Hepatol2008;23:e165–e169.

[164]Cho JM,Kim KM,Oh SH,Lee YJ,Rhee KW,Yu E.De novo autoimmune hepatitis in Korean children after liver transplantation:a single institu-tion’s experience.Transplant Proc2011;43:2394–2396.

[165]Hernandez HM,Kovarik P,Whitington PF,Alonso EM.Autoimmune hepatitis as a late complication of liver transplantation.J Pediatr Gastro-enterol Nutr2001;32:131–136

.

JOURNAL OF HEPATOLOGY

Journal of Hepatology2014vol.60j210–223223