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Post-Transplant Immunosuppression in Autoimmune Liver Disease

      Highlights

      • Collectively, autoimmune liver diseases (AILDs) represent a significant requirement for organs in liver transplant programs. Long-term outcomes for these patients have improved, with excellent one- and five-year survival (90% and 70%, respectively).
      • As well as the transplant indications seen in other forms of chronic liver disease, there are unique indications for transplantation seen in AILDs such as recurrent cholangitis in primary sclerosing cholangitis.
      • Furthermore, there are also special considerations post liver transplantation in these conditions. All forms of AILD can recur post transplantation, and there is an increased risk of rejection. In this article, we discuss the need to balance the selection of immunosuppression for long-term optimal graft and patient survival with the complications of these drugs.
      • Additionally, we highlight prognostic- and disease- specific treatment options for each of the main AILDs after liver transplantation in terms of immunosuppression strategy and any disease modifying therapies.
      Autoimmune liver diseases (AILDs) are a group of conditions where immune-mediated liver damage can lead to the need for transplantation. Collectively, they account for almost a quarter of all liver transplants.
      Outcomes in terms of graft and patient survival for all liver transplants have improved markedly over decades with improvements in patient selection, surgical techniques and longer-term care and this is also seen in patients with AILDs. The current five- and ten-year survival rates post-transplant in autoimmune disease are excellent, at 88% and 78%, respectively.
      A key factor in maintaining good outcomes post liver transplant for these autoimmune conditions is the immunosuppression strategy. These patients have increased the rates of rejection, and autoimmune conditions can all recur in the graft ranging from 12 to 60% depending on the population studied. Immunosuppressive regimens are centred on calcineurin inhibitors, often combined with low dose corticosteroids, with or without the addition of antimetabolite therapy. There is no clear evidence-based immunosuppressive regimen for these conditions, and a tailored approach balancing the individuals’ immunological profile against the risks of immunosuppression is often used.
      There are disease-specific considerations to optimised graft function including the role of ursodeoxycholic acid in both primary biliary cholangitis and primary sclerosing cholangitis and the role and timing of colectomy in primary sclerosing cholangitis in inflammatory bowel disease patients.
      However, unmet needs still exist in the management of AILDs post liver transplantation particularly in building the evidence base for optimal immunosuppression as well as mitigating the risk of recurrent disease.

      Graphical abstract

      Keywords

      Abbreviations:

      AIH (Autoimmune hepatitis), AILD (Autoimmune liver disease), CNI (Calcineurin inhibitors), IBD (Inflammatory bowel disease), LT (Liver transplantation), PBC (Primary biliary cholangitis), PSC (Primary sclerosing cholangitis), rAIH (Recurrent autoimmune hepatitis), rPBC (Recurrent primary biliary cholangitis), rPSC (Recurrent primary sclerosing cholangitis)
      Autoimmune liver disease (AILD) describes a range of conditions, predominantly autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In these AILDs, immune-mediated liver damage can result in the need for liver transplantation (LT). Indications for LT in patients with AILDs are similar to those in other chronic liver diseases that result in liver failure (decompensated cirrhosis and hepatocellular carcinoma). However, other distinct indications exist for each group (pruritis in PBC, cholangitis in PSC and acute liver failure in AIH).
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      Autoimmune liver disease, autoimmunity and liver transplantation.
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      Liver transplantation and autoimmune liver diseases.
      Collectively, these AILDs represent the third commonest indication for LT in most liver transplant centres and account for approximately 24% of all LTs
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      Liver transplantation and autoimmune liver diseases.
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      Risk factors for recurrence of autoimmune hepatitis after liver transplantation.
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      Cyclosporine A protects against primary biliary cirrhosis recurrence after liver transplantation.
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      Systematic review: recurrent autoimmune liver diseases after liver transplantation.
      .
      Improvement in surgical techniques, patient selection, perioperative care and immunosuppressive regimens have helped increase post-LT patient and graft survival in AILD.
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      Increased posttransplant mortality for autoimmune hepatitis compared with other autoimmune liver diseases.
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      Long-term outcomes after liver transplantation in the Hispanic population.
      Outcomes after LT for AILD are good, with the European Liver Transplant Registry showing survival rates of approximately 88% and 78%, at five- and ten-years, respectively, in donation after brainstem death (DBD) donors from 1998 to 2017.
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      Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: experience from the European Liver Transplant Registry.
      This registry also analysed survival in living donor liver transplantation (LDLT) in AILD (n = 705) finding 85% and 74% alive after one- and ten-years. However, all AILD can recur post-LT with the potential for graft loss and need for re-transplantation.
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      Risk factors for recurrence of autoimmune hepatitis after liver transplantation.
      ,
      • Prados E.
      • et al.
      Outcome of autoimmune hepatitis after liver transplantation.
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      Recurrence of autoimmune hepatitis after liver transplantation.
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      Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease.
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      Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience.
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      Recurrence of primary sclerosing cholangitis following liver transplantation.
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      Risk factors for recurrence of primary sclerosing cholangitis of liver allograft.
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      Long-term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation.
      Recurrent disease in AILD is common, and the prevalence increases with time following LT, ranging from 17 to 42% in AIH, 12 to 30% in PBC and 12 to 60% in PSC.
      • Montano-Loza A.J.
      • et al.
      Risk factors for recurrence of autoimmune hepatitis after liver transplantation.
      ,
      • Montano-Loza A.J.
      • et al.
      Cyclosporine A protects against primary biliary cirrhosis recurrence after liver transplantation.
      ,
      • Mottershead M.
      • Neuberger J.
      Transplantation in autoimmune liver diseases.
      ,
      • Campsen J.
      • et al.
      Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course.
      The variability in rates of recurrent disease in likely related to whether protocol or clinically indicated liver biopsies post-LT are performed. It is known that recurrent disease negatively impacts quality of life as well as graft and overall survival.
      • Ilyas J.A.
      • O'Mahony C.A.
      • Vierling J.M.
      Liver transplantation in autoimmune liver diseases.
      ,
      • Manns M.P.
      • Bahr M.J.
      Recurrent autoimmune hepatitis after liver transplantation-when non-self becomes self.
      There is, therefore, a need to risk stratify patients to tailor post-transplant care and immunosuppressive strategy to optimise patient outcomes.

      Autoimmune Hepatitis

      AIH is a complex immune-mediated necroinflammatory condition where liver damage occurs through a combination of immunological, genetic and environmental factors. The prevalence of AIH varies, ranging from 4 (Singapore) to 42.9 (Alaska) cases per 100,000 persons, but it is clear that disease prevalence is increasing worldwide.
      • Lee Y.M.
      • et al.
      Autoimmune hepatitis in Singapore: a rare syndrome affecting middle-aged women.
      • Czaja A.J.
      Global disparities and their implications in the occurrence and outcome of autoimmune hepatitis.
      • Hurlburt K.J.
      • et al.
      Prevalence of autoimmune liver disease in Alaska Natives.
      The clinical presentation of AIH is variable, with acute, chronic or acute-on-chronic manifestations.
      European association for the study of the, L.
      Patients with AIH who require LT can have any phenotype of disease and those with chronic disease can present with their index presentation of liver disease or following treatment with immunosuppressants.
      • Montano-Loza A.J.
      • Carpenter H.A.
      • Czaja A.J.
      Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease.
      ,
      • Ferraz-Neto B.H.
      • et al.
      Analysis of Model for End-Stage Liver Disease (MELD) score in a liver transplantation waiting list.
      Moreover, of all the AILD's, AIH is unique in presenting with acute liver failure.
      Factors associated with a lack of response to the standard treatment include younger age and model for end-stage liver disease score >12 at diagnosis as well as acute presentations, high bilirubin and HLA DRB1∗03.
      • Montano-Loza A.J.
      • Carpenter H.A.
      • Czaja A.J.
      Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease.
      Lack of response to standard immunosuppression regimens is predictive for LT, particularly after six months of treatment.
      • Tan P.
      • et al.
      Early treatment response predicts the need for liver transplantation in autoimmune hepatitis.
      AIH accounts for 5% of the indications for LT performed in the United States and 7% of those performed in the United Kingdom.
      • Ilyas J.A.
      • O'Mahony C.A.
      • Vierling J.M.
      Liver transplantation in autoimmune liver diseases.
      ,
      • Neuberger J.
      Liver transplantation in the United Kingdom.
      Outcomes post-LT for patients with AIH are good, with five- and ten-year patient survival rates of 81% and 77%, respectively.
      • Montano-Loza A.J.
      • et al.
      Risk factors for recurrence of autoimmune hepatitis after liver transplantation.
      ,
      • Manns M.P.
      • et al.
      Diagnosis and management of autoimmune hepatitis.
      • Suri J.S.
      • et al.
      Mortality on the UNOS waitlist for patients with autoimmune liver disease.
      • Tanaka A.
      Autoimmune hepatitis: 2019 update.
      • Stirnimann G.
      • et al.
      Recurrent and de novo autoimmune hepatitis.
      However, a long-term analysis of mortality suggested a reduced one-year survival post-LT for patients with AIH compared to other indications for LT.
      • Gelson W.
      • et al.
      The pattern of late mortality in liver transplant recipients in the United Kingdom.
      The European Liver Transplant Registry reported on long-term outcomes post-LT in AILD, comparing LDLT and DBD grafts. Patients with AIH had the highest rate of LDLT (P < 0.001) but this was likely related to a high proportion of children in this AIH cohort.
      • Heinemann M.
      • et al.
      Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: experience from the European Liver Transplant Registry.
      Despite the overall good outcomes, managing these patients post-LT can pose distinct challenges. There is a higher risk of late acute rejection (9%), chronic rejection (16%) and disease recurrence (36–68% at five years) than other LT indications.
      • Carbone M.
      • Neuberger J.M.
      Autoimmune liver disease, autoimmunity and liver transplantation.
      ,
      • Montano-Loza A.J.
      • et al.
      Systematic review: recurrent autoimmune liver diseases after liver transplantation.
      ,
      • Milkiewicz P.
      • et al.
      Recurrence of autoimmune hepatitis after liver transplantation.
      ,
      • Stirnimann G.
      • et al.
      Recurrent and de novo autoimmune hepatitis.
      ,
      • Mack C.L.
      • et al.
      Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.
      ,
      • Marudanayagam R.
      • et al.
      Liver retransplantation in adults: a single-centre, 25-year experience.
      This immunological risk needs to be taken into account with the choice of immunosuppressive strategy.

      Immunosuppressive Therapy

      A key factor in the post-LT management of AIH is maintenance immunosuppressive strategy. Successful post-LT management strikes a balance between the complications of drug therapy and the optimisation of patient and graft survival. However, despite published data on post-LT outcomes in patients with AIH, there is no evidence-based optimal regimen available.
      • Montano-Loza A.J.
      • et al.
      Systematic review: recurrent autoimmune liver diseases after liver transplantation.
      ,
      • Gautam M.
      • Cheruvattath R.
      • Balan V.
      Recurrence of autoimmune liver disease after liver transplantation: a systematic review.
      Thus, many patients have a tailored strategy to balance their perceived individual risks and benefits.
      Treatment with CNI therapy is the mainstay of post-LT immunosuppression.
      • Mack C.L.
      • et al.
      Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.
      ,
      • Sucher E.
      • et al.
      Autoimmune hepatitis-immunologically triggered liver pathogenesis-diagnostic and therapeutic strategies.
      In many centres, the CNI is combined with steroid therapy (dual immunosuppressive strategy) either alone or in conjunction with an antimetabolite as a triple immunosuppressive strategy.
      • Mack C.L.
      • et al.
      Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.
      ,
      • Sucher E.
      • et al.
      Autoimmune hepatitis-immunologically triggered liver pathogenesis-diagnostic and therapeutic strategies.
      ,
      • Doycheva I.
      • Watt K.D.
      • Gulamhusein A.F.
      Autoimmune hepatitis: current and future therapeutic options.
      In our centre, first-line therapy is with tacrolimus and long-term low-dose steroid therapy. There are reports of dual immunosuppressive strategies (steroid and CNI) having a higher risk of AIH recurrence than triple immunosuppression with the addition of an antimetabolite (OR 1.47; P = 0.018).
      • Puustinen L.
      • et al.
      Histologic surveillance after liver transplantation due to autoimmune hepatitis.
      However, other reports suggest the rates of recurrent AIH (rAIH) are similar in those on triple immunosuppression to those not on this strategy.
      • de Quadros Onofrio F.
      • et al.
      Single-Center North American experience of liver transplantation in autoimmune hepatitis: infrequent indication but good outcomes for patients.
      Type of CNI (ciclosporin versus tacrolimus) has not been associated with a significant difference in recurrence rates.
      • Renz J.F.
      • Ascher N.L.
      Liver transplantation for nonviral, nonmalignant diseases:problem of recurrence.
      • Duclos-Vallee J.C.
      • et al.
      A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence.
      • Krishnamoorthy T.L.
      • et al.
      Longterm corticosteroid use after liver transplantation for autoimmune hepatitis is safe and associated with a lower incidence of recurrent disease.
      Interestingly, recent publication of the largest dataset reporting over 700 patients transplanted for AIH highlights MMF use as a risk factor for recurrence.
      • Montano-Loza A.J.
      • et al.
      Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation.

      Maintenance Steroid Therapy

      The role of steroid maintenance therapy is controversial. Many transplant centres use long-term low-dose steroid therapy as part of their maintenance immunosuppressive strategy in AILD, as this has been reported to minimise rAIH.
      • Thurairajah P.H.
      • et al.
      Late acute liver allograft rejection; a study of its natural history and graft survival in the current era.
      However, concerns remain about the side-effect profile of these drugs. Steroid withdrawal in non-AILDs improves metabolic profile (hypertension, hyperlipidaemia and diabetes mellitus) without increasing the risk to the graft. However, there is concern that steroid withdrawal increases the recurrence of AIH in the graft post-LT.
      • Montano-Loza A.J.
      • et al.
      Systematic review: recurrent autoimmune liver diseases after liver transplantation.
      ,
      • Milkiewicz P.
      • et al.
      Recurrence of autoimmune hepatitis after liver transplantation.
      In our centre, low-dose steroids (prednisolone 5 mg) are continued long-term in post-LT AIH patients. It has been suggested that this approach provides a good balance, reducing the incidence of rAIH without increasing the risk of osteoporosis and infection.
      • Gautam M.
      • Cheruvattath R.
      • Balan V.
      Recurrence of autoimmune liver disease after liver transplantation: a systematic review.
      ,
      • Krishnamoorthy T.L.
      • et al.
      Longterm corticosteroid use after liver transplantation for autoimmune hepatitis is safe and associated with a lower incidence of recurrent disease.
      Other studies have conflicting results, with steroid withdrawal not increasing the risk of rAIH, acute cellular rejection, graft loss or death.
      • D'Antiga L.
      Coronaviruses and immunosuppressed patients: the facts during the third epidemic.
      ,
      • Vierling J.M.
      • et al.
      Immunosuppressive treatment regimens in autoimmune hepatitis: systematic reviews and meta-analyses supporting American association for the study of liver diseases guidelines.
      However, there are also reports that steroids do not present an increased side-effect profile (infections and metabolic parameters).
      • Llado L.
      • et al.
      Immunosuppression without steroids in liver transplantation is safe and reduces infection and metabolic complications: results from a prospective multicenter randomized study.
      The American Association for the Study of Liver Diseases suggests that a gradual withdrawal of steroids should be considered in AIH patients’ post-LT as this approach has benefits without increasing risk.
      • Mack C.L.
      • et al.
      Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.
      One must take into consideration the previous duration of steroid therapy pre-LT and the risk of adrenal suppression.

      Disease Recurrence

      AIH can recur post-LT, and this is associated with a higher risk of graft loss, with overall survival reported at 76% at five years in rAIH.
      • Rowe I.A.
      • et al.
      The impact of disease recurrence on graft survival following liver transplantation: a single centre experience.
      However, it can be challenging to diagnose rAIH, as it can be difficult to distinguish from graft rejection.
      • Mack C.L.
      • et al.
      Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.
      Establishing an accurate frequency of rAIH has been challenging as the diagnostic criteria for rAIH have not been standardised, with the international AIH group report and simplified score not validated post-LT.
      • Alvarez F.
      • et al.
      International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.
      ,
      • Hennes E.M.
      • et al.
      Simplified criteria for the diagnosis of autoimmune hepatitis.
      AIH is reported to recur in 8%–68% of transplanted patients. The frequency is reported to increase over time, from 8 to 12% at 1 year and 36–68% at 5 years.
      • Montano-Loza A.J.
      • et al.
      Risk factors for recurrence of autoimmune hepatitis after liver transplantation.
      ,
      • Prados E.
      • et al.
      Outcome of autoimmune hepatitis after liver transplantation.
      ,
      • Campsen J.
      • et al.
      Liver transplantation for autoimmune hepatitis and the success of aggressive corticosteroid withdrawal.
      Risk factors implicated in recurrence include the susceptibility alleles HLA-DRB1∗0301 or DRB1∗0401 in the transplant recipient and HLA-DR locus mismatching.
      • Balan V.
      • 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.
      Control of disease activity prior to LT for patients with AIH is associated with a lower risk of rAIH.
      • Montano-Loza A.J.
      • et al.
      Risk factors for recurrence of autoimmune hepatitis after liver transplantation.
      However, immunosuppression escalation to achieve this outcome needs to be balanced against the increased risk of perioperative infection. A summary of the factors that have been linked to recurrent disease are shown in Figure 1.
      • Montano-Loza A.J.
      • et al.
      Risk factors for recurrence of autoimmune hepatitis after liver transplantation.
      ,
      • Prados E.
      • et al.
      Outcome of autoimmune hepatitis after liver transplantation.
      ,
      • Milkiewicz P.
      • et al.
      Recurrence of autoimmune hepatitis after liver transplantation.
      ,
      • Reich D.J.
      • et al.
      Liver transplantation for autoimmune hepatitis.
      ,
      • Ayata G.
      • et al.
      Liver transplantation for autoimmune hepatitis: a long-term pathologic study.
      Figure 1
      Figure 1Factors associated with AIH recurrence post-LT. AIH, autoimmune hepatitis; LT, liver transplantation.
      Inadequate maintenance immunosuppression, especially discontinuation of steroid therapy, has been reported to play a role in disease recurrence.
      • Milkiewicz P.
      • et al.
      Recurrence of autoimmune hepatitis after liver transplantation.
      However, rAIH has also been reported to those on an immunosuppression regimen that should be adequate to prevent rejection.
      • O'Grady J.G.
      Phenotypic expression of recurrent disease after liver transplantation.
      Generally, asymptomatic rAIH with minimal histological changes may be suppressed by optimising immunosuppression.
      • Prados E.
      • et al.
      Outcome of autoimmune hepatitis after liver transplantation.
      ,
      • Khalaf H.
      • et al.
      Liver transplantation for autoimmune hepatitis: a single-center experience.
      However, more significant changes are more likely to require higher doses of corticosteroids alone or in conjunction with additional immunosuppressive agents. Re-transplantation may be required for those who develop graft cirrhosis despite the optimisation of immunosuppressive treatment, with graft loss reported in 13–50% with rAIH among adults.
      • Milkiewicz P.
      • et al.
      Recurrence of autoimmune hepatitis after liver transplantation.
      ,
      • Reich D.J.
      • et al.
      Liver transplantation for autoimmune hepatitis.

      PBC

      PBC is a chronic liver disease, with immune-mediated injury to biliary epithelial cells and represents an interaction between genetic and environmental factors.
      • Leung K.K.
      • Deeb M.
      • Hirschfield G.M.
      Review article: pathophysiology and management of primary biliary cholangitis.
      The prevalence ranges from 19.1 (Australia) to 40.2 (USA) cases per million persons. The mean age at diagnosis is 60 years and there is a female preponderance, with a female to male ratio of 4:1.
      • Lu M.
      • et al.
      Factors associated with prevalence and treatment of primary biliary cholangitis in United States health systems.
      PBC tends to be more aggressive in men, with higher rates of both transplantation and mortality reported.
      • Lleo A.
      • et al.
      Evolving trends in female to male incidence and male mortality of primary biliary cholangitis.
      While approximately half of patients are asymptomatic at diagnosis, PBC can progress to symptomatic disease, including intractable pruritus, fatigue and decompensated cirrhosis resulting in the need for LT in up to one-third of patients.
      • Gao L.
      • et al.
      Clinical management of primary biliary cholangitis-strategies and evolving trends.
      ,
      • Onofrio F.Q.
      • Hirschfield G.M.
      • Gulamhusein A.F.
      A practical review of primary biliary cholangitis for the gastroenterologist.
      The indications for LT in PBC are those seen in other end-stage liver diseases, with intractable pruritus a disease-specific indication.
      • Lindor K.D.
      • et al.
      Primary biliary cholangitis: 2018 practice guidance from the American association for the study of liver diseases.
      • Aguilar M.T.
      • Carey E.J.
      Current status of liver transplantation for primary biliary cholangitis.
      • Martin P.
      • et al.
      Evaluation for liver transplantation in adults: 2013 practice guideline by the American association for the study of liver diseases and the American society of transplantation.
      Although PBC is considered a relatively rare disease, up to 10% of the patients listed for LT in North America and Europe have this diagnosis.
      • Montano-Loza A.J.
      • et al.
      Cyclosporine A protects against primary biliary cirrhosis recurrence after liver transplantation.
      ,
      • Poupon R.
      Primary biliary cirrhosis: a 2010 update.
      However, this need for LT has been reducing, which may be related to earlier treatment with ursodeoxycholic acid (UDCA) and the development of new therapies for UDCA non-responsive disease.
      • Galoosian A.
      • et al.
      Clinical updates in primary biliary cholangitis: trends, epidemiology, diagnostics, and new therapeutic approaches.
      PBC has excellent outcomes post-LT, with five-year overall survival of 90%.
      • Kashyap R.
      • et al.
      Living donor and deceased donor liver transplantation for autoimmune and cholestatic liver diseases--an analysis of the UNOS database.
      Despite this, PBC can recur in the graft and a small proportion of patients will require re-transplantation as a result.

      Immunosuppressive Therapy

      CNI therapy is also the corner stone of post-LT immunosuppressive maintenance therapy for patients with PBC. Two meta-analyses reported on the risk of recurrent PBC (rPBC) by immunosuppression type. Whilst one did not find an association, the other reported recurrent disease in 29% of their cohort and an increased rPBC risk with tacrolimus.
      • Chen C.
      • et al.
      Risk factors for recurrent autoimmune liver diseases after liver transplantation: a meta-analysis.
      ,
      • Li X.
      • et al.
      Risk factors for recurrent primary biliary cirrhosis after liver transplantation: a systematic review and meta-analysis.
      In the largest cohort reported thus far, the Global PBC Study Group have shown that tacrolimus increases the risk of rPBC (HR 2.06, P < 0.0001) and supported the use of ciclosporin in post-LT PBC.
      • Corpechot C.
      • et al.
      Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis.
      However, it should be remembered that patients with PBC have both an increased frequency of acute cellular rejection and late onset acute rejection and thus optimal immunosuppression is also important.
      • Thurairajah P.H.
      • et al.
      Late acute liver allograft rejection; a study of its natural history and graft survival in the current era.
      ,
      • Berlakovich G.A.
      • et al.
      The importance of the effect of underlying disease on rejection outcomes following orthotopic liver transplantation.
      • Milkiewicz P.
      • et al.
      Increased incidence of chronic rejection in adult patients transplanted for autoimmune hepatitis: assessment of risk factors.
      • Uemura T.
      • et al.
      Late acute rejection after liver transplantation impacts patient survival.
      Acute cellular rejection post-LT in PBC ranges from 21.7% to 83.3%.
      • Satapathy S.K.
      • et al.
      Outcomes of liver transplant recipients with autoimmune liver disease using long-term dual immunosuppression regimen without corticosteroid.
      • Jacob D.A.
      • et al.
      Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients.
      • Hayashi M.
      • et al.
      Allograft rejection after liver transplantation for autoimmune liver diseases.
      This can decrease patient and graft survival and play a role in disease recurrence.
      • Satapathy S.K.
      • et al.
      Outcomes of liver transplant recipients with autoimmune liver disease using long-term dual immunosuppression regimen without corticosteroid.
      ,
      • Levitsky J.
      • et al.
      Acute rejection increases risk of graft failure and death in recent liver transplant recipients.
      In our centre, tacrolimus is used initially, with a consideration of switch to ciclosporin after three months, particularly in higher-risk individuals. This switch is instituted on a tailored basis and depends on whether there have been episodes of rejection.

      UDCA

      The administration of prophylactic UDCA post-LT for PBC is associated with reduced rPBC, graft loss, liver-related death and all-cause mortality.
      • Corpechot C.
      • et al.
      Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis.
      Furthermore, a combination of ciclosporin and UDCA was associated with an even lower risk of both rPBC and mortality.
      • Corpechot C.
      • et al.
      Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis.
      This has been confirmed by other researchers, showing UDCA prophylaxis significantly decreased the rate of rPBC.
      • Corpechot C.
      • et al.
      Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis.
      ,
      • Pedersen M.R.
      • et al.
      Ursodeoxycholic acid decreases incidence of primary biliary cholangitis and biliary complications after liver transplantation: a meta-analysis.
      Therefore, prophylactic UDCA should be administered (10–15 mg/kg/day) after LT to prevent rPBC and improve graft and patient survival.
      • Corpechot C.
      • et al.
      Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis.
      ,
      • Bosch A.
      • et al.
      Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence.
      The role of second-line therapies in post-LT PBC patients remains uncertain, although is probably appropriate for individuals who are either non-responsive to UDCA or who have symptoms relating to rPBC despite appropriate weight-based UDCA dosing. In our institution, all patients with PBC are started on UDCA post-LT unless intolerant of it previously.

      rPBC

      The recurrence of immune features, such as high IgM, antimitochondrial antibody and aberrant mitochondrial protein expression in biliary epithelium, has been recorded in approximately 70% of patients with PBC post-LT. However, histological disease characteristic of PBC is only found in a subset.
      • Van de Water J.
      • et al.
      Immunohistochemical evidence of disease recurrence after liver transplantation for primary biliary cirrhosis.
      The frequency for rPBC has been reported to range from 17% to 46% after LT, with differences impacted by differing practices over the use of protocol or clinically indicated graft biopsies.
      • Montano-Loza A.J.
      • et al.
      Cyclosporine A protects against primary biliary cirrhosis recurrence after liver transplantation.
      ,
      • Gao L.
      • et al.
      Clinical management of primary biliary cholangitis-strategies and evolving trends.
      ,
      • Duclos-Vallee J.C.
      • Sebagh M.
      Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation.
      ,
      • Nevens F.
      PBC-transplantation and disease recurrence.
      Data suggests rPBC can negatively affect patient and graft survival.
      • Montano-Loza A.J.
      • et al.
      Factors associated with recurrence of primary biliary cholangitis after liver transplantation and effects on graft and patient survival.
      The median time from transplantation to diagnosis of rPBC is approximately five years. Rates of rPBC increase with time, with 30% prevalence ten years after LT.
      • Jacob D.A.
      • et al.
      Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients.
      ,
      • Neuberger J.
      • et al.
      Recurrence of primary biliary cirrhosis after liver transplantation.
      ,
      • Sanchez E.Q.
      • et al.
      The changing clinical presentation of recurrent primary biliary cirrhosis after liver transplantation.
      However, PBC may recur earlier, even as early as nine months post-LT
      • Robertson H.
      • et al.
      Biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis.
      .
      Many factors have been linked with rPBC, including young donor age, older recipient, long cold ischaemia time and immunosuppression regimen (see Figure 2).
      • Jacob D.A.
      • et al.
      Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients.
      ,
      • Silveira M.G.
      • et al.
      Recurrent primary biliary cirrhosis after liver transplantation.
      Increased ALT and ALP within the first year after LT and initial immunosuppression with tacrolimus were both associated with a higher risk of rPBC.
      • Bosch A.
      • et al.
      Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence.
      Patients receiving tacrolimus have earlier onset and more severe rPBC, whereas, the use of ciclosporin is protective.
      • Montano-Loza A.J.
      • et al.
      Cyclosporine A protects against primary biliary cirrhosis recurrence after liver transplantation.
      ,
      • Dmitrewski J.
      • et al.
      Recurrence of primary biliary cirrhosis in the liver allograft: the effect of immunosuppression.
      ,
      • Wong P.Y.
      • et al.
      Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression.
      Of note, rPBC has been reported to occur with weaning of ciclosporin and disease resolution reported with the reintroduction of ciclosporin and prednisone.
      • Mazariegos G.V.
      • et al.
      Weaning of immunosuppression in liver transplant recipients.
      Figure 2
      Figure 2Factors associated with PBC recurrence post-LT. LT, liver transplantation; PBC, primary biliary cholangitis.

      PSC

      PSC is a chronic, immune-mediated cholestatic liver disease affecting intrahepatic and extrahepatic bile ducts, causing progressive inflammation and obliterative fibrosis.
      • Carbone M.
      • Neuberger J.M.
      Autoimmune liver disease, autoimmunity and liver transplantation.
      ,
      • Chapman R.W.
      Primary sclerosing cholangitis.
      • Hirschfield G.M.
      • et al.
      Primary sclerosing cholangitis.
      • Karlsen T.H.
      • et al.
      Primary sclerosing cholangitis - a comprehensive review.
      It has a strong association with inflammatory bowel disease (IBD) particularly in men with up to 75% of these IBD cases ulcerative colitis.
      • de Vries A.B.
      • et al.
      Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis.
      ,
      • Palmela C.
      • et al.
      Inflammatory bowel disease and primary sclerosing cholangitis: a review of the phenotype and associated specific features.
      This association with ulcerative colitis increases the risk of liver disease progression when compared to Crohn's disease.
      • Weismuller T.J.
      • et al.
      Patient Age, sex, and inflammatory bowel disease phenotype Associate with course of primary sclerosing cholangitis.
      ,
      • Irles-Depe M.
      • et al.
      Impact of preexisting inflammatory bowel disease on the outcome of liver transplantation for primary sclerosing cholangitis.
      PSC is a rare disease, seen more commonly in Northern European countries with a prevalence of 23.99 per 100,000 persons in the USA.
      • Bakhshi Z.
      • et al.
      An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort.
      It is more prevalent in men with a mean age at diagnosis of 37 years.
      • Weismuller T.J.
      • et al.
      Patient Age, sex, and inflammatory bowel disease phenotype Associate with course of primary sclerosing cholangitis.
      Clinical presentation is variable, with many patients diagnosed when asymptomatic on the basis of abnormal liver function tests.
      • Karlsen T.H.
      • et al.
      Primary sclerosing cholangitis - a comprehensive review.
      ,
      • Tabibian J.H.
      • Ali A.H.
      • Lindor K.D.
      Primary sclerosing cholangitis, Part 1: epidemiology, etiopathogenesis, clinical features, and treatment.
      Symptomatic patients present most commonly with fatigue, abdominal pain and pruritus.
      • Bakhshi Z.
      • et al.
      An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort.
      A more aggressive presentation can occur, characterised by recurrent biliary obstruction and cholangitis that may progress to cirrhosis, liver failure or hepatobiliary malignancies.
      • Lindor K.D.
      • et al.
      Primary biliary cholangitis: 2018 practice guidance from the American association for the study of liver diseases.
      ,
      • Hirschfield G.M.
      • et al.
      Primary sclerosing cholangitis.
      However, in general, patients with PSC have a poor prognosis and require a LT within 10–15 years of diagnosis as a result of the complications of cirrhosis.
      • Salguero O.
      • et al.
      Recurrence of primary biliary cirrhosis after liver transplantation.
      Patients with PSC can also be listed for recurrent cholangitis, but these patients are often low priority due to low model for end-stage liver disease or equivalent scores.
      • Wiesner R.H.
      Liver transplantation for primary sclerosing cholangitis: timing, outcome, impact of inflammatory bowel disease and recurrence of disease.
      In the USA, they often require exception points and in the UK may need to be listed for LT as a ‘variant’. There are no therapeutic options currently available to prevent disease progression in patients with PSC.
      • Vesterhus M.
      • Karlsen T.H.
      Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities.
      LT is the only proven treatment to improve survival for patients with PSC and end-stage liver disease, with 36.7% of patients progressing to LT or death during a median follow-up of 14.5 years.
      • Weismuller T.J.
      • et al.
      Patient Age, sex, and inflammatory bowel disease phenotype Associate with course of primary sclerosing cholangitis.
      ,
      • Sirpal S.
      • Chandok N.
      Primary sclerosing cholangitis: diagnostic and management challenges.
      Based on the United Network for Organ Sharing (UNOS) database, PSC has been the most frequent cause of end-stage liver disease requiring LT among AILDs, accounting for 48% of total liver transplants for this patient group and 4.5% of LT indications overall.
      • Lee J.Y.
      • et al.
      Increased posttransplant mortality for autoimmune hepatitis compared with other autoimmune liver diseases.
      Furthermore, the need for LT in PSC has increased over recent years. Post-LT outcomes are favourable, with five-year graft and patient survival of 85.4% and 85.5%, respectively.
      • Bayable A.
      • et al.
      Ethnicity-specific differences in liver transplant outcomes among adults with primary sclerosing cholangitis: 2005-2017 united Network for organ sharing/organ procurement and transplantation Network.
      Post-LT, the main complications are acute cellular rejection, chronic rejection, hepatic artery thrombosis, biliary strictures and disease recurrence.
      • Graziadei I.W.
      • et al.
      Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.
      PSC is now the most common disease to recur after LT.
      • Karlsen T.H.
      • et al.
      Primary sclerosing cholangitis - a comprehensive review.
      Recurrence occurs in up to 20% of LT recipients within five years and increases the risk of graft failure and mortality.
      • Henson J.B.
      • et al.
      Outcomes of liver retransplantation in patients with primary sclerosing cholangitis.
      An additional factor to be considered in the post-LT PSC patient is the higher risk of gastrointestinal malignancy, and the need to ensure any IBD is managed expediently. Attention to these factors helps improve post LT outcomes for these patients.

      Immunosuppressive Therapy

      The immunosuppression regimen after LT in patients with PSC consists of a CNI, mainly tacrolimus, either with corticosteroids as dual therapy or with the addition of an antimetabolite as a triple regimen. Like with other autoimmune indications, the regimen intends to prevent disease recurrence and improve graft survival. In our centre, tacrolimus is the first-line therapeutic agent used with the addition of a second agent based on individual patient risk.
      Data regarding the impact of the type of immunosuppression used on PSC recurrence rate is inconclusive. Two studies reviewing the influence of CNI type on rPSC after LT, did not find a statistically significant link between tacrolimus use and rPSC, with one suggesting a non-significant trend towards increased rPSC with ciclosporin.
      • Ravikumar R.
      • et al.
      Risk factors for recurrent primary sclerosing cholangitis after liver transplantation.
      ,
      • Hildebrand T.
      • et al.
      Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: a retrospective multicenter analysis.
      However, others have reported an increased risk of rPSC with tacrolimus.
      • Lindstrom L.
      • et al.
      Risk factors and prognosis for recurrent primary sclerosing cholangitis after liver transplantation: a Nordic Multicentre Study.
      A meta-analysis described ciclosporin as decreasing the risk of rPSC after LT, whereas tacrolimus did not.
      • Chen C.
      • et al.
      Risk factors for recurrent autoimmune liver diseases after liver transplantation: a meta-analysis.
      Despite this, our practice is to use tacrolimus-based regimens.
      One factor that may influence immunosuppression choice is underlying IBD activity. Data have shown that both tacrolimus and a dual immunosuppressive regimen with mycophenolate mofetil increase the risk of IBD relapse post-LT.
      • Martin E.F.
      • Levy C.
      Timing, management, and outcomes of liver transplantation in primary sclerosing cholangitis.
      Further studies are required to confirm which immunosuppressive regimen is more beneficial in patients with PSC after LT.

      Role of Colectomy on Post-LT Outcomes

      The presence of active ulcerative colitis post-LT increases the risk of disease recurrence, therefore the control of colitis should be prioritised.
      • Cholongitas E.
      • et al.
      Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.
      Colectomy has been shown to decreases the risk of recurrence of PSC.
      • Chen C.
      • et al.
      Risk factors for recurrent autoimmune liver diseases after liver transplantation: a meta-analysis.
      ,
      • Lindstrom L.
      • et al.
      Risk factors and prognosis for recurrent primary sclerosing cholangitis after liver transplantation: a Nordic Multicentre Study.
      ,
      • Steenstraten I.C.
      • et al.
      Systematic review with meta-analysis: risk factors for recurrent primary sclerosing cholangitis after liver transplantation.
      The timing of colectomy, whether before, at the time of LT or after remains uncertain. However, a lower threshold for colectomy should be considered in patients with PSC-IBD who need transplantation, and this would also reduce colonic cancer risk.
      • Chen C.
      • et al.
      Risk factors for recurrent autoimmune liver diseases after liver transplantation: a meta-analysis.
      ,
      • Steenstraten I.C.
      • et al.
      Systematic review with meta-analysis: risk factors for recurrent primary sclerosing cholangitis after liver transplantation.
      In our institution, colectomy is considered at the time of transplant for those who have active IBD despite medical therapy.

      rPSC

      The diagnosis of rPSC can be challenging because biliary strictures can occur post-LT for other reasons. Criteria for establishing a diagnosis of rPSC include evidence of biliary strictures more than ninety days after LT.
      • Graziadei I.W.
      • et al.
      Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.
      However, there is a need to exclude other potential contributory factors for biliary disease, including hepatic artery thrombosis, ductopenic rejection, non-anastomotic strictures less than 90 days after LT and donation after cardiac death related complications. Liver biopsy can be helpful in establishing the diagnosis.
      • Graziadei I.W.
      • et al.
      Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.
      Recurrent PSC is estimated to occur in approximately one quarter of patients (20–25%) over a 10-year period post-LT.
      • Graziadei I.W.
      • et al.
      Recurrence of primary sclerosing cholangitis following liver transplantation.
      ,
      • Graziadei I.W.
      • et al.
      Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.
      ,
      • Fosby B.
      • Karlsen T.H.
      • Melum E.
      Recurrence and rejection in liver transplantation for primary sclerosing cholangitis.
      Over one-third (36%) of patients develop biliary strictures over 8 years follow up, and rPSC was recognised in 20%, with a mean time to diagnosis of 4.6 years post-LT.
      • Hildebrand T.
      • et al.
      Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: a retrospective multicenter analysis.
      A variety of risk factors have been identified for the development of rPSC (see Figure 3). Recipient factors include a younger or older age at the time of LT, male gender and the presence of cholangiocarcinoma.
      • Vera A.
      • et al.
      Risk factors for recurrence of primary sclerosing cholangitis of liver allograft.
      ,
      • Campsen J.
      • et al.
      Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course.
      ,
      • Jeyarajah D.R.
      • et al.
      Recurrent primary sclerosing cholangitis after orthotopic liver transplantation: is chronic rejection part of the disease process?.
      Donor factors include gender mismatch, CMV mismatch and the use of living related donor, mainly with the use of grafts from parents.
      • Khettry U.
      • et al.
      Liver transplantation for primary sclerosing cholangitis: a long-term clinicopathologic study.
      ,
      • Egawa H.
      • et al.
      Risk factors for recurrence of primary sclerosing cholangitis after living donor liver transplantation: a single center experience.
      It is uncertain whether the increased biliary complications with living donor LT is a trigger for rPSC or whether genetics given donors are often first-degree relatives are key.
      • Melum E.
      • et al.
      Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.
      ,
      • Alexander J.
      • et al.
      Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.
      Steroid-resistant acute cellular rejection and late onset acute rejection have both been linked with rPSC.
      • Gelson W.
      • et al.
      The pattern of late mortality in liver transplant recipients in the United Kingdom.
      ,
      • Thurairajah P.H.
      • et al.
      Late acute liver allograft rejection; a study of its natural history and graft survival in the current era.
      Patients with cholestasis at three months post-LT have a higher probability of developing rPSC.
      • Mason A.L.
      • Montano-Loza A.J.
      Systematic investigation of elevated cholestatic enzymes during the third posttransplant month.
      Figure 3
      Figure 3Factors associated with PSC recurrence post-LT. LT, liver transplantation; PSC, primary sclerosing cholangitis.
      A key factor in rPSC is the co-existence of IBD, particularly if the IBD is active.
      • Alabraba E.
      • et al.
      A re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts.
      Additionally, the presence of IBD following LT is associated with a reduction in patient survival.
      • Joshi D.
      • et al.
      The impact of inflammatory bowel disease post-liver transplantation for primary sclerosing cholangitis.
      The use of tacrolimus has been shown to be associated with an increased risk of developing de novo IBD after LT.
      • Joshi D.
      • et al.
      The impact of inflammatory bowel disease post-liver transplantation for primary sclerosing cholangitis.
      ,
      • Verdonk R.C.
      • et al.
      Inflammatory bowel disease after liver transplantation: a role for cytomegalovirus infection.
      The exacerbation of pre-existent IBD may be observed post-LT for PSC, and IBD tends to be more severe post-LT.
      • Liberal R.
      • Vergani D.
      • Mieli-Vergani G.
      Recurrence of autoimmune liver disease and inflammatory bowel disease after pediatric liver transplantation.
      Disease recurrence in PSC is associated with a decreased graft survival, and this is compounded by the lack of treatment options before pre- and post-LT.
      • Rowe I.A.
      • et al.
      The impact of disease recurrence on graft survival following liver transplantation: a single centre experience.
      ,
      • Hirschfield G.M.
      • et al.
      Primary sclerosing cholangitis.
      Of those with rPSC, nearly half (46%) progressed to graft failure with an associated increased risk of death.
      • Ravikumar R.
      • et al.
      Risk factors for recurrent primary sclerosing cholangitis after liver transplantation.
      Some centres continue to use 13–15 mg/kg UDCA for rPSC, as it improves liver biochemistry. However, it is unknown if this has any impact on overall outcomes.
      • Lindor K.D.
      • et al.
      ACG clinical guideline: primary sclerosing cholangitis.
      ,
      • Lindor K.D.
      • et al.
      High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.
      Recently, increased mortality in patients having LDLT compared to DBD LT (hazard ratio 1.95, P < 0.001) was described that was not seen in AIH (P = 0.787), PBC (P = 0.0.314) or a non-AILD cohort with alcohol-related disorders (P = 0.49).
      • Heinemann M.
      • et al.
      Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: experience from the European Liver Transplant Registry.
      When data were adjusted to include the 10 centers with the greatest LDLT volume, this association with mortality was comparable (PSC P = 0.033; AIH, PBC, control group P = NS). The risk of death from graft failure and non-liver causes in patients with PSC undergoing LDLT remained significant when compared to DBD grafts (P = 0.02) but this was not seen in other AILDs.
      • Heinemann M.
      • et al.
      Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: experience from the European Liver Transplant Registry.
      Further analysis of predictors of mortality in PSC LDLT found no relationship with recipient sex, blood group mismatch, ischaemic time and donor-recipient sex matching. However, multivariate analysis did find recipient age of 28 years or older, a donor of 50 years or older and donation from a male were associated with an increased risk of death (P = 0.013, P = 0.008, P = 0.025, respectively).
      • Heinemann M.
      • et al.
      Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: experience from the European Liver Transplant Registry.
      There was no significant link with donor sex and mortality in the PSC DBD group (P = 0.637). Risk for requiring redo-LT was similar in LDLT and DBD grafts.
      • Heinemann M.
      • et al.
      Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: experience from the European Liver Transplant Registry.
      Additionally, death associated with PSC recurrence was higher in the LDLT than DBD groups (P = 0.044). Biliary complications were also higher in patients with LDLT PSC (P = 0.031).
      • Heinemann M.
      • et al.
      Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: experience from the European Liver Transplant Registry.

      Overlap Syndromes

      Although there are no strict definitions, overlap syndromes represent the combined features of AIH and PBC or PSC.
      • Gish R.G.
      • Mason A.
      Autoimmune liver disease. Current standards, future directions.
      ,
      • Beuers U.
      • Rust C.
      Overlap syndromes.
      Patients with overlap syndromes have an earlier onset and an increased frequency of recurrence when compared to their counterparts receiving LT for AIH, PBC or PSC.
      • Gautam M.
      • Cheruvattath R.
      • Balan V.
      Recurrence of autoimmune liver disease after liver transplantation: a systematic review.
      ,
      • Bhanji R.A.
      • et al.
      Liver transplantation for overlap syndromes of autoimmune liver diseases.
      Taken together, the data suggest that overlap syndromes represent more severe end of the spectrum of AILDs that are more likely to manifest in the graft. Whether increased immunosuppression with or continued corticosteroid use would be of benefit remains uncertain.

      Plasma cell rich rejection

      As outcomes post-LT in AILD improve, late graft dysfunction becomes more prominent and can be challenging to manage. As well as recurrent disease and late cellular rejection, an important cause of graft dysfunction includes plasma cell rich rejection (formerly known as de novo AIH, post-transplant allograft hepatitis and de novo immune hepatitis). It has overlapping features with AIH and is not only seen more frequently in paediatric liver transplant recipients (up to 5%) but can also be found in adults (1–2%).
      • Gupta P.
      • et al.
      De novo hepatitis with autoimmune antibodies and atypical histology: a rare cause of late graft dysfunction after pediatric liver transplantation.
      • Miyagawa-Hayashino A.
      • et al.
      Outcome and risk factors of de novo autoimmune hepatitis in living-donor liver transplantation.
      • Cho J.M.
      • et al.
      De novo autoimmune hepatitis in Korean children after liver transplantation: a single institution's experience.
      • Hernandez H.M.
      • et al.
      Autoimmune hepatitis as a late complication of liver transplantation.
      It was not only mainly seen in children transplanted for biliary atresia but is also more frequently in PBC.
      • Kerkar N.
      • et al.
      De-novo autoimmune hepatitis after liver transplantation.
      ,
      • Montano-Loza A.J.
      • et al.
      Incidence and risk factors associated with de novo autoimmune hepatitis after liver transplantation.
      The aetiology is unclear; however, it is associated with several risk factors, including the number of acute rejection episodes, steroid dependence, HLA DR3 and pegylated interferon use which was formerly used in the treatment of recurrent hepatitis C infection.
      • Venick R.S.
      • et al.
      Rejection and steroid dependence: unique risk factors in the development of pediatric posttransplant de novo autoimmune hepatitis.
      • Salcedo M.
      • et al.
      Response to steroids in de novo autoimmune hepatitis after liver transplantation.
      • Berardi S.
      • et al.
      High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?.
      • Aguilera I.
      • et al.
      De novo autoimmune hepatitis after interferon treatment in a liver transplant recipient with common variable immunodeficiency.
      Grafts from older women have been reported as being associated with increased risk, although this has not been universally acknowledged.
      • Montano-Loza A.J.
      • et al.
      Incidence and risk factors associated with de novo autoimmune hepatitis after liver transplantation.
      ,
      • Venick R.S.
      • et al.
      Rejection and steroid dependence: unique risk factors in the development of pediatric posttransplant de novo autoimmune hepatitis.
      It is characterised by a plasma cell rich interface hepatitis, with centrilobular necroinflammation with plasma cell infiltration also described (see Figure 4).
      • Sebagh M.
      • et al.
      Histologic findings predictive of a diagnosis of de novo autoimmune hepatitis after liver transplantation in adults.
      IgG4 positive plasma cells are over-represented, and donor specific antibodies are positive in over half of cases with portal microvascular C4d staining.
      • Demetris A.J.
      • et al.
      Comprehensive update of the banff working group on liver allograft pathology: introduction of antibody-mediated rejection.
      Serum IgG levels are increased and there can be positive autoantibodies with elevated liver enzymes.
      • Kerkar N.
      • et al.
      De-novo autoimmune hepatitis after liver transplantation.
      The features of plasma cell rich rejection are summarised in Figure 5.
      Figure 4
      Figure 4Histopathology of plasma cell-rich rejection. (A): The portal tract is expanded with a dense inflammatory infiltrate and intense interface hepatitis (arrows) (x200). (B): The portal infiltrate contains many mature plasma cells (x400). (C): A focus of perivenular confluent necrosis is associated with plasma cell infiltration (x200). (D): IgG4 immunostaining demonstrates many IgG4-positive plasma cells in the portal tract (x200).
      Figure 5
      Figure 5Features of plasma cell rich rejection.
      Treatment differs from that used in rejection, with the inflammation more responsive to classical AIH therapy such as steroids and anti-metabolites.
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune liver diseases in children - what is different from adulthood?.
      ,
      • Floreani A.
      • et al.
      Autoimmune hepatitis: contrasts and comparisons in children and adults - a comprehensive review.
      In our institution, steroid therapy is considered a mandatory part of immunosuppressive therapy for these patients. With regard to immunosuppression type, patients maintained on tacrolimus or mycophenolate mofetil have been reported to be at a higher risk of developing plasma cell rich rejection, whereas LT recipients treated with ciclosporin have a reduced risk.
      • Montano-Loza A.J.
      • et al.
      Incidence and risk factors associated with de novo autoimmune hepatitis after liver transplantation.
      It may be that patients with LT on ciclosporin are more likely to be on corticosteroids, which could be protective.
      Whilst outcomes for AILD patients post-LT are good, these patients pose particular challenges. There are increased immunological complications, particularly acute cellular rejection and disease recurrence. This needs to be balanced against the complications of immunosuppressive therapy. This is particularly true for patients having a re-do LT for recurrent disease.
      However, there is no clear evidence-based treatment regimen for these patients, with often contradictory findings in the literature. However, calcineurin inhibitors remain the corner-stone of management. At present, the management of patients with AILD requires not only a tailored approach with the assessment of immunological risk but that also takes into account disease specific modifying treatment such as prophylactic UDCA in PBC.
      There remains unmet needs in the post-LT care of AILD. First, optimal immunosuppression regimen for the increased risk of acute cellular rejection, taking into account disease type. Second, the prevention of disease recurrence post-LT is challenging. Currently, there is no clear approach that is successful in mitigating the risk of disease recurrence in all AILDs. As long-term outcomes continue to improve, experience graft loss from disease recurrence could become a more pressing concern for management given the poor outcomes seen.
      • Rowe I.A.
      • et al.
      The impact of disease recurrence on graft survival following liver transplantation: a single centre experience.

      Credit authorship statement

      All authors contributed to (1) the conception and design of the manuscript (2) drafting and revising the manuscript critically for important intellectual content (3) final approval of the submitted version.

      Conflicts of interest

      The authors have none to declare.

      Funding information

      None.

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