Recurrent Autoimmune Hepatitis Research Articles

Racial disparities in presentation and outcomes of paediatric autoimmune hepatitis.

Most studies on autoimmune hepatitis (AIH) in children are in predominantly Caucasian cohorts. Paediatric AIH in African Americans (AA) is understudied, with a dearth of clinical predictors of outcome, often leading to serious complications and even mortality. The aim of the study was to define disease presentation, progression, response to therapy and outcomes in paediatric AIH in a well-defined, large, single centre, demographically diverse population. We conducted a review of patients with AIH who were followed at this tertiary liver transplant centre. Clinical and laboratory covariates were assessed with regard to disease presentation, progression and outcomes in AA vs Non-AA children. African Americans patients constituted 42% of this cohort. At 1-year follow-up, AA children were receiving significantly higher doses of steroids compared to non-AA. More AA presented with end-stage liver disease (ESLD) with high immunoglobulin G and GGT:platelet ratio. After adjusting for other risk factor variables like gender, age at presentation and ESLD, AA children were at 4.5 times higher risk for significant outcome liver transplant/death within the first 12months of presentation. Post-transplant, recurrent AIH was seen in 50% of AA vs 8% in non-AA. African American patients with AIH are more likely to present with ESLD and have an increased early risk for transplantation with high likelihood of disease recurrence post-transplantation. Studies are needed to delineate factors such as inherent biology, genetics and access to care. Early referral and tailored immunosuppressive regimens are required for AA patients with AIH.

Autoimmune hepatitis: Current and future therapeutic options.

Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.

Recurrent and De Novo Autoimmune Hepatitis.

Clinical indications for liver transplantation (LT) in patients with autoimmune hepatitis (AIH) are identical to those of patients with other chronic liver diseases that end in acute or semiacute liver failure, decompensated cirrhosis, or hepatocellular carcinoma. Recurrent disease after LT has been reported in 10%-50% of patients with AIH, and the frequency of detection is influenced in part by the use of protocol or clinically indicated liver biopsy. De novo AIH connotes the development of AIH in patients transplanted for liver diseases other than AIH, and it has been reported in 5%-10% of pediatric and 1%-2% of adult recipients. Recurrent disease can negatively impact on graft and patient survival, and retransplantation has been required in 8%-23%. De novo AIH is within the spectrum of graft dysfunction that includes plasma cell-rich rejection, and it can also progress to cirrhosis and graft failure. Treatment for recurrent or de novo disease is based on the conventional regimens for AIH, and corticosteroid therapy alone or combined with azathioprine is standard. Better control of disease activity prior to LT has been associated with less recurrence, and maintenance corticosteroid treatment after LT can reduce its frequency. In conclusion, recurrent AIH is far more frequent than de novo AIH. Both may have negative impacts on graft and patient survival, and early detection and treatment are key objectives. Future investigations must codify the diagnostic criteria for each graft dysfunction, seek diagnostic biomarkers, and evaluate treatments that improve outcomes without increasing the risk of pre- and post-LT infections.

Normal Primary Graft Function Despite Early Hepatic Artery Thrombosis After Living-Donor Liver Transplant.

Early hepatic artery thrombosis is rare but devastating in living-donor liver transplant recipients. In this study, our aim was to evaluate the results of all patients with early hepatic artery thrombosis at our center. Between October 2004 and November 2015, 841 patients underwent liver transplant for end-stage liver disease at our center. All recipients with early hepatic artery thrombosis were identified and retrospectively analyzed. Early hepatic artery thrombosis was defined in our study as its occurrence within the first postoperative week. Early hepatic artery thrombosis was seen in 12 patients (1.8%). Seven of these 12 patients developed hepatic artery thrombosis on postoperative day 1 after intraoperative dissection of the hepatic artery with necessity of repeated reconstruction. However, the primary liver function of these patients was excellent, with nearly normal serum liver panel results. The other 5 patients were diagnosed after sudden significant increases of liver values followed by graft dysfunction within the first postoperative week. All patients were listed as high urgent and underwent retransplant. Two patients died perioperatively due to primary nonfunction, and 2 other patients died due to liver cirrhosis based on recurrent autoimmune hepatitis 29 and 106 months after retransplant. The remaining patients were alive with good liver function after a median time of 18 months (interquartile range, 13-45 mo). Early hepatic artery thrombosis is not always associated with graft dysfunction. Retransplant is still necessary due to ischemic cholangiopathy in the long-term follow-up. However, an elective retransplant, which could mean better outcomes, should be preferred instead of an emergency retransplant.

Pro: Steroids Can Be Withdrawn After Transplant in Recipients With Autoimmune Hepatitis.

Corticosteroids have been a mainstay of immunosuppression following liver transplantation. However, evolution in the field of transplant immunology has produced steroid-free options, resulting in most transplant centers weaning steroids after transplant within days to months-an evidence-based management decision. Patients with autoimmune hepatitis (AIH), however, receive corticosteroids prior to transplant. This raises the question of whether these patients should also be weaned from corticosteroids. In this review, we discuss the benefits of avoiding steroid use in this population of patients-an approach that not only avoids the adverse effects of corticosteroids but does so without risking graft failure from recurrent AIH or from acute cellular rejection.

Con: Steroids Should Not Be Withdrawn in Transplant Recipients With Autoimmune Hepatitis.

Autoimmune liver diseases (AILDs) can recur following liver transplantation (LT) despite immunosuppressive therapy, with implications for graft survival. Although the evidence is not robust, disease recurrence seems to occur in the presence of less intense and/or steroid-free immunosuppression (IS) in particular in the case of autoimmune hepatitis (AIH). The main risk factor for AIH recurrence is the severity of disease activity in the explant and potential donor/recipient human leukocyte antigen D-related 3 (DR3) mismatch. The treatment for AIH recurrence includes reintroduction or increase in the dose of steroids with or without the addition of azathioprine. T cell-mediated rejection episodes are also more common in AILD. Steroid withdrawal is the common practice in LT for non-AILD, eliminating the risks associated with longterm exposure to steroids. In AILD, maintenance of steroids at a low dose in the long term may reduce the risk of disease recurrence and rejection. This strategy is safe when there is vigilance for steroid-related adverse effects. Alternatively, identifying patients who are at the greatest risk for disease recurrence and who would benefit from intensified IS might be an option.

8. Liver transplantation for autoimmune liver disease: a single centre experience

Background and Aims: Autoimmune liver diseases (AILD) include Autoimmune hepatitis (AIH), Primary biliary cirrhosis (PBC), Primary sclerosing cholangitis (PSC), and Overlap syndromes. Patients with these conditions eventually progress to End stage liver disease requiring transplantation. Long term outcome of Liver transplantation (LT) in India for this condition is unknown. We aim to evaluate the outcome of patients who underwent Liver transplantation for AILD. Methods: A retrospective analysis of 60 adult patients with AILD who underwent LT in Gleneagles Global Health City, Chennai, from August 2009 to April 2018 was carried out. Patient demographics, dosage of immunosuppressant level, number of rejection episodes and graft and patient survival were calculated. Results: A total of 60 patients underwent LT for AILD. Out of 60 patients, 30 had AIH, 14 had PSC, 4 had PBC and 5 had Overlap syndrome. 53% of population was males. Median age was 39 years (18 to 52 years). The Model for End-stage Liver Disease (MELD) score was 18 (7 to 36). All patients were commenced on triple immunosuppression (tacrolimus, mycophenolate and corticosteroids) and maintained on long term corticosteroids. Biopsy proven acute cellular rejection (BPAR) occurred in 15 (25%) recipients and two thirds of ACR occurred within the first 10 post-operative days. These patients were treated with intravenous methylprednisolone therapy and improved with no graft loss. Thirteen patients developed sepsis but had no graft loss. One patient developed recurrent PSC and is managed medically. Overall patient survival was 95%. Three patients (5%) died during the follow up period. The cause of death were recurrent AIH, ischaemic heart disease and sepsis, respectively. Conclusions: Patients transplanted for AILD may have higher incidence of acute cellular rejection. However, this did not affect the overall outcome. Liver transplantation is the effective treatment for end stage AILD with excellent long term graft and patient survival. The authors have none to declare.

Comparative Analysis of the Clinical Outcomes of Liver Transplantation for Probable and Definite Auto-immune Hepatitis by International Diagnostic Scoring Criteria

BackgroundLiver transplantation (LT) is an effective treatment for patients with end-stage liver disease caused by auto-immune hepatitis (AIH). However, diagnosis of AIH can be challenging for patients with end-stage liver disease at the time of transplantation. We classified patients into “probable” or “definite” AIH groups, using the diagnostic criteria of the International Autoimmune Hepatitis Group, and compared the clinical outcomes of AIH after LT in these 2 groups. MethodsWe performed a retrospective study of 18 patients who were diagnosed with AIH and underwent LT from March 2003 to March 2015 at a single institute. Of the 18 patients, 8 were diagnosed with definite AIH and 10 were diagnosed with probable AIH, according to the international scoring criteria. We evaluated the patient characteristics, recurrence rate, graft loss, and survival rates after LT. ResultsThe mean follow-up duration was 59.3 months. Age, sex, medical condition at transplantation, warm ischemic time, cold ischemic time, and Model for End-Stage Liver Disease score did not differ significantly between the 2 groups. No patient died after LT in either group, but 1 patient in the definite AIH group had graft failure. In Kaplan-Meier analysis, the 5-year recurrence rates of the definite and probable groups were 14.3% and 0%, respectively (P = .992). ConclusionsThe recurrence of definite AIH appeared to be higher than that of probable AIH. However, careful immunosuppressive therapy allowed the long-term survival of both definite and probable AIH patients after LT.

Histologic surveillance after liver transplantation due to autoimmune hepatitis.

Autoimmune hepatitis (AIH) often recurs after liver transplantation (LT). Our aim was to evaluate the recurrence rate of AIH after LT, impact of AIH recurrence on survival and fibrosis progression, and find risk factors for AIH recurrence. Forty-two patients with AIH prior to LT with ≥1 protocol biopsy ≥1year post-LT were included with a median follow-up of 5.0years (1.0-17.0). Follow-up liver biopsies were re-evaluated for AIH recurrence, fibrosis progression, and cirrhosis development. A histological recurrence of AIH was diagnosed in 15 (36%) patients at a median of 5years of follow-up. Recurrent AIH lead to progressive fibrosis (METAVIR stage 3-4) in two but did not cause a single patient or graft loss. Transaminases were normal in three patients with recurrent AIH (20%). AIH recurrence was more common in patients with no overlapping cholangitis (OR 1.44, P=.021). Immunosuppression without antimetabolite increased the risk of AIH recurrence (OR 1.47, P=.018). Patient and graft survival rates at 1, 5, and 10years were 94%, 86%, and 86% and 91%, 77%, and 74%. AIH recurrence did not affect survival. AIH recurrence occurs in 36% in 5years, but does not affect patient or graft outcome.

281 - Hla Dr Mismatch is Associated with Recurrent Autoimmune Hepatitis After Liver Transplantation: A Single Center Experience with Tacrolimus Based Immunosuppression

281 - Hla Dr Mismatch is Associated with Recurrent Autoimmune Hepatitis After Liver Transplantation: A Single Center Experience with Tacrolimus Based Immunosuppression

Systematic review: recurrent autoimmune liver diseases after liver transplantation.

Autoimmune liver diseases (AILD) constitute the third most common indication for liver transplantation (LT) worldwide. Outcomes post LT are generally good but recurrent disease is frequently observed. To describe the frequency and risk factors associated with recurrent AILD post-LT and provide recommendations to reduce the incidence of recurrence based on levels of evidence. A systematic review was performed for full-text papers published in English-language journals, using the keywords 'autoimmune hepatitis (AIH)', 'primary biliary cholangitis and/or cirrhosis (PBC)', 'primary sclerosing cholangitis (PSC)', 'liver transplantation' and 'recurrent disease'. Management strategies to reduce recurrence after LT were classified according to grade and level of evidence. Survival rates post-LT are approximately 90% and 70% at 1 and 5 years and recurrent disease occurs in a range of 10-50% of patients with AILD. Recurrent AIH is associated with elevated liver enzymes and IgG before LT, lymphoplasmacytic infiltrates in the explants and lack of steroids after LT (Grade B). Tacrolimus use is associated with increased risk; use of ciclosporin and preventive ursodeoxycholic acid with reduced risk of PBC recurrence (all Grade B). Intact colon, active ulcerative colitis and early cholestasis are associated with recurrent PSC (Grade B). Recommendations based on grade A level of evidence are lacking. The need for further study and management includes active immunosuppression before liver transplantation and steroid use after liver transplantation in autoimmune hepatitis; selective immunosuppression with ciclosporin and preventive ursodeoxycholic acid treatment for primary biliary cholangitis; and improved control of inflammatory bowel disease or even colectomy in primary sclerosing cholangitis.

Recurrence of autoimmune liver disease and inflammatory bowel disease after pediatric liver transplantation

Approximately 10% of children with autoimmune hepatitis (AIH) and 30% of those with sclerosing cholangitis (SC) require liver transplantation (LT). LT is indicated in patients who present with fulminant hepatic failure (ie, with encephalopathy) and in those who develop end-stage liver disease despite treatment. After LT, recurrent AIH is reported in approximately 30% of patients and recurrent SC in up to 50%. Diagnosis of recurrence is based on biochemical abnormalities, seropositivity for autoantibodies, interface hepatitis on histology, steroid dependence, and, for SC, presence of cholangiopathy. Recurrence of SC after LT is often associated with poorly controlled inflammatory bowel disease (IBD). Recurrence may even appear years after LT; therefore, steroid-based immunosuppression should be maintained at a higher dose than that used for patients transplanted for nonautoimmune liver diseases. Although the impact of recurrent disease on graft function is controversial, it seems that in pediatric LT recipients recurrence of AIH or SC is associated with compromised graft survival. Exacerbation of preexistent IBD may be observed after LT for SC or AIH, and IBD appears to have a more aggressive course than before LT. In addition, IBD can develop de novo following LT. Liver Transplantation 22 1275-1283 2016 AASLD.

First-Degree Living-Related Donor Liver Transplantation in Autoimmune Liver Diseases.

Liver transplantation (LT) is the treatment of choice for end-stage autoimmune liver diseases. However, the underlying disease may recur in the graft in some 20% of cases. The aim of this study is to determine whether LT using living donor grafts from first-degree relatives results in higher rates of recurrence than grafts from more distant/unrelated donors. Two hundred sixty-three patients, who underwent a first LT in the Toronto liver transplant program between January 2000 and March 2015 for autoimmune liver diseases, and had at least 6 months of post-LT follow-up, were included in this study. Of these, 72 (27%) received a graft from a first-degree living-related donor, 56 (21%) from a distant/unrelated living donor, and 135 (51%) from a deceased donor for primary sclerosing cholangitis (PSC) (n = 138, 52%), primary biliary cholangitis (PBC) (n = 69, 26%), autoimmune hepatitis (AIH) (n = 44, 17%), and overlap syndromes (n = 12, 5%). Recurrence occurred in 52 (20%) patients. Recurrence rates for each autoimmune liver disease were not significantly different after first-degree living-related, living-unrelated, or deceased-donor LT. Similarly, time to recurrence, recurrence-related graft failure, graft survival, and patient survival were not significantly different between groups. In conclusion, first-degree living-related donor LT for PSC, PBC, or AIH is not associated with an increased risk of disease recurrence.

Autoimmune Liver Disease Post-Liver Transplantation: A Summary and Proposed Areas for Future Research.

Autoimmune liver diseases (AILD) are rare diseases with a reported prevalence of less than 50 per 100 000 population. As the research landscape and our understanding of AILDs and liver transplantation evolves, there remain areas of unmet needs. One of these areas of unmet needs is prevention of disease recurrence after liver transplantation. Disease recurrence is not an insignificant event because allograft loss with the need for retransplantation can occur. Patients transplanted for AILD are more likely to experience acute rejection compared to those transplanted for non-AILD, and the reason(s) behind this observation is unclear. Tasks for the future include a better understanding of the pathogenesis of AILD, definition of the precise pathogenetic mechanisms of recurrent AILD, and development of strategies that can identify recipients at risk for disease recurrence. Importantly, the role of crosstalk between alloimmune responses and autoimmune responses in AILD is an important area that needs further study.This article reviews the relevant literature of de novo autoimmune hepatitis, recurrent autoimmune hepatitis, recurrent primary sclerosing cholangitis, and recurrent primary biliary cirrhosis in terms of the clinical entity, the scientific advancements, and future scientific goals to enhance our understanding of these diseases.

Longterm corticosteroid use after liver transplantation for autoimmune hepatitis is safe and associated with a lower incidence of recurrent disease.

Patients transplanted for autoimmune hepatitis (AIH) are at risk of recurrent disease. Our current practice is to maintain long-term low-dose corticosteroids with additional immunosuppressive agents. This study describes the implications on patients' outcomes, sepsis, and osteoporosis. We collected data on patients transplanted between January 1999 and October 2014 in a single center who survived for more than 6 months. AIH recurrence was diagnosed by a combination of histology, raised immunoglobulin G levels, and exclusion of other etiologies. Sepsis was defined as any infection that resulted in significant morbidity or mortality. Osteoporosis was defined as a bone densitometry T score of less than -2.0 or evidence of osteoporosis-related fractures. Outcomes were assessed using Kaplan-Meier survival analysis methods. Seventy-three AIH patients underwent liver transplantation with a median follow-up of 94 months (interquartile range, 55-144). The cohort was mainly Caucasian (78%), female (79%), with type 1 AIH (90%), and a mean age of 43 ± 15 years. Overall survival was 92%, 90%, 86%, and 73%, and regraft-free survival was 86%, 81%, 78%, and 64% at 1, 3, 5, and 10 years, respectively. Five patients developed AIH recurrence, giving recurrence rates of 0%, 4%, 6%, and 11% at 1, 3, 5, and 10 years, respectively. Pneumonia was the most common infection, but gastroenteritis and cholangitis were the most recurrent. Freedom from sepsis was 91%, 82%, 80%, and 63%, and freedom from osteoporosis was 100%, 94%, 82%, and 58% at 1, 3, 5, and 10 years, respectively. Longterm low-dose corticosteroid in combination with other immunosuppressive agents seems to reduce AIH recurrence without jeopardizing patient and graft survival. Sepsis and osteoporosis did not occur more often compared to the published literature on liver transplant recipients.

Clinical analysis of liver transplantation for autoimmune hepatitis

To describe the outcomes and recurrence of autoimmune hepatitis (AIH) after liver transplantation. Clinical data of 16 patients with AIH who underwent liver transplantation were analyzed retrospectively. The postoperative cumulative survival rate of the patients was calculated. The postoperative rejections and AIH recurrence were analyzed. The Kaplan-Meier method was used for statistical analysis of survival. All patients were female, with an average age of 52.6 years (range: 41-66 years), and an average MELD score of 21.4. According serological analysis, 15 patients were AIH type 1 and 1 patient was AIH type 2. Three patients died, including 2 of pulmonary infection and 1 of graft dysfunction.The 1-, 2-and 5-year cumulative survival rates were 93.8%, 87.1% and 79.1%, respectively. Five cases (31.3%) of recurrent AIH were diagnosed based on histological evidence. Acute rejection occurred in 6 (37.5%) patients, and de novo HBV infection occurred in 1 (6.3%) patient. Liver transplantation is an effective treatment for end-stage AIH. Recurrence and rejection were commonly associated with AIH, but did not negatively impact patient survival.

Autoimmune hepatitis.

Autoimmune hepatitis is a chronic liver disease putatively caused by loss of tolerance to hepatocyte-specific autoantigens. It is characterized by female predilection, elevated aminotransferase levels, autoantibodies, increased γ-globulin or IgG levels and biopsy evidence of interface hepatitis. It is currently divided into types 1 and 2, based on expression of autoantibodies. Autoantigenic epitopes have been identified only for the less frequent type 2. Although autoimmune hepatitis occurs in childhood, this review focuses on disease in adults. In the absence of pathognomonic biomarkers, diagnosis requires consideration of clinical, biochemical, serological and histological features, which have been codified into validated diagnostic scoring systems. Since many features also occur in other chronic liver diseases, these scoring systems aid evaluation of the differential diagnosis. New practice guidelines have redefined criteria for remission to include complete biochemical and histological normalization on immunosuppressive therapy. Immunosuppression is most often successful using prednisone or prednisolone and azathioprine; however, the combination of budesonide and azathioprine for non-cirrhotic patients offers distinct advantages. Patients failing standard immunosuppression are candidates for alternative immunosuppressive regimens, yet none of the options has been studied in a randomized, controlled trial. Overlap syndromes with either primary sclerosing cholangitis or primary biliary cirrhosis occur in a minority. Liver transplantation represents a life-saving option for patients presenting with acute liver failure, severely decompensated cirrhosis or hepatocellular carcinoma. Transplant recipients are at risk for recurrent autoimmune hepatitis in the allograft, and de novo disease may occur in patients transplanted for other indications. Patients transplanted for AIH are also at risk for recurrent or de novo inflammatory bowel disease. Progress in our understanding of the immunopathogenesis should lead to identification of specific diagnostic and prognostic biomarkers and new therapeutic strategies.

Liver transplantation and autoimmune hepatitis.

Liver Transplantation (LT) is an effective treatment for patients with end-stage liver disease including autoimmune hepatitis (AIH). Indication for LT for AIH does not differ basically from other liver diseases including both acute and chronic types of disease progression, although it is reported to be an infrequent indication for LT worldwide due to the therapeutic advances of immunosuppression. The outcome following LT is feasible, with current patient and graft survival exceeding 75% at 5 years. Recurrent and de-novo AIH posttranslant has also been reported; and this seems to have important clinical implications because its management differs from the standard treatment for allograft rejection. In this review, we discuss the characteristics of AIH, focusing on the indication for LT and issues raised following LT.

Possible benefit of splenectomy in liver transplantation for autoimmune hepatitis

Liver transplantation for autoimmune hepatitis (AIH) is usually successful with excellent long-term outcomes, but primary disease may recur. The recurrence of AIH is a significant cause of graft loss. This study was to analyze the effect of splenectomy in preventing AIH relapse. The clinical courses of 12 patients who had transplantation for AIH were analyzed retrospectively. All patients were subjected to transplantation for end-stage liver disease caused by chronic AIH. Based on the duration of immunosuppressive treatment before liver transplantation, simultaneous splenectomy was performed in ten patients. Two patients underwent liver transplantation without splenectomy, one of them developed recurrent AIH and died from graft failure caused by AIH relapse. However, no episode of AIH recurrence was observed in patients who had undergone simultaneous splenectomy. Splenectomy might be an option to prevent AIH relapse in some patients with high risk factors.

Recurrence of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis after transplantation.

Recurrence of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis after transplantation.