tacrolimus and Hepatitis--Autoimmune

Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by elevated levels of transaminases, immunoglobulin G, and positive autoantibodies. The disease course is dynamic and presents heterogeneous disease manifestations at diagnosis. This review summarizes the issues regarding the treatment and monitoring of AIH in adult patients. Glucocorticoids and azathioprine are the first line of treatment. Alternative first-line treatments include budesonide or mycophenolate mofetil (MMF). Although no randomized controlled trials have been performed, MMF, cyclosporine, tacrolimus, 6-mercaptopurine, 6-thioguanine, allopurinol, sirolimus, everolimus, infliximab, or rituximab have been attempted in patients not responding to or intolerant to first-line treatments. Most patients require life-long special monitoring, with or without maintenance treatment.

Topics: Adult; Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus

Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis.. A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded.. The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88-6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27-3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02-1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00-2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49-0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00-2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39-0.88) were associated with the risk of rALD.. Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.

Topics: Adult; Calcineurin Inhibitors; Cholangiocarcinoma; Cholangitis, Sclerosing; Colectomy; Cyclosporine; End Stage Liver Disease; Enzyme Inhibitors; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus

The standard management of autoimmune hepatitis (AIH) is based on corticosteroids, alone or in combination with azathioprine. Second-line treatments are needed for patients who have refractory disease. However, high-quality data on the alternative management of AIH are scarce.. To evaluate the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) and the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).. A systematic review and meta-analysis of the available data were performed. We calculated pooled event rates for three outcome measures: Biochemical remission, adverse events, and mortality, with their corresponding 95% confidence intervals (CI).. The pooled biochemical remission rate was 68.9% (95%CI: 60.4-76.2) for tacrolimus, and 59.6% (95%CI: 54.8-64.2) for MMF, and rates of adverse events were 25.5% (95%CI: 12.4-45.3) for tacrolimus and 24.1% (95%CI: 15.4-35.7) for MMF. The pooled mortality rate was estimated at 11.5% (95%CI: 7.1-18.1) for tacrolimus and 9.01% (95%CI: 6.2-12.8) for MMF. Pooled biochemical remission rates for tacrolimus and MMF in patients with intolerance to standard therapy were 56.6% (CI: 43.4-56.6). Tacrolimus and MMF are in practice considered effective for patients with AIH who are non-responders or intolerant to first-line treatment, but we found no high-quality evidence to support this statement.

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus; Treatment Outcome

There is paucity of data on alternative drug therapies for patients with autoimmune hepatitis (AIH). Tacrolimus (TAC) is a promising salvage agent. We present a review of TAC therapy in AIH patients.. A search for studies with keywords 'autoimmune hepatitis' and 'tacrolimus' was performed. Reviews, studies of AIH post-transplant and AIH in children were excluded. Diagnosis of AIH was based on criteria established by the International Autoimmune Hepatitis Group. Complete biochemical response was defined as normalisation of aspartate aminotransferase (AST <45) and alanine aminotransferase (ALT <50). No biochemical response was defined as failure to return to normalisation at the end of follow-up. Demographic information and details of pre- and post-treatment liver biopsy were collected.. Seven articles achieved the inclusion criteria and reported data for a total of 162 adult patients. The majority of studies reported average ages approximately 35 years old. Treatment duration ranged from 1 to 136 months. Indications for therapy were mostly AIH refractory to steroid treatment or inability to tolerate standard steroid treatment. Eighty-three patients (51.2%) were reported to have pre-therapy liver biopsy. Of 49 patients for whom stage was reported, 6 patients were stage 1, 16 were stage 2, 14 were stage 3 and 13 were stage 4. Of 40 patients for whom grade was reported, 1 patient was grade 0, 3 were grade 1, 9 were grade 2, 14 were grade 3 and 13 were grade 4. Dosing regimens were between 1 and 8 mg/day. Target trough TAC serum concentrations ranged from 0.5 to 10.7 ng/mL TAC was discontinued in 28 (17.3%) patients for various reasons. Renal function remained stable in most patients. One hundred and twenty-one patients (74.7%) demonstrated complete biochemical response to treatment. Post-therapy liver biopsy was obtained for 30 (18.5%) patients, and 25 (15.4%) of these patients were noted to have histological remission according to the grade of inflammation or stage of fibrosis.. TAC is relatively effective in the treatment of AIH refractory to traditional therapy. It appears that liver function can be enhanced at a minimal cost to renal function. Key Points There is a cohort of patients with autoimmune hepatitis (AIH) who do not respond to standard therapy. Alternative treatment options for these patients have been explored, but outcomes have not been comprehensively examined. We report the use and efficacy of tacrolimus (TAC) in patients with AIH. We found that TAC can be safely and effectively used in patients with AIH with minimal side effects. TAC can be a potential treatment option for patients with AIH refractory to standard therapy.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Tacrolimus; Treatment Outcome

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.

Topics: Animals; Azathioprine; Disease Management; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic; Remission Induction; Tacrolimus

The gold-standard treatment for autoimmune hepatitis (AIH) is a prednisone/azathioprine combination. However, subgroups of patients may be unresponsive to this treatment. The aim of this study is to evaluate the efficacy of second-line immunosuppressive therapies for AIH through a systematic review and meta-analysis in adult patients.. The systematic review was registered at the PROSPERO platform under number 42015019831. Databases MEDLINE (PubMed), Lilacs, Cochrane, and Scielo were searched. The keywords used were 'Hepatitis, Autoimmune' and descriptors terms (MeSH and DeCS). These terms were linked with each immunosuppressant of interest.. A total of 1532 studies were identified. Of these, 1492 were excluded on the basis of title and abstract reading. Among the 40 studies retrieved for detailed full-text analysis, a total of 15 fulfilled the inclusion criteria for the analysis. The most studied second-line immunosuppressive was mycophenolate mofetil (MM). The mean reduction of aminotransferases was observed in 94.3% with tacrolimus/prednisone, 91.3% for cyclosporine/prednisone, 85.5% for budesonide, and 78.7% MM/prednisone. For MM/prednisone, the mean rate of histological remission was 88.6%, liver transplantation was indicated in 11.4%, and the mortality rate was 7.2%. Limitations were also present, such as the lack of randomized-controlled trials and prospective studies, the small number of patients, and the heterogeneity between remission criteria.. This is the first systematic review and meta-analysis to compare the second-line imunossupressant therapy for AIH. The most studied second-line immunosuppressive is the MM, with a reasonable histological remission. The use of combined tacrolimus/prednisone was the most effective for the normalization of aminotransferases.

Topics: Anti-Inflammatory Agents; Budesonide; Cyclophosphamide; Drug Therapy, Combination; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prednisone; Retreatment; Tacrolimus

Ten percent to 20% of children with autoimmune hepatitis (AIH) require second-line therapy to achieve remission. Although current guidelines exist on first-line management, evidence for second-line therapy in treatment-refractory patients is lacking. Our aim was to perform a systematic review and meta-analysis of the efficacy and safety of second-line treatments used in this population.. Electronic and manual searches were used to identify potential studies for inclusion. Studies were selected based on reported response rates to second-line therapies in children who failed response to prednisone and azathioprine. Data extraction and risk of bias assessment were performed independently by 2 reviewers. Meta-analysis using weighted estimate of response rates at 6 months was performed for each treatment option. Heterogeneity was assessed.. Fifteen studies of 76 pediatric patients with AIH were included in the review. Overall response rates at 6 months were estimated as 36% for mycophenolate mofetil (MMF) (N = 34, 95% confidence interval [CI] (16-57)), and 50% for tacrolimus (N = 4, 95% CI (0-100%)) and 83% for cyclosporine (N = 15, 95% CI (66%-100%)). Adverse effects were most frequent with cyclosporine (64% experiencing at least 1 adverse effect) followed by tacrolimus (54%) and MMF (48%). Pooled estimates of adverse events were 78% for cyclosporine (95% CI (54%-100%)), 42% for tacrolimus (95% CI (0%-85%)) and 45% for MMF (95% CI (25%-68%)). Sensitivity analyses were not performed due to small sample size.. Cyclosporine had the highest response rate at 6 months in children with standard-treatment-refractory AIH; however, it also had the highest rate of adverse events. MMF was the second most efficacious option with a low adverse effect rate.

Topics: Azathioprine; Child; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Induction Chemotherapy; Models, Statistical; Mycophenolic Acid; Pediatrics; Prednisone; Tacrolimus; Treatment Outcome

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.

Topics: Adult; Clinical Trials as Topic; Cyclosporine; Female; Graft Survival; Hepatitis, Autoimmune; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Recurrence; Steroids; Survival Rate; Tacrolimus; Ursodeoxycholic Acid

This review presents the author's personal perspective and contributions to the first steps, the development, the current status, and the remaining issues of pediatric liver transplantation (LT). Innumerable children around the world who have undergone LT have reached adulthood. The techniques have reached maturity. As shown by my own group's experience, grafts donated by living donors might provide the best short-term and longterm results. Debate persists about the optimal immunosuppression (IS), although the place of tacrolimus remains unchallenged. Tolerance induction protocols aiming to induce microchimerism have been tried in clinical transplantation without convincing results. Withdrawal of maintenance IS is possible in some children who underwent liver transplantation who have excellent clinical status and normal liver function tests but is not without risk of rejection and subsequent worsening of histology. The current trend favored by the Brussels' group is to minimize IS as soon after transplant as possible, aiming to obtain a state of "prope" or "almost" tolerance. Liver grafts are threatened in the long term by increasing hepatitis-related fibrosis, resulting most likely from immunological assault. Nowadays, the focus is on the longterm survival, quality of life (growth, academic performance, employment, self-fulfillment, fertility, raising a family, etc.), induction of tolerance, prevention of risks bound to decades of IS (nephrotoxicity and neurotoxicity, cardiovascular risk, de novo malignancies, etc.), and prevention of graft fibrosis. All these issues are fertile fields for younger scientists. Liver Transplantation 22 1284-1294 2016 AASLD.

Topics: Achievement; Allografts; Biliary Atresia; Child; Drug Therapy, Combination; Fibrosis; Graft Rejection; Hepatitis, Autoimmune; Hepatoblastoma; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Living Donors; Patient Selection; Preoperative Care; Quality of Life; Risk Factors; Survival Rate; Tacrolimus; Withholding Treatment

Nonstandard drugs that target critical pathogenic pathways or immune regulatory mechanisms constitute the next generation of treatments for autoimmune hepatitis. Mycophenolate mofetil impairs the proliferation of lymphocytes, decreases autoantibody production, and induces apoptosis of activated immunocytes. Patients treated for azathioprine intolerance improve more frequently than patients treated for refractory liver disease (54% versus 10%), and mycophenolate mofetil is emerging as a rescue therapy for this population. Complete corticosteroid withdrawal is possible in 40% of patients treated with mycophenolate mofetil, and the frequency of side effects ranges from 3-34%. Budesonide in combination with azathioprine has normalized liver tests more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than standard therapy after 6 months. Budesonide is emerging as a frontline treatment in non-cirrhotic patients with uncomplicated disease or contraindications to conventional corticosteroids. Cyclosporine and tacrolimus are effective salvage agents for steroid-refractory disease, but side effects have been common and occasionally serious. The 6- thioguanine nucleotides and rapamycin are feasible treatments for autoimmune hepatitis, but 6-thioguanine has major obstacles to overcome, especially the risk of liver toxicity or nodular regenerative hyperplasia. The nonstandard drug therapies emerging for autoimmune hepatitis reflect the need to supplement or supplant current treatment regimens. None has been licensed for use in autoimmune hepatitis, and their applications have been based on results from small singlecenter experiences.

Topics: Animals; Budesonide; Cyclosporine; Drug Discovery; Hepatitis, Autoimmune; Humans; Immunosuppression Therapy; Mycophenolic Acid; Tacrolimus; Thioguanine

Autoimmune hepatitis (AIH) is a chronic, progressive hepatitis of uncertain cause which has fluctuating activity characterized by periods of flares and remissions. Initial placebo-controlled trials carried out in the 1970s demonstrated that immunosuppression with steroids was extremely effective in reducing flares and progression of disease. The late 1980s-1990s could be described as the 'Dark Ages' of AIH treatment research. Very few clinical studies were performed during this time, although it became increasingly apparent that not all patients tolerated or responded to traditional immunosuppression, and that not all patients were easy to diagnose because of overlapping features with other autoimmune conditions. Fortunately, clinical research in the treatment of AIH has experienced a renaissance in the 21st century.. This review highlights some of the more important recent discoveries, including the creation of the clinically useful short form of the autoimmune hepatitis diagnostic scoring system; accumulation of data supporting the use of mycophenolate and tacrolimus as second-line treatment; and the recent completion of the largest, double-blind, placebo-controlled trial of AIH treatment to date, comparing budesonide to prednisone.. These new findings are pertinent to the everyday clinical management of patients with AIH.

Topics: Azathioprine; Budesonide; Drug Hypersensitivity; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Purine-Pyrimidine Metabolism, Inborn Errors; Tacrolimus

Topics: Anti-Inflammatory Agents; Antimetabolites; Azathioprine; Calcineurin Inhibitors; Cyclophosphamide; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Mycophenolic Acid; Recurrence; Remission Induction; Risk Factors; Steroids; Tacrolimus; Treatment Outcome

Topics: Azathioprine; Folic Acid Antagonists; Hepatitis, Autoimmune; Humans; Immunity, Cellular; Immunosuppressive Agents; Interferon-gamma; Liver Transplantation; Methotrexate; Mycophenolic Acid; Tacrolimus; Tumor Necrosis Factor-alpha

Prednisone alone or a lower dose in combination with azathioprine is effective in improving symptoms, resolving laboratory and histologic features, and prolonging survival in patients with autoimmune hepatitis. The combination regimen of prednisone and azathioprine is preferred because of its lower frequency of corticosteroid-related side effects. Only patients with severe inflammatory activity have absolute indications for therapy. Treatment must be individualized in patients with mild-to-moderate disease. Medication should be continued at fixed daily maintenance levels until a remission, treatment failure, drug intolerance, or incomplete response has been established. Histologic examination before drug withdrawal ensures remission when symptoms and laboratory tests are normal or near normal. Treatment failure warrants high-dose therapy, whereas drug toxicity and incomplete response compel regimens that are modified individually according to response. Low-dose prednisone or indefinite azathioprine therapy are indicated in patients who have relapsed multiply. Empiric nonsteroidal treatments include ursodeoxycholic acid, cyclosporine, mycophenolate mofetil, and tacrolimus, and they have been used in limited studies to treat recalcitrant disease or corticosteroid intolerance. Investigational therapies promise to target critical pathogenic mechanisms affecting immunocyte activation, autoantigen recognition, cytokine interactions, and regenerative activity.

Topics: Azathioprine; Budesonide; Clinical Trials as Topic; Cyclosporine; Disease Progression; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome; Ursodeoxycholic Acid

Refinements in the understanding of the mechanisms of immunocyte activation and the emergence of new immunosuppressive agents with highly selective actions has created opportunities for improving the treatment of autoimmune hepatitis. Drugs, such as budesonide and deflazacort, may inhibit immunocyte activation and limit corticosteroid-related side effects. Agents, such as cyclosporine and tacrolimus, can impair calcineurin activity and restrict the generation of transcription factors necessary for T cell responses. Intravenous immunoglobulin can bind anti-idiotype antibodies and reduce interleukin-2 secretion, and monoclonal antibodies directed against critical components of the T cell activation cascade can dampen the immune reaction. Drugs, such as mycophenolate mofetil, cyclophosphamide, methotrexate, and KF20444, can inhibit T cell proliferation, and other interventions promise to deplete activated T cells, impair effector mechanisms, and induce self-tolerance.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Autoantibodies; Budesonide; Cyclophosphamide; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Methotrexate; Mycophenolic Acid; Signal Transduction; Tacrolimus

Autoimmune hepatitis has been described as recurrent or de novo disease after transplantation. The legitimacy of these diagnoses and the bases for their occurrence are unknown. To better understand these aspects of allograft dysfunction, the purported pathogenic mechanisms of classical autoimmune hepatitis were reviewed and extrapolated to recurrent and de novo disease after transplantation. Loss of self-tolerance may relate to defects in the negative selection of autoreactive immunocytes and the clonal expansion of promiscuous lymphocytes that are cross-reactive to homologous antigens (molecular mimicry). Repopulation of the allograft with recipient antigen-presenting cells and the presence of primed promiscuous cytotoxic T cells within the recipient are likely factors for recurrent disease. Targets may be the same peptides that triggered the original disease, donor-derived class II antigens of the major histocompatibility complex, or homologous antigens associated with unidentified hepatotrophic viruses. De novo disease is probably due to similar mechanisms, but its predilection for children suggests that thymic dysfunction associated with cyclosporine treatment may be a factor. Corticosteroid therapy is effective in each condition. In conclusion, recurrent and de novo autoimmune hepatitis after transplantation are examples of self-intolerance. The mechanisms that perturb immunologic homeostasis in this human model of the classical disease must be studied more rigorously.

Topics: Autoimmunity; Child; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Transplantation; Molecular Mimicry; Recurrence; Self Tolerance; T-Lymphocytes; Tacrolimus

The aim of this study was to evaluate the success of steroid (PRED) withdrawal due to replacement by mycophenolate mofetil (MMF) in orthotopic liver transplant (OLT) recipients with autoimmune hepatitis (AIH). Thirty patients with AIH > 12 months after OLT randomized to receive either PRED and tacrolimus (TAC) or MMF and TAC were followed for 24 months. Withdrawal of steroids showed no difference regarding graft and patient survival. Also we demonstrated significantly lower glucose levels with lower HbA1c and a reduced need for insulin as well as a significantly lower serum cholesterol in the MMF group. Patients without steroids showed a lower incidence of osteopenia. Maintenance therapy in OLT patients with AIH may be performed safely using MMF instead of prednisone.

Topics: Adult; Anti-Inflammatory Agents; Bone Density; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Mycophenolic Acid; Prednisone; Tacrolimus; Time Factors

Conventional treatment of autoimmune hepatitis consists of either prednisone alone or in combination with azathioprine. Ten to 20% of patients do not respond to or are intolerant of this treatment. Novel drug treatments include immunosuppressive drugs such as tacrolimus (TAC), mycophenolate mofetil (MMF), methotrexate and cyclosporine. We describe a multi-centre Canadian experience with MMF and TAC.. To study a multi-centre patient population who had failed conventional therapy and were treated with non-conventional medical therapy for autoimmune hepatitis and document response.. Members of the Canadian Association for the Study of Liver (CASL) obtained MMF from Hoffmann-La Roche Ltd, as part of a compassionate release program, were contacted for standardized data on patients with AIH who received MMF or TAC. Response definitions based on aminotransferase changes were: Complete response (CR)-sustained normalization, partial response (PR)-improvement by greater than 50%, non-response (NR)-less than 50% improvement and relapse (RP)-initial CR or PR followed by an increase in aminotransferases.. A total of 16 patients were identified: six in Ontario, one in Quebec, five in Alberta and four in British Columbia. Three were treated with TAC, eleven with MMF and two with combination MMF and TAC. CR was observed in 50%, PR in 12.5%, RP in 25% and NR occurred in 12.5%. The CR for MMF without TAC was approximately 64%.. MMF is effective and well tolerated by patients with autoimmune hepatitis who do not respond to, or are intolerant of, conventional immunosuppressive agents.

Topics: Adult; Aged; Canada; Drug Therapy, Combination; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Secondary Prevention; Tacrolimus; Transaminases; Treatment Outcome

Autoimmune hepatitis (AIH) is an immune mediated chronic liver disease with a prevalence of 17 cases/100,000. Resistance to the standard treatment of AIH (prednisone and azathioprine) occurs in 15% to 20%. There is currently no standard treatment of patients with steroid refractory AIH.. Determine the efficacy of tacrolimus in the treatment of steroid refractory AIH.. This is a retrospective study evaluating the efficacy of Tacrolimus in the treatment of steroid refractory AIH.. Between October 1998 and February 2002, 11 patients with steroid refractory AIH were treated with tacrolimus. Mean age was 63 years. Median duration of steroid treatment before starting tacrolimus was 9 months. Median duration of tacrolimus treatment was 25 months. Median follow-up period was 16 months. Median baseline ALT, AST were 77 U/L and 68 U/L and became 21 U/L and 32 U/L respectively at end of follow-up (P = 0.005 and 0.01 respectively). Significant weight reduction was seen in all patients (P = 0.02). Tacrolimus treatment was safe and well tolerated.. Use of low dose tacrolimus led to successful biochemical and histologic remission and weaning off prednisone in patients with steroid refractory AIH. This data supports further studies in evaluating the use of tacrolimus in the treatment of AIH.

Topics: Adult; Aged; Aged, 80 and over; Azathioprine; Biopsy; Female; Fibrosis; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Male; Middle Aged; Prednisone; Steroids; Tacrolimus; Treatment Outcome

Topics: Causality; COVID-19; Hepatitis, Autoimmune; Humans; SARS-CoV-2; Tacrolimus

Autoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis.. We recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with drug-induced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an. HLA-DR11 was prominent in our AIH cohort. Activated Tregs and MAIT cell frequencies were lower before IS. Importantly, we discovered a previously unrecognized and long-lasting Bregs scarcity in AIH patients after IS. Tacrolimus and 6MP increased IL-10+ B-cells

Topics: Adult; B-Lymphocytes, Regulatory; Child; Forkhead Transcription Factors; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Interleukin-10; Tacrolimus

Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity.. To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients.. Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG.. A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496).. Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH.

Topics: Adult; Chronic Disease; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver; Male; Middle Aged; Retrospective Studies; Tacrolimus

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Calcineurin Inhibitors; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Salvage Therapy; Tacrolimus

Topics: COVID-19; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; SARS-CoV-2; Tacrolimus

Therapy for autoimmune hepatitis (AIH) consists of steroid induction therapy, followed by maintenance therapy with azathioprine. However, up to 20% of patients experience either insufficient response or intolerance on first-line therapy. Calcineurin inhibitors (CNIs) are frequently used when first-line therapy fails. Although a number of studies report on efficacy, less is known on the patient trajectory before switch to CNIs. Our aim was to describe the road toward CNI therapy in AIH patients.. Patients with an AIH diagnosis who used CNIs as either second- or third-line treatment were included in the study. Reason for switch to CNI was assessed as either an insufficient response or intolerance to prior therapy. Efficacy was assessed by normalization of transaminases at last moment of follow-up.. Final analysis included 20 patients who were treated with CNIs. Ten patients were treated with tacrolimus and ten patients received cyclosporine. In patients who used CNI treatment as third-line therapy (n = 13), duration of first-line therapy was almost twice as long as duration of second-line therapy (2.58 years vs. 1.33 years; P = 0.67). Patients treated with tacrolimus had relatively high trough levels (7.6 ng/mL) and more (minor) adverse events. Fifty-five percent of patients had normalization of transaminases at last moment of follow-up.. CNI treatment in AIH as second- or third-line therapy is effective in ~50% of patients. The trajectory before switch varies considerably between patients.

Topics: Adult; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Treatment Failure; Treatment Outcome; Young Adult

As data is limited on the outcomes of calcineurin inhibitors (CNI) in autoimmune hepatitis (AIH), we evaluated the efficacy and safety of CNI in AIH patients who failed prior treatment(s).. A retrospective study was performed of AIH patients who received cyclosporine A (CsA) and/or tacrolimus (TAC) after prior treatment(s) failure. Records were reviewed for baseline demographic and clinical characteristics, and treatment outcomes. The primary outcome was biochemical remission.. CNI salvage therapy is well tolerated and moderately effective achieving remission in around 50% of AIH who failed standard therapy.

Topics: Calcineurin Inhibitors; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Retrospective Studies; Salvage Therapy; Tacrolimus; Treatment Outcome

We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine).. We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8-182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy.. Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal.. Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.

Topics: Adolescent; Child; Drug Administration Schedule; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Hepatitis, Autoimmune; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Liver Diseases; Tacrolimus

Topics: Hepatitis, Autoimmune; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Liver Diseases; Tacrolimus

Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH.. We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC.. There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal.. Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Topics: Adolescent; Adult; Aged; Canada; Child; China; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome; United States; Young Adult

Topics: Adolescent; Adult; Azathioprine; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Tacrolimus; Treatment Outcome; Young Adult

High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based.. To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH.. A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH.. Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres.. There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.

Topics: Azathioprine; Biopsy; Budesonide; Cyclosporine; Health Care Surveys; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Methyltransferases; Mycophenolic Acid; Rituximab; Tacrolimus

Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (T

Topics: Adolescent; Adult; Case-Control Studies; Cell Proliferation; Child; Cyclosporine; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Interferon-gamma; Kinetics; Middle Aged; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Tacrolimus; Th1 Cells; Young Adult

Autoimmune hepatitis (AIH) is an immune-mediated liver disease, which requires long-term immunosuppression. Ten to fifteen percent of patients experience insufficient/intolerance response to standard therapy. Although alternate immunosuppression has been applied, there is little long-term data reported on safety, efficacy, steroid-dose reduction and disease evolution in patients with difficult AIH who were on Tacrolimus therapy.. Clinical, biochemical, immunological profiles, treatment response and side effects of 17 AIH patients treated with Tacrolimus between 2003 and 2014 were analyzed from two tertiary referral liver centers.. Tacrolimus was started on 16/17 (94%) patients due to insufficient response to standard therapy. The median duration of treatment was 24 months and patients were followed up for median of 60 months. Tacrolimus dosage was 2 mg/day (median). During first year of therapy, there was a significant improvement in immunoglobulin G and Aspartate transaminase level. 9/17 (52%) compliant and definite AIH patients remained on Tacrolimus at end of follow-up and prednisolone dose reduction was achieved from 10 to 5 mg. All patients are alive and one patient underwent liver transplantation. 4/17 (24%) patients developed overlap with primary sclerosing cholangitis over follow-up period. No significant side effects were observed with Tacrolimus therapy.. Tacrolimus could be used in compliant patients with difficult to treat AIH in experienced centers. Its use is safe and can improve liver biochemistry, IgG and reduce steroid requirement. However, due to the lack of immunomodulatory effect, unmet need for effective immune-regulatory therapies still remain for AIH patients.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Aspartate Aminotransferases; Azathioprine; Cholangitis, Sclerosing; Cyclosporine; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Mycophenolic Acid; Prednisolone; Retreatment; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Although the development of de novo autoimmune liver disease after liver transplantation (LT) has been described in both children and adults, autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap syndrome has rarely been seen in liver transplant recipients. Here, we report a 50-year-old man who underwent LT for decompensated liver disease secondary to alcoholic steatohepatitis. His liver function tests became markedly abnormal 8 years after LT. Standard autoimmune serological tests were positive for anti-nuclear and anti-mitochondrial antibodies, and a marked biochemical response was observed to a regimen consisting of prednisone and ursodeoxycholic acid added to maintain immunosuppressant tacrolimus. Liver biopsy showed moderate bile duct lesions and periportal lymphocytes infiltrating along with light fibrosis, which confirmed the diagnosis of AIH-PBC overlap syndrome. We believe that this may be a case of post-LT de novo AIH-PBC overlap syndrome; a novel type of autoimmune overlap syndrome.

Topics: Cholagogues and Choleretics; Cholestasis; Fatty Liver, Alcoholic; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Prednisone; Tacrolimus; Treatment Outcome; Ursodeoxycholic Acid

The role of donor-specific HLA antibodies (DSA) after pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes.. Serum samples were collected at routine clinic visits from 50 pediatric LTx recipients classified into 3 clinical phenotypes: nontolerant (n = 18) with de novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n = 25) on maintenance tacrolimus; operationally tolerant (n = 7). Samples were blinded, and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA.. DSA were detected in 54% (n = 27) of the patients, with the majority directed at HLA class II antigens (DR, 41%; DQ, 53%). Patients with DSA were younger at the time of LTx (P = 0.016) and time of study (P = 0.024). Mean aspartate aminotransferase, alanine aminotransferase, total bilirubin, and gamma glutamyl transferase were higher in DSA-positive patients, though did not reach statistical significance. Nontolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (P = 0.021). The nontolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (P = 0.015) and 8.6 (P = 0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (P = 0.004) and 10.8 (P = 0.006), respectively.. Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection.

Topics: Acute Disease; Adolescent; Age Factors; Biomarkers; Chi-Square Distribution; Child; Child, Preschool; Chronic Disease; Complement C1q; Cross-Sectional Studies; Female; Graft Rejection; Graft Survival; Hepatitis, Autoimmune; Histocompatibility; Histocompatibility Testing; HLA Antigens; HLA-DQ Antigens; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Isoantibodies; Liver Transplantation; Logistic Models; Male; Multivariate Analysis; Odds Ratio; Phenotype; Risk Factors; Tacrolimus; Time Factors; Transplantation Tolerance; Treatment Outcome; Young Adult

Topics: Adult; Aged; Antibodies, Monoclonal; Antibody Specificity; Basiliximab; Blood Donors; Blood Grouping and Crossmatching; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Isoantibodies; Isoantigens; Kidd Blood-Group System; Liver Transplantation; Mycophenolic Acid; Operative Blood Salvage; Platelet Transfusion; Prednisolone; Recombinant Fusion Proteins; Rh-Hr Blood-Group System; Tacrolimus; Tissue Donors; Transplantation Immunology

To investigate tacrolimus (Tac)-based treatment in juvenile autoimmune hepatitis (AIH). Twenty patients (13 girls; age, 8-17 years; median, 13.25 years) with AIH were treated with two daily oral doses of Tac. Six of them had advanced liver disease and/or cirrhosis.. Drug concentrations in blood were measured regularly, and the target trough levels were 2.5-5 ng/mL. The patients were followed up for 1 year. Their clinical, biochemical, immunological and histological status was obtained at baseline and after 1 year.. In three cases, Tac alone led to complete remission. In 14 cases, additional low doses of prednisolone or azathioprine were used for a short time to achieve remission. In two cases, the treatment was discontinued: in one because of therapeutic failure, in another because of a suspected but unverified adverse event. Ten patients reported headache and/or recurrent abdominal pain. Two patients developed inflammatory bowel disease. Renal function remained intact.. Tac is a promising alternative first line of treatment for AIH. Although monotherapy with Tac is usually not sufficient to achieve complete remission, the prednisolone and azathioprine doses can be drastically reduced, and most of their side effects avoided.

Topics: Adolescent; Child; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Intention to Treat Analysis; Male; Prospective Studies; Tacrolimus

De novo autoimmune hepatitis (AIH) describes the development of hepatitis with autoimmune features in liver transplant (LT) patients without prior diagnosis of AIH. We aimed to evaluate the incidence and risk factors for de novo AIH.. A cohort of 576 patients with LT for aetiologies other than AIH was evaluated.. De novo AIH was diagnosed in 17 patients (3%) with an overall incidence of 4.0 cases per 1000 patient-years. By univariate Cox analysis, patients who received cyclosporine A had lower risk (HR 0.24, 95% CI 0.07-0.80, P = 0.02), whereas patients who had female donors (HR 3.03, 95% CI 1.11-8.25, P = 0.03), donors ≥40-years (HR 6.95, 95% CI 1.93-25.03, P = 0.003), and those who received tacrolimus (HR 4.39, 95% CI 1.47-13.13, P = 0.008) and mycophenolate mofetil (HR 6.37, 95% CI 1.62-25.13, P = 0.008) had higher risk. Survival was similar in patients with de novo AIH compared with the LT population (mean survival time, 17 ± 1.5 vs. 16 ± 0.5 years, Log-rank test; P = 0.4).. The incidence of de novo AIH is low and does not impact on long-term survival. Recipients of female or older donor grafts, or recipients using tacrolimus, or mycophenolate mofetil as part of their immunosuppressive regimen have a higher risk of de novo AIH, whereas LT recipients maintained on cyclosporine A have a lower risk.

Topics: Adolescent; Adult; Age Factors; Aged; Canada; Child; Child, Preschool; Cohort Studies; Cyclosporine; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Risk Factors; Sex Factors; Survival Rate; Tacrolimus; Tissue Donors; Young Adult

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12-hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus-related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3-month patient survival (88.8% versus 95.4%) and 5-year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64-patient group with CNS complications and the asymptomatic group of 331 patients.

Topics: Adult; Carcinoid Tumor; Carcinoma, Hepatocellular; Central Nervous System Diseases; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus

Liver transplantation is the only curative treatment in patients with end-stage liver disease. Neurological complications (NC) are increasingly reported to occur in patients after cadaveric liver transplantation. This retrospective cohort study aims to evaluate the incidence and causes of NC in living donor liver transplant (LDLT) patients in our transplant center. Between August 1998 and December 2005, 121 adult LDLT patients were recruited into our study. 17% of patients experienced NC, and it occurred significantly more frequently in patients with alcoholic cirrhosis (42%) and autoimmune hepatitis (43%) as compared with patients with hepatitis B or C (9/10%, P = 0.013). The most common NC was encephalopathy (47.6%) followed by seizures (9.5%). The choice of immunosuppression by calcineurin inhibitor (Tacrolimus or Cyclosporin A) showed no significant difference in the incidence of NC (19 vs. 17%). The occurrence of NC did not influence the clinical outcome, since mortality rate, median ICU stay and length of hospital stay were similar between the two groups. Most patients who survived showed a nearly complete recovery of their NC. NCs occur in approximately 1 in 6 patients after LDLT and seem to be predominantly transient in nature, without major impact on clinical outcome.

Topics: Brain Diseases; Cohort Studies; Cyclosporine; Female; Hepatitis B; Hepatitis C; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Retrospective Studies; Seizures; Tacrolimus; Treatment Outcome

Graft rejection and disease recurrence are well-recognized complications of liver transplantation (LT) for autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC). We describe indications and outcome of LT for childhood AIH and AISC.. Twenty-year retrospective review of a cohort of children (n = 101) with AIH, AISC, or AIH/sclerosing cholangitis overlap syndrome from a single center.. AIH type 1 (AIH1, n = 67) was more common than AIH type 2 (AIH2, n = 18), AISC (n = 8), or overlap syndrome (n = 8). Overall, 18 patients (18%) required LT, the indications being failure of medical therapy (n = 16) and fulminant liver failure (n = 2). Patients with AIH who required LT had a more prolonged prothrombin time at presentation compared with those who did not undergo transplantation (P = 0.01). Patients with AIH1 who received LT had a lower aspartate transaminase (P = 0.009) and alanine transaminase (P = 0.02) levels at initial diagnosis compared with those with AIH1 who did not undergo transplantation. Post-LT, 11 patients (61%) had 18 episodes of rejection, most were steroid sensitive. Disease recurrence was observed in 7 patients (39%, median duration post-LT 33 months), more common in AIH2 (80% recurrence rate), and those taking cyclosporine (71%, 5/7 patients) compared with those taking tacrolimus (18%, 2/11 patients; P < 0.05) and in 3 of 3 children who did not have maintenance steroids post-LT. The overall 5- and 7-year post-LT survival rate was 94% and 88%, respectively.. LT is a good therapeutic option for progressive AIH and AISC, although recurrence of the primary autoimmune process limits the outcome.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Child; Cholangitis, Sclerosing; Cyclosporine; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Liver Failure, Acute; Liver Transplantation; Male; Prothrombin Time; Recurrence; Retrospective Studies; Steroids; Survival Analysis; Survival Rate; Syndrome; Tacrolimus; Treatment Outcome

A perfect or nearly perfect human leukocyte antigen (HLA) match has been associated with better immediate and long-term survival of diseased donor kidney transplants. However, the effect of HLA matching for hepatic allografts remains poorly defined. Using data from the National Institutes of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database, we investigated the association between HLA mismatches and hepatic allograft survival, disease recurrence, and immunosuppression interactions. A, B, and DR loci were used to calculate total mismatch scores of 0 (no mismatches in any loci) to 6 (mismatches in all loci). Seven hundred ninety-nine adults (male, 55%; female, 45%) underwent 883 liver transplants. The 10-year graft survival according to total mismatch score was as follows: 0-2, 60%; 3-4, 54%; and 5-6, 57%. There was a negative effect of mismatching at the A locus on patient survival, with shorter survival for patients with 1 or 2 mismatches compared with 0 mismatches [P = 0.05, hazard ratio (HR) = 1.6]. Patients on tacrolimus with 1 or 2 mismatches at B or DR loci appeared to have increased rates of patient and graft survival compared to patients with 0 mismatches, with the appearance of a protective effect of tacrolimus (HR = 0.67). The effect of HLA mismatching was more pronounced on certain disease recurrences. DR-locus mismatch increased recurrence of autoimmune hepatitis (P = 0.01, HR = 4.2) and primary biliary cirrhosis (P = 0.04, HR = 2). Mismatch in the A locus was associated with more recurrence of hepatitis C virus (P = 0.01, HR = 1.6) and primary sclerosing cholangitis (P = 0.03, HR = 2.9).. Mismatching at the A locus decreases patient survival in liver transplant recipients, and mismatching at the DR and A loci affects recurrence of autoimmune liver diseases and hepatitis C, respectively.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cyclosporine; Databases as Topic; Female; Follow-Up Studies; Graft Survival; Hepatitis C; Hepatitis, Autoimmune; HLA Antigens; HLA-A Antigens; HLA-DR Antigens; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; National Institute of Diabetes and Digestive and Kidney Diseases (U.S.); Tacrolimus; Treatment Outcome; United States

Topics: Adolescent; Animals; Azathioprine; Child; Cyclosporine; Disease Models, Animal; Genetic Predisposition to Disease; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mice; Tacrolimus

To determine the efficacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH).. Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records.. Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P=0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P=0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P=0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P=0.016), while the degree of fibrosis tended to decrease (P=0.049).. The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of fibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis; Male; Middle Aged; Retrospective Studies; Tacrolimus

Topics: Adult; Drug Therapy, Combination; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Prednisone; Tacrolimus; Vaccination

Topics: Anti-Inflammatory Agents; Budesonide; Cyclophosphamide; Cyclosporine; Hepatitis, Autoimmune; Humans; Immunologic Factors; Immunosuppressive Agents; Interleukins; Methotrexate; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome

Patients with post-transplant immune-mediated hepatitis (IMH) and recurrent autoimmune hepatitis (RAIH) have a poor outcome and a higher need for retransplantation. Azathioprine (AZA) is used as adjunctive immunosuppression after transplantation; optimizing its dose may be a key point in preserving graft function. Complications of high AZA dosing make dose escalation potentially problematic. Our aim was to correlate AZA metabolite levels with therapeutic effects, toxicity, and adherence to medication in children with IMH and RAIH. Charts of 14 patients were retrospectively reviewed. The post-transplant diagnosis was based on liver biopsy and autoimmune markers. AZA was prescribed after establishing the post-transplant diagnosis. AZA was started at 1.1 (1.0-1.8) mg/kg/day. Routine biochemical studies, tacrolimus levels, 6-thioguanine (6-TG) and 6-methylmercaptopurine levels were assessed every 8 wk. AZA dose was routinely adjusted to achieve 6-TG levels between 235 and 450 pmol per 8 x 10(8) RBC. A total of 92 samples from 14 patients were reviewed. Four patients were excluded because of non-adherence. AZA dose was increased by 245% resulting in eight of 10 patients in the target range; no hepatic or bone marrow toxicity was observed. ALT levels and steroid requirements were significantly reduced (p < 0.05). The AZA dose required to achieve target 6-TG levels was significantly greater in children <10 yr. AZA metabolite testing in children post-liver transplant is useful in assessing adherence to medication and it is potentially helpful in optimizing medication dosing. In younger children the AZA dose requirements were two to four times higher than previously reported standard doses.

Topics: Adolescent; Azathioprine; Child; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Monitoring, Physiologic; Recurrence; Retrospective Studies; Tacrolimus; Thioguanine

Topics: Adrenal Cortex Hormones; Cholangitis, Sclerosing; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

A 34-year-old woman underwent orthotopic liver transplantation (OLT) for decompensated type 1 autoimmune hepatitis (AIH). She was administered standard triple-drug immunosuppressive therapy (cyclosporine, steroids, and azathioprine). Ten years after OLT, she developed a recurrence of AIH, with emergence of serological markers of autoimmunity (high anti--smooth muscle antibody [ASMA] titer, high serum gamma globulin level), abnormal liver function test results, and characteristic histological features on liver biopsy. Despite intensified steroid therapy, her clinical and liver function deteriorated. The onset of cutaneous alternariosis led to a steroid dose reduction and cyclosporine replacement by tacrolimus. Clear-cut amelioration was observed, with an improvement in liver function test results and reduction in ASMA titer. One year after the recurrence of AIH, the patient has normal liver function and physical findings. Tacrolimus therefore may be effective in patients with severe recurrent autoimmune liver disease. Further studies are needed to assess tacrolimus therapy in patients who fail to respond to standard immunosuppressive therapy.

Topics: Adult; Alanine Transaminase; Autoantibodies; Female; gamma-Globulins; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Transplantation; Recurrence; Tacrolimus

Cases of so-called autoimmune hepatitis (AH) have been reported after liver transplantation. Our aim was to evaluate the incidence in a series of 471 pediatric liver transplant recipients.. Between 1984 and 1998, 471 children had orthotopic liver transplantation (OLT). Children are followed up on a regular basis, with full clinical, biochemical, and histologic evaluation at 6 months, 1, 2, 5, 7, and 10 years after OLT. Children with unexplained abnormal liver tests were screened for autoimmune markers (total gamma-globulins, smooth muscle antibodies [SMA], liver kidney microsome antibodies [LKM], antinuclear factor [ANA]). From January of 1998 until December of 1998, autoimmune markers were prospectively searched in all children admitted for regular posttransplant follow-up (n = 118).. Eleven of 471 children (2.35%) were found with autoimmune hepatitis, 9 retrospectively and 2 prospectively. None had previous autoimmune liver disease. Patients had a history of steroid-dependent hepatitis. Histology showed variable degree of portal and lobular inflammation, piecemeal necrosis, and bridging collapse. Mean (+/-SDS) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities at diagnosis were 173+/-145 and 196+/-157 IU/L, respectively (nl<32). Median gamma-globulin levels reached 1365 mg/dl versus 931 mg/dl in controls (P<0.05). Nine had ANA (titer 1/80 up to 1/10,000), 1 SMA (1/320), and 2 LKM1 antibodies (1/1280). Patients did not respond to increasing charge of cyclosporine (n=10) or tacrolimus (n=1). Eleven received steroids (prednisolone: 2 mg/kg per day, then tapered) and azathioprine (1.5 to 2.5 mg/kg per day). All patients normalized within 3 months (mean AST/ALT levels of 26+/-8 and 30+/-9 IU/L). Three had mild to moderate relapse with increase of ALT thereafter. Gamma-globulins decreased to 1190 mg/dl (ns). Amongst the 116 remaining prospectively evaluated patients, 85 had normal evaluation, despite low titers of autoantibodies in 15 (SMA< or =1/40, ANA 1/80). Thirty-one patients had graft dysfunction, related to well-explained posttransplant causes, among which 7 had similar low levels of autoantibodies.. A total of 2.35% of our transplant children present evidence of immune hepatitis after transplantation. Patients do not respond to increasing cyclosporine or tacrolimus levels and require steroid and azathioprine. In view of this specific treatment, systematic screening for "autoimmune" markers is advised in children with liver transplant.

Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Azathioprine; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Male; Postoperative Complications; Prednisone; Retrospective Studies; Tacrolimus

The aim of the study was to investigate the effect of the immunosuppressant FK 506 (tacrolimus hydrate) on acute liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS). Acute liver injury was induced in male Wistar rats by injecting the animals with P. acnes (10 mg/rat), and administering LPS (10 microg/rat) seven days later. One group was given FK 506 (1 mg/kg) 24 and 2 hr before administration of LPS, and the other group was given the same dose of saline. The 24-hr survival rate, serum alanine aminotransferase (ALT) concentration, and tumor necrosis factor (TNF) -alpha mRNA and protein concentrations in the liver and spleen were then compared. Hepatic macrophages were also isolated from rats seven days after P. acnes injection, LPS, and FK 506 or saline were added to the culture supernatant, and TNF-alpha production was studied. The 24-hr survival rate was 100% in the FK 506-treated group, in contrast with 16.6% in the saline group. Four hours after LPS injection, the serum ALT concentration was 755 +/- 401 in the saline group versus 119 +/- 42 units/ml (P < 0.01) in the FK 506-treated group. The serum TNF-alpha concentration was lower in the FK 506-treated group (1,419 +/- 957 pg/ml) than in the saline group (9205 +/- 2215) (P < 0.01). The mRNA and protein concentrations in the liver and spleen in the two groups did not differ significantly 1 hr after LPS injection but were significantly lower in the FK 506-treated group after 4 hr. FK 506 did not directly inhibit TNF-alpha production by isolated cultured hepatic macrophages. FK 506 is unable to inhibit initial TNF-alpha production by hepatic macrophages (or probably that by splenic macrophages either) stimulated by injection of LPS in P. acnes + LPS-induced acute liver injury. However, the immunosuppressant does limit hepatic damage by inhibiting subsequent aggravation of inflammation by the cytokine network.

Topics: Alanine Transaminase; Animals; Hepatitis, Autoimmune; Immunosuppressive Agents; Lipopolysaccharides; Liver; Liver Failure, Acute; Macrophages; Male; Propionibacterium acnes; Rats; Rats, Wistar; Tacrolimus; Tumor Necrosis Factor-alpha

Autoimmune liver diseases (AILD) may progress to liver failure, requiring liver transplantation as definitive therapy, and these immune-mediated disorders may predispose the patient to more frequent graft rejection. The objective of this study was to determine the effect of preexisting AILD on the incidence of allograft rejection after liver transplantation. Sixty-three patients who underwent liver transplantation between March 1988 and December 1994 for AILDs that included autoimmune hepatitis (AIH; n = 33) and primary biliary cirrhosis (PBC; n = 30) were retrospectively compared with 47 patients who underwent liver transplantation for alcoholic cirrhosis during the same time period. There was a lower incidence of acute allograft rejection in patients with AILD who received tacrolimus-based compared with cyclosporine-based immunosuppression (50% v 85.5%; P = .02). However, patients with AILDs overall had a higher incidence of acute rejection than patients with alcoholic cirrhosis (81% v 46.8%; P < .001), regardless of the type of immunosuppression. In addition, steroid-resistant rejection occurred more frequently in patients with AILDs than in patients with alcoholic cirrhosis (38.1% v 12.8%; P = .003). There was also a trend toward a higher incidence of chronic rejection in patients with AILDs compared with patients with alcoholic cirrhosis (11.1% v 2.1%), but this difference did not reach statistical significance. Patient and graft survivals at 1 and 3 years were similar between patients with AILDs and alcoholic liver disease. Compared with alcoholic cirrhosis, preexisting AILDs are associated with a higher incidence of acute allograft rejection and a trend toward more frequent chronic rejection.

Topics: Adult; Autoimmune Diseases; Case-Control Studies; Chi-Square Distribution; Cyclosporine; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prednisone; Retrospective Studies; Statistics, Nonparametric; Tacrolimus; Transplantation, Homologous

Liver transplantation is recognized as the appropriate treatment for end-stage liver disease due to chronic active autoimmune hepatitis. While it was initially thought that the disease did not recur after transplant, it is now generally accepted that adult patients may develop recurrent disease, with studies reporting a recurrence rate of < or = 25%. We have noted a higher incidence of recurrent autoimmune hepatitis in our pediatric patients undergoing liver transplant, with a high incidence of associated morbidity.. We reviewed the records of six children followed up for autoimmune hepatitis who underwent orthotopic liver transplant for complications of end-stage liver disease.. Of the six, five developed recurrent autoimmune hepatitis at a mean time of 11.4 months after transplant. The disease was aggressive, leading to cirrhosis and retransplant in three patients, within 1 year of recurrence. A second recurrence of disease occurred in all three retransplanted patients. One patient has received a third liver transplant, one has died, and one patient is asymptomatic on medical therapy. Autoimmune hepatitis recurred in all four patients receiving tacrolimus.. We conclude that liver transplant for autoimmune hepatitis is likely to be palliative for most pediatric patients. Potent immunosuppressives such as tacrolimus do not protect against the development of recurrent autoimmune hepatitis.

Topics: Adolescent; Biomarkers; Child; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Liver Failure; Liver Transplantation; Male; Recurrence; Retrospective Studies; Tacrolimus