mycophenolic-acid and Liver-Cirrhosis--Biliary

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

Primary biliary cholangitis (PBC, primary biliary cirrhosis) is an autoimmune cholestatic liver disease characterized by chronic nonsuppurative destructive cholangitis and the presence of serum antimitochondrial antibodies. Ursodeoxycholic acid is the only drug approved by the US Food and Drug Administration to treat PBC. However, one-third of patients show incomplete responses to ursodeoxycholic acid and a poor prognosis. A number of old and new medications have been used in these patients, such as fibrates, glucocorticoids, immunosuppressants, obeticholic acid, mesenchymal stem cells, biological agents (anti-interleukin-12, cytotoxic T-lymphocyte antigen 4 immunoglobulin, anti-CD20), and antifibrotic drugs. This article reviews the therapeutic advances of these old and new medications in patients with PBC.

Topics: Abatacept; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cyclosporine; Enzyme Inhibitors; Fibric Acids; Glucocorticoids; Humans; Immunosuppressive Agents; Indoles; Liver Cirrhosis, Biliary; Mesenchymal Stem Cell Transplantation; Methotrexate; Mycophenolic Acid; Pyridones; Rituximab; Tacrolimus; Ursodeoxycholic Acid; Ustekinumab

Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis.

Topics: Animals; Autoantibodies; Autoantigens; Biomarkers; Budesonide; Cholangitis, Sclerosing; Cyclosporine; Glucocorticoids; Hepatitis, Autoimmune; Humans; Hypergammaglobulinemia; Immunity, Cellular; Immunoglobulin G; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Mice; Mycophenolic Acid; Rats; Transaminases

Autoimmune Hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and overlap syndromes of these three disease entities are regarded as autoimmune liver diseases. These conditions are important differential diagnoses of elevated liver function tests as about 10 % of liver transplantations in Europe and North America are for these indications. The diagnosis is often difficult but can be facilitated by sequential measurement of relevant autoantibodies, exclusion of other liver disease, ultrasound, ERCP and liver histology. In AIH immunosuppressive therapy has been shown to prevent or stop the development of cirrhosis and improve the prognosis of the patients decisively. In other autoimmune liver diseases this evidence is missing making individual therapeutic decisions necessary. Ursodesoxycholic acid (UDCA) seems to slow disease progression in particular in early stages of PBC.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Azathioprine; Biopsy; Child; Cholagogues and Choleretics; Cholangiopancreatography, Endoscopic Retrograde; Cholangitis, Sclerosing; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; Hepatitis, Autoimmune; Humans; Immunoassay; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Ultrasonography; Ursodeoxycholic Acid

Topics: Clinical Trials as Topic; Drug Administration Schedule; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Mycophenolic Acid; Pilot Projects

Despite evidence for therapeutic efficacy with ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC), only 30-50% of patients achieve complete biochemical remission within 1 year of therapy. Mycophenolate mofetil (MMF) is an immunosuppressive medication that inhibits T and B lymphocyte proliferation. The aim of this investigation was to determine the safety and estimated efficacy of MMF in patients with PBC.. Twenty-five patients with incomplete responses to UDCA (defined as persistent elevation of serum alkaline phosphatase > or =2 times the upper limit of normal) received MMF 1 g daily to a maximum of 3 g daily with UDCA (13-15 mg/kg per day) for 1 year. Liver biochemistries were determined at 3-month intervals with Mayo Risk Score calculated at baseline and end of therapy.. Nineteen (76%) patients completed 1 year of therapy. Despite improvements in serum alkaline phosphatase (920 +/- 308 vs. 709 +/- 242 IU/L, P = 0.001) and AST (65 +/- 31 vs. 51 +/- 19 IU/L, P = 0.007) levels, these findings were clinically insignificant. Exploratory analysis revealed a strong correlation between advanced PBC defined by higher Mayo Risk Score and reduction in serum alkaline phosphatase levels (r = -0.74, P = 0.006). Six patients (24%) did not complete therapy; adverse drug events were responsible for study withdrawal in 3 individuals. Adverse reactions that resolved spontaneously or by dose reduction occurred in 13 patients.. MMF is not associated with important clinical benefits in PBC based on the results of this pilot investigation.

Topics: Administration, Oral; Adolescent; Adult; Aged; Alkaline Phosphatase; Autoantibodies; Cholagogues and Choleretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Male; Middle Aged; Mitochondria, Liver; Mycophenolic Acid; Pilot Projects; Risk Factors; Treatment Outcome; Ursodeoxycholic Acid

The Swiss Autoimmune Hepatitis Cohort Study is a nationwide registry, initiated in 2017, that collects retrospective and prospective clinical data and biological samples from patients of all ages with autoimmune hepatitis treated at Swiss hepatology centres. Here, we report the analysis of the first 5 years of registry data.. A total of 291 patients with autoimmune hepatitis have been enrolled, 30 of whom were diagnosed before 18 years of age and composed the paediatric cohort. Paediatric cohort: median age at diagnosis 12.5 years (range 1-17, interquartile range (IQR) 8-15), 16 (53%) girls, 6 (32%) with type 2 autoimmune hepatitis, 8 (27%) with autoimmune sclerosing cholangitis, 1 with primary biliary cholangitis variant syndrome, 4 (15%) with inflammatory bowel disease and 10 (41%) with advanced liver fibrosis at diagnosis. Adult cohort: median age at diagnosis 54 years (range 42-64, IQR 18-81), 185 (71%) women, 51 (20%) with primary biliary cholangitis variant syndrome, 22 (8%) with primary sclerosing cholangitis variant syndrome, 9 (4%) with inflammatory bowel disease and 66 (32%) with advanced liver fibrosis at diagnosis. The median follow-up time for the entire cohort was 5.2 years (IQR 3-9.3 years). Treatment in children: 29 (97%) children were initially treated with corticosteroids, 28 of whom received combination treatment with azathioprine. Budesonide was used in four children, all in combination with azathioprine. Mycophenolate mofetil was used in five children, all of whom had previously received corticosteroids and thiopurine. Treatment in adults (data available for 228 patients): 219 (96%) were treated with corticosteroids, mostly in combination with azathioprine. Predniso(lo)ne was the corticosteroid used in three-quarters of patients; the other patients received budesonide. A total of 78 (33%) patients received mycophenolate mofetil, 62 of whom had previously been treated with azathioprine. Complete biochemical response was achieved in 13 of 19 (68%) children and 137 of 182 (75%) adults with available follow-up data. All children were alive at the last follow-up, and none had undergone liver transplantation. Five (2%) adults underwent liver transplantation, two of whom had a fulminant presentation. Four (2%) adults with autoimmune hepatitis died (two from liver-associated causes).. Patients with autoimmune hepatitis in Switzerland had clinical features similar to those in other cohorts. The proportion of patients diagnosed with primary biliary cholangitis variant syndrome was higher than expected. Autoimmune hepatitis was managed according to guidelines, except for the use of budesonide in a small proportion of paediatric patients. The outcomes were excellent, but the findings must be confirmed over a longer follow-up period.

Topics: Adolescent; Adult; Azathioprine; Budesonide; Child; Child, Preschool; Cohort Studies; Female; Hepatitis, Autoimmune; Humans; Infant; Inflammatory Bowel Diseases; Liver Cirrhosis; Liver Cirrhosis, Biliary; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Retrospective Studies; Switzerland

A case of primary cutaneous post liver transplant lymphoproliferative disorder (PTLD) mimicking squamous cell carcinoma-in-situ is presented.. Lesions mimicking SCC-in-situ were confirmed to be PTLD on histopathology and immunohistochemistry. Immunosuppression was gradually reduced and the lesions were successfully treated with 50 gray (Gy) in 25 fractions of radiotherapy.. There was no recurrence of lesions at 3 months follow-up.. Radiotherapy is an effective form of cutaneous directed treatment for localized PTLD.

Topics: Aged; Antibiotics, Antineoplastic; B-Lymphocytes; Carcinoma, Squamous Cell; Follow-Up Studies; Gamma Rays; Humans; Immunohistochemistry; Liver Cirrhosis, Biliary; Liver Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Topics: Adult; Antibodies, Antinuclear; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Mycophenolic Acid; Nuclear Pore Complex Proteins

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cholagogues and Choleretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Liver Cirrhosis, Biliary; Middle Aged; Mycophenolic Acid; Ursodeoxycholic Acid

The development of de novo autoimmune liver disease after liver transplantation (LT) has been described in both children and adults. Reported herein is a case that is best characterized as post-LT de novo hepatitis with features of autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap. A 56-year-old man underwent LT for decompensated liver disease secondary to non-alcoholic steatohepatitis. His liver function tests became markedly abnormal 8 months after LT. Sequential liver transplant biopsy findings were confusing and shared findings seen with both AIH and PBC. Although standard autoimmune serological tests were negative, a dramatic biochemical response was observed to a regimen consisting of prednisone, mycophenolate mofetil, and ursodeoxycholic acid added to maintainance tacrolimus. The donor was histocompatibility leukocyte antigen, DR4, positive, a haplotype associated with the development of AIH-PBC overlap syndrome. In conclusion the authors believe that this may be a case of post-LT de novo overlap syndrome of AIH-PBC, a novel 'autoimmune-type' response.

Topics: Cholagogues and Choleretics; Drug Therapy, Combination; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Treatment Outcome; Ursodeoxycholic Acid

Topics: Adult; Female; Humans; Immunosuppressive Agents; Jaundice; Liver Cirrhosis, Biliary; Mycophenolic Acid

Topics: Cholagogues and Choleretics; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Mycophenolic Acid; Ursodeoxycholic Acid

Topics: Cholangitis, Sclerosing; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Mycophenolic Acid

Evidence of autoimmunity in primary biliary cirrhosis (PBC) provides a rationale for treatment with an immunosuppressant. Such a drug should be sufficiently free from serious toxicities to enable patients with asymptomatic, but progressive, disease to be treated longterm. Mycophenolate mofetil (MMF) mediates immunosuppression by selectively and reversibly inhibiting lymphocyte function, and has a more acceptable safety profile than other immunosuppressants that have been used in the treatment of this disease. Two patients, whose response to long-term treatment with ursodeoxycholic acid (UDCA) had been inadequate, were treated with a combination of MMF 2 g daily and UDCA 1 g daily for 12 months. In both patients this regimen was associated with no clinically significant adverse events, a decrease in elevated serum alkaline phosphatase levels to values close to the upper limit of normal, and an almost complete disappearance of the chronic inflammatory cell infiltrate that had been present in pre-combination treatment liver biopsies. MMF may be an appropriate immunosuppressive drug for use in the long-term treatment of patients with PBC, including asymptomatic patients.

Topics: Alkaline Phosphatase; Cholagogues and Choleretics; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammation; Liver; Liver Cirrhosis, Biliary; Liver Function Tests; Middle Aged; Mycophenolic Acid; Ursodeoxycholic Acid

Topics: Child; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver; Liver Cirrhosis, Biliary; Male; Mycophenolic Acid; Prednisone