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Alimentary Pharmacology & Therapeutics Feb 2017Autoimmune liver diseases (AILD) constitute the third most common indication for liver transplantation (LT) worldwide. Outcomes post LT are generally good but recurrent... (Review)
Review
BACKGROUND
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.
AIMS
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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
PubMed: 27957759
DOI: 10.1111/apt.13894 -
Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?Frontiers in Immunology 2023Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by cholestasis, biliary injuries, liver fibrosis, and chronic non-suppurative... (Review)
Review
Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by cholestasis, biliary injuries, liver fibrosis, and chronic non-suppurative cholangitis. The pathogenesis of PBC is multifactorial and involves immune dysregulation, abnormal bile metabolism, and progressive fibrosis, ultimately leading to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are currently used as first- and second-line treatments, respectively. However, many patients do not respond adequately to UDCA, and the long-term effects of these drugs are limited. Recent research has advanced our understanding the mechanisms of pathogenesis in PBC and greatly facilitated development of novel drugs to target mechanistic checkpoints. Animal studies and clinical trials of pipeline drugs have yielded promising results in slowing disease progression. Targeting immune mediated pathogenesis and anti-inflammatory therapies are focused on the early stage, while anti-cholestatic and anti-fibrotic therapies are emphasized in the late stage of disease, which is characterized by fibrosis and cirrhosis development. Nonetheless, it is worth noting that currently, there exists a dearth of therapeutic options that can effectively impede the progression of the disease to its terminal stages. Hence, there is an urgent need for further research aimed at investigating the underlying pathophysiology mechanisms with potential therapeutic effects. This review highlights our current knowledge of the underlying immunological and cellular mechanisms of pathogenesis in PBC. Further, we also address current mechanism-based target therapies for PBC and potential therapeutic strategies to improve the efficacy of existing treatments.
Topics: Animals; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid; Cholangitis; Cholestasis; Fibrosis
PubMed: 37325634
DOI: 10.3389/fimmu.2023.1184252 -
Current Opinion in Gastroenterology Mar 2021Primary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC... (Review)
Review
PURPOSE OF REVIEW
Primary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.
RECENT FINDINGS
PBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.
SUMMARY
PBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.
Topics: Apoptosis; Bile Ducts, Intrahepatic; Chloride-Bicarbonate Antiporters; Epithelial Cells; Female; Humans; Liver Cirrhosis, Biliary; Male
PubMed: 33332913
DOI: 10.1097/MOG.0000000000000703 -
International Journal of Molecular... Mar 2015Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and... (Review)
Review
Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated injury of small intrahepatic bile ducts. Unique apoptotic feature of biliary epithelial cells (BECs) may contribute to apotope presentation to the immune system, causing unique tissue damage in PBC. Perpetuation of inflammation may result in senescence of BECs, contributing to irreversible loss of bile duct. In addition to the classic liver manifestations, focal inflammation and tissue damage are also seen in salivary glands and urinary tract in a significant proportion of PBC patients. These findings provide potent support to the idea that molecular mimicry may be involved in the breakdown of autoimmune tolerance and mucosal immunity may lead to a systematic epithelitis in PBC patients. Thus, PBC is considered a generalized epithelitis in clinical practice.
Topics: Apoptosis; Bile Ducts; Humans; Liver Cirrhosis, Biliary; Salivary Glands
PubMed: 25803105
DOI: 10.3390/ijms16036432 -
Seminars in Immunopathology Jul 2022Genome-wide association studies (GWAS) for autoimmune hepatitis (AIH) and GWAS/genome-wide meta-analyses (GWMA) for primary biliary cholangitis (PBC) and primary... (Review)
Review
Genome-wide association studies (GWAS) for autoimmune hepatitis (AIH) and GWAS/genome-wide meta-analyses (GWMA) for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) have been successful over the past decade, identifying about 100 susceptibility loci in the human genome, with strong associations with the HLA locus and many susceptibility variants outside the HLA locus with relatively low risk. However, identifying causative variants and genes and determining their effects on liver cells and their immunological microenvironment is far from trivial. Polygenic risk scores (PRSs) based on current genome-wide data have limited potential to predict individual disease risk. Interestingly, results of mediated expression score regression analysis provide evidence that a substantial portion of gene expression at susceptibility loci is mediated by genetic risk variants, in contrast to many other complex diseases. Genome- and transcriptome-wide comparisons between AIH, PBC, and PSC could help to better delineate the shared inherited component of autoimmune liver diseases (AILDs), and statistical fine-mapping, chromosome X-wide association testing, and genome-wide in silico drug screening approaches recently applied to GWMA data from PBC could potentially be successfully applied to AIH and PSC. Initial successes through single-cell RNA sequencing (scRNA-seq) experiments in PBC and PSC now raise high hopes for understanding the impact of genetic risk variants in the context of liver-resident immune cells and liver cell subpopulations, and for bridging the gap between genetics and disease.
Topics: Autoimmune Diseases; Cholangitis, Sclerosing; Genome-Wide Association Study; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Risk Factors
PubMed: 35650446
DOI: 10.1007/s00281-022-00950-8 -
Revista de Gastroenterologia de Mexico... 2019
Topics: Autoimmune Diseases; Cohort Studies; Humans; Liver Cirrhosis, Biliary; Mexico
PubMed: 30541671
DOI: 10.1016/j.rgmx.2018.07.005 -
Biomedicine & Pharmacotherapy =... Aug 2021Primary biliary cholangitis (PBC) is an autoimmune disease characterized by the destruction of intrahepatic small bile ducts and the presence of antimitochondrial... (Review)
Review
Primary biliary cholangitis (PBC) is an autoimmune disease characterized by the destruction of intrahepatic small bile ducts and the presence of antimitochondrial antibody (AMA), eventually progresses to liver fibrosis and cirrhosis. Genetic predisposition and environmental factors are involved in the occurrence of PBC, and the epitopes exposure and the imbalance of autoimmune tolerance are the last straw. The apoptosis of biliary epithelial cell (BEC) leads to the release of autoantigen epitopes, which activate the immune system, and the disorder of innate and adaptive immunity eventually leads to the start of disease. Animal models have unique advantages in investigating the pathogenesis and drug exploitation of PBC. Multiple models have been reported, and spontaneous model and induced model have been widely used in relevant research of PBC in recent years. Currently, the only drugs licensed for PBC are ursodesoxycholic acid (UDCA) and obeticholic acid (OCA). In the last few years, as the learned more about the pathogenesis of PBC, more and more targets have been discovered, and multiple targeted drugs are being in developed. In this review, the pathogenesis, murine models and treatment strategies of PBC were summarized, and the current research status was discussed to provide insights for the further study of PBC.
Topics: Animals; Disease Models, Animal; Humans; Liver Cirrhosis, Biliary
PubMed: 34044277
DOI: 10.1016/j.biopha.2021.111754 -
Gut and Liver Jul 2023
Topics: Humans; Liver Cirrhosis, Biliary; Cholangitis
PubMed: 37449431
DOI: 10.5009/gnl230239 -
Canadian Journal of Gastroenterology &... 2022Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by progressive cholangiocyte and bile duct destruction leading to... (Review)
Review
Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by progressive cholangiocyte and bile duct destruction leading to fibrosis and finally to liver cirrhosis. The presence of disease-specific serological antimitochondrial antibody (AMA) together with elevated alkaline phosphatase (ALP) as a biomarker of cholestasis is sufficient for diagnosis. Ursodeoxycholic acid (UDCA) is the first treatment option for PBC. Up to 40% of patients have an incomplete response to therapy, and over time disease progresses to liver cirrhosis. Several risk scores are proposed for better evaluation of patients before and during treatment to stratify patients at increased risk of disease progression. GLOBE score and UK PBC risk score are used for the evaluation of UDCA treatment and Mayo risk score for transplant-free survival. Liver transplantation (LT) is the only treatment option for end-stage liver disease. More than 10 years after LT, 40% of patients experience recurrence of the disease. A liver biopsy is required to establish rPBC (recurrent primary biliary cholangitis). The only treatment option for rPBC is UDCA, and data show biochemical and clinical improvement, plus potential beneficial effects for use after transplantation for the prevention of rPBC development. Additional studies are required to assess the full impact of rPBC on graft and recipient survival and for treatment options for rPBC.
Topics: Autoimmune Diseases; Cholagogues and Choleretics; Cholestasis; End Stage Liver Disease; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Ursodeoxycholic Acid
PubMed: 35910038
DOI: 10.1155/2022/7831165 -
Expert Review of Clinical Pharmacology 2016Primary biliary cirrhosis (PBC) is characterized by progressive nonsuppurative destruction of small bile ducts, resulting in intrahepatic cholestasis, fibrosis and... (Review)
Review
Primary biliary cirrhosis (PBC) is characterized by progressive nonsuppurative destruction of small bile ducts, resulting in intrahepatic cholestasis, fibrosis and ultimately end-stage liver disease. Timely intervention with ursodeoxycholic acid is associated with excellent survival, although approximately one-third of all patients fail to achieve biochemical response, signifying a critical need for additional therapeutic strategies. Obeticholic acid (OCA) is a potent ligand of the nuclear hormone receptor farnesoid X receptor (FXR). Activation of FXR inhibits bile acid synthesis and protects against toxic accumulation in models of cholestasis and facilitates hepatic regeneration in preclinical studies. Data from recent Phase II and III controlled trials suggest a therapeutic impact of OCA in PBC biochemical nonresponders, as evidenced by change in proven laboratory surrogates of long-term outcome. Dose-dependent pruritus is a common adverse effect, but may be overcome through dose-titration. Longer term studies are needed with focus on safety and long-term clinical efficacy.
Topics: Animals; Chenodeoxycholic Acid; Dose-Response Relationship, Drug; End Stage Liver Disease; Humans; Liver Cirrhosis, Biliary; Pruritus; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid
PubMed: 26549695
DOI: 10.1586/17512433.2015.1092381