obeticholic-acid and Liver-Cirrhosis--Biliary

Obeticholic acid (OCA) is the second-line therapy for primary biliary cholangitis (PBC), as well as an attractive candidate as a treatment for metabolic dysfunction-associated steatohepatitis (MASH). This meta-analysis aims to assess the impact of OCA on lipid profiles and clinical outcomes in patients with PBC and MASH. A comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) from five major databases were conducted. Changes in lipid profiles from baseline were compared between groups receiving placebo and OCA. Efficacy outcomes were evaluated separately for PBC and MASH trials, while safety outcomes included pruritus, gastrointestinal disturbances, and headache. OCA treatment exhibited a significant increase in low-density lipoprotein cholesterol (LDL-C) (standardized mean difference [SMD] = 0.39; 95 % confidence interval [CI] = 0.15 to 0.63) and a decrease in high-density lipoprotein cholesterol (HDL-C) (SMD = -0.80; 95 % CI = -1.13 to -0.47) in both PBC and MASH patients compared to placebo. OCA demonstrated superior efficacy to placebo in treating PBC and MASH, evident in both primary and secondary outcomes. The incidence of pruritus was significantly higher with OCA compared to placebo (risk ratio = 1.78, 95 % CI = 1.42 to 2.25). OCA is more efficacious than a placebo in the treatment of PBC and MASH. However, caution is needed given the association of OCA use with a significant increase in LDL-C levels and a decrease in HDL-C levels among patients with these conditions.

Topics: Cholesterol, LDL; Fatty Liver; Humans; Liver Cirrhosis, Biliary; Pruritus

Up to 40% of patients with primary biliary cholangitis (PBC) have an inadequate response to ursodeoxycholic acid (UDCA). Obeticholic acid (OCA) is considered the addition of treatment, but the response rate based on commonly referenced biochemical response criteria and lipids' impact was unclear. Previous studies reported inconsistency results partially due to small sample size. Therefore, we performed a meta-analysis and aimed to explore OCA treatment's response rate and effect on lipids' profiles in PBC patients.. We performed PubMed, Embase, and Cochrane controlled trials register (updated to JUN 2019) databases and manual bibliographical searches for randomized controlled trials reporting on OCA treatment in PBC patients. Two researchers independently extracted data and assessed the risk of bias of studies. We calculated risk ratio (RR) for the overall complete response rate, and the standardized mean difference (SMD) for the serum lipids changes after OCA treatment, all with 95% confidence intervals (CIs) using fixed-effects models. We registered this meta-analysis with PROSPERO (registration number: CRD42020148550).. This meta-analysis demonstrated that OCA was a promising additional treatment for PBC patients and might reduce serum cholesterol levels. The longer follow-up studies are needed to give more evidence.

Topics: Chenodeoxycholic Acid; Humans; Lipids; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA.. We performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67 ULN) in PBC, and the adverse effects of OCA.. Seven RCTs (n = 2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47-2.59; p < 0.001)]. With the 10 mg OCA dose, the odds of improvement was 1.61 (1.03-2.51; p = 0.03), while with the 25 mg dose, it was 2.23 (1.55-3.18; p < 0.001). However, 25 mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42-3.02); p < 0.001)] compared with 10 mg OCA [0.95 (0.6-1.5); p = 0.84] in NASH patients. In PBC patients, the response to 5 mg OCA was better than with the higher doses [5 mg: 7.66 (3.12-18.81; p < 0.001), 10 mg: 5.18 (2-13.41; p = 0.001), 25 mg: 2.36 (0.94-5.93; p = 0.06), 50 mg: 4.08 (1.05-15.78; p = 0.04)]. The risk of pruritus was lowest with 5 mg OCA.. Lower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10 mg OCA is effective for NASH fibrosis regression, only 5 mg OCA is required for PBC.

Topics: Chenodeoxycholic Acid; Cholestasis; Humans; Liver Cirrhosis, Biliary; Non-alcoholic Fatty Liver Disease; Pharmaceutical Preparations; Ursodeoxycholic Acid

PBC is a chronic progressive autoimmune disorder involving the destruction of intrahepatic small bile ducts, cholestasis, fibrosis, and ultimately cirrhosis if left untreated. It is largely driven by the autoimmune response, but bile acids and the intestinal microbiota are implicated in disease progression as well. The only drugs licensed for PBC are UDCA and OCA. UDCA as a first-line and OCA as a second-line therapy are safe and effective, but the lack of response in a significant portion of patients and inadequate control of symptoms such as fatigue and pruritus remain as concerns. Liver transplantation is an end-stage therapy for many patients refractory to UDCA, which gives excellent survival rates but also moderate to high recurrence rates. The limited options for FDA-approved PBC therapies necessitate the development of alternative approaches. Currently, a wide variety of experimental drugs exist targeting immunological and physiological aspects of PBC to suppress inflammation. Immunological therapies include drugs targeting immune molecules in the B cell and T cell response, and specific cytokines and chemokines implicated in inflammation. Drugs targeting bile acids are also noteworthy as bile acids can perpetuate hepatic inflammation and lead to fibrosis over time. These include FXR agonists, ASBT inhibitors, and PPAR agonists such as bezafibrate and fenofibrate. Nonetheless, many of these drugs can only delay disease progression and fail to enhance patients' quality of life. Nanomedicine shows great potential for treatment of autoimmune diseases, as it provides a new approach that focuses on tolerance induction rather than immunosuppression. Tolerogenic nanoparticles carrying immune-modifying agents can be engineered to safely and effectively target the antigen-specific immune response in autoimmune diseases. These may work well with PBC especially, given the anatomical features and immunological specificity of the disease. Nanobiological therapy is thus an area of highly promising research for future treatment of PBC.

Topics: Animals; Bile Acids and Salts; Biomarkers; Chenodeoxycholic Acid; Combined Modality Therapy; Disease Management; Disease Progression; Disease Susceptibility; Fibrosis; Humans; Immunotherapy; Liver Cirrhosis, Biliary; Liver Transplantation; Molecular Targeted Therapy; Severity of Illness Index; Symptom Assessment; Treatment Outcome; Ursodeoxycholic Acid

Up to 40% of patients with primary biliary cholangitis have an incomplete response to first-line treatment with ursodeoxycholic acid. Obeticholic acid was approved by the US Food and Drug Administration in 2016 as a second-line treatment for patients with primary biliary cholangitis who are unresponsive to ursodeoxycholic acid; however, approximately 50% of patients might need additional treatments to reach therapeutic goals. A considerable need exists for effective treatment options to prevent progression to liver transplantation or death in these patients. Drugs that might modulate immunological abnormalities in primary biliary cholangitis have been studied but their effectiveness varies. Budesonide, ciclosporin, and rituximab have shown potential in modifying the disease process. Bezafibrate, a pan-peroxisome proliferator-activated receptor agonist, has been shown to ameliorate deranged bile acid homoeostasis and attenuate raised concentrations of liver enzymes associated with primary biliary cholangitis. As the mechanisms underlying the pathogenesis and progression of primary biliary cholangitis are further clarified, specific targeted therapies are under development with promising early results. Various therapeutic target bile acid homeostasis, immune dysfunction, and fibrogenetic pathways are being studied. A better understanding of the biochemical and clinical effects of the therapies in development bear discussion, both to guide the discovery of new therapies and to inform clinicians so that rational treatment regimens can be tailored to patients once they become available.

Topics: Benzothiazoles; Bezafibrate; Bile Acids and Salts; Budesonide; Case-Control Studies; Chenodeoxycholic Acid; Cholagogues and Choleretics; Clinical Trials as Topic; Cyclosporine; Disease Progression; Glucocorticoids; Homeostasis; Humans; Immunologic Factors; Immunosuppressive Agents; Isoxazoles; Liver Cirrhosis, Biliary; Liver Transplantation; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Rituximab; Treatment Outcome; United States; United States Food and Drug Administration; Ursodeoxycholic Acid

Primary biliary cholangitis is a chronic, seropositive and female-predominant inflammatory and cholestatic liver disease, which has a variable rate of progression towards biliary cirrhosis. Substantial progress has been made in patient risk stratification with the goal of personalized care, including early adoption of next-generation therapy with licensed use of obeticholic acid or off-label fibrate derivatives for those with insufficient benefit from ursodeoxycholic acid, the current first-line drug. The disease biology spans genetic risk, epigenetic changes, dysregulated mucosal immunity and altered biliary epithelial cell function, all of which interact and arise in the context of ill-defined environmental triggers. A current focus of research on nuclear receptor pathway modulation that specifically and potently improves biliary excretion, reduces inflammation and attenuates fibrosis is redefining therapy. Patients are benefiting from pharmacological agonists of farnesoid X receptor and peroxisome proliferator-activated receptors. Immunotherapy remains a challenge, with a lack of target definition, pleiotropic immune pathways and an interplay between hepatic immune responses and cholestasis, wherein bile acid-induced inflammation and fibrosis are dominant clinically. The management of patient symptoms, particularly pruritus, is a notable goal reflected in the development of rational therapy with apical sodium-dependent bile acid transporter inhibitors.

Topics: Adaptive Immunity; Animals; Autoimmunity; Bile Acids and Salts; Chenodeoxycholic Acid; Chloride-Bicarbonate Antiporters; Cholagogues and Choleretics; Dihydrolipoyllysine-Residue Acetyltransferase; Disease Progression; Environmental Exposure; Epigenesis, Genetic; Humans; Immunity, Innate; Liver Cirrhosis; Liver Cirrhosis, Biliary; MicroRNAs; Organic Anion Transporters, Sodium-Dependent; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Symporters; Ursodeoxycholic Acid

Primary biliary cholangitis is an uncommon cholestatic liver disease predominantly affecting middle-aged women. Left untreated, there is a high risk of progression to end-stage liver disease. Few treatment options exist. To date, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only medical therapies approved for use, other than symptomatic treatments and liver transplantation, the latter of which is reserved for those developing complications of cirrhosis or with intractable pruritus. UDCA improves outcomes, but many patients do not adequately respond. OCA therapy may improve response, but long-term data are limited. New therapies are desperately needed, but evaluation has been limited by the fact that the disease is heterogeneous, hard end points take years to develop, and there are different criteria in use for determining therapeutic response based on surrogate biomarkers. Fibrates appear to be the most promising new therapy and have beneficially affected surrogate end points and are beginning to show improvement in clinical end points.

Topics: Chenodeoxycholic Acid; Disease Progression; End Stage Liver Disease; Female; Fibric Acids; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is a progressive inflammatory autoimmune cholestatic liver disease. Without treatment, it may result in fibrosis and eventually end stage liver disease. In addition to the disease burden, the symptom impact on the quality of life for PBC patients is significant. Ursodeoxycholic acid, and the second-line therapy, Obeticholic acid, are the only available licensed treatments. Although there has been rapid development of novel therapies in recent years for the treatment of PBC, there are very few symptoms directed therapies.. This literature review aims to review the current treatment landscape in PBC and to explore how the next few years may unfold in the field. The current guidelines and emerging therapies in phase 2, 3 and 4 clinical trials have been included.. The currently available therapies are effective, but their use has limitations and challenges and there is still significant unmet need. Although there have been promising therapeutic interventions in recent years, further research into personalizing therapeutic strategies with available treatments and new agents is needed.

Topics: Animals; Chenodeoxycholic Acid; Cholagogues and Choleretics; Disease Progression; Drug Development; Humans; Liver Cirrhosis, Biliary; Quality of Life; Ursodeoxycholic Acid

Obeticholic acid (OCA) is a semi-synthetic hydrophobic bile acid (BA) analogue that is highly selective agonist of farnesoid X receptor (FXR), a key nuclear BA receptor, which induces expression of gut-derived hormones, in particular fibroblast growth factor 19. The resulting beneficial effects of OCA on glucose and lipid metabolism and particularly hepatic inflammation make it a candidate for the treatment of a variety of conditions including primary biliary cholangitis (PBC) and nonalcoholic steatohepatitis (NASH).. In PBC patients who have not initially responded to ursodeoxycholic acid, OCA has been shown in double-blind controlled clinical trials to significantly reduce serum alkaline phosphatase. To date, OCA is the only therapy licensed by the FDA, EMA and endorsed by NICE as second line therapy for PBC.No medications are currently approved in Europe or the USA for the treatment of NASH.In recent clinical trials, OCA has been shown encouraging results by improving liver blood tests and reducing liver fibrosis with no worsening of NASH.. OCA is the established second line therapy for PBC in those patients who fail to adequately respond to ursodeoxycholic acid.. The main side effects of OCA treatment in both PBC and NASH is that of dose-dependent pruritis which can lead to treatment discontinuation in ~1-10% of patients. In addition, OCA-treated patients may also exhibit (reversible) alterations in serum lipid levels; most notably a small decrease in high density lipoprotein cholesterol. It is not yet known whether these changes carry a long-term cardiovascular risk in NASH.In addition, the relatively high cost of OCA may limit its use in cash-limited health systems.. Additional clinical trials are in progress to ascertain the long-term effects of OCA on survival in PBC and NASH.. New FXR agonists with a lower rate of side effects are being developed and trialed. Combination therapy with other agents may offer increased efficacy.

Topics: Chenodeoxycholic Acid; Gastrointestinal Agents; Humans; Liver Cirrhosis, Biliary; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Treatment Outcome

Primary biliary cholangitis is a cholestatic, chronic autoimmune liver disease with a wide individual variation in disease progression. The diagnosis is predominantly based on chronic elevation of alkaline phosphatase and the presence of anti-mitochondrial antibodies or other specific antinuclear antibodies (i.e. anti-gp210 and anti-sp100). Even in early-stage disease, health-related quality of life can be severely impaired by symptoms such as pruritus, fatigue, and sicca syndrome and metabolic bone disease should be assessed and treated. The prognosis of the disease is, however, largely determined by the development of cirrhosis and its complications. Ursodeoxycholic acid is associated with an improved prognosis and should be initiated and continued in all patients. Clinical outcome is related to the biochemical response to ursodeoxycholic acid, but the prognosis of those with an incomplete response is still better than those who remain untreated. Obeticholic acid was recently approved as second-line treatment and bezafibrate may serve as an adequate off-label alternative, particularly in patients with pruritus. Preliminary data suggest an additive effect of triple therapy with ursodeoxycholic acid, obeticholic acid, and bezafibrate, whereas other promising drugs are being evaluated in clinical trials.

Topics: Autoantigens; Autoimmune Diseases; Bezafibrate; Biomarkers; Biopsy; Chenodeoxycholic Acid; Cholagogues and Choleretics; Disease Progression; Drug Therapy, Combination; Elasticity Imaging Techniques; End Stage Liver Disease; Fatigue; Female; Humans; Immunoglobulin M; Liver; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Middle Aged; Off-Label Use; Prognosis; Pruritus; Quality of Life; Severity of Illness Index; Sjogren's Syndrome; Survival Rate; Treatment Outcome; Ursodeoxycholic Acid

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are immune-mediated chronic liver diseases. PSC is a rare disorder characterized by multi-focal bile duct strictures and progressive liver diseases that ultimately results in the need for liver transplantation in most patients. Imaging studies, such as MRCP, have an essential role in the diagnosis of most cases of PSC. PSC is usually accompanied by inflammatory bowel disease, and there is a high risk of cholangiocarcinoma and colorectal cancer in PSC. No medical therapies have been proven to delay the progression of PSC. Endoscopic intervention for tissue diagnosis or biliary drainage is frequently required in cases of PSC with a dominant stricture, acute cholangitis, or clinically suspected cholangiocarcinoma. PBC is a chronic inflammatory autoimmune cholestatic liver disease, which, when untreated, will culminate in end-stage biliary cirrhosis requiring liver transplantation. A diagnosis is usually based on the presence of serum liver tests indicative of cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse in PBC, and risk stratification is important for ensuring that all patients receive a personalized approach to their care. Medical therapy using ursodeoxycholic acid or obeticholic acid has an important role in reducing the progression to end-stage liver disease in PBC.

Topics: Alkaline Phosphatase; Chenodeoxycholic Acid; Cholangitis, Sclerosing; Humans; Liver Cirrhosis, Biliary; Prognosis; Risk Factors; Ursodeoxycholic Acid

Although the efficacy of ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) for primary biliary cholangitis (PBC) has been suggested by small trials, a meta-analysis to summarize the evidence has not yet been carried out. The aim of this study was to evaluate the clinical outcomes of the combination therapy of UDCA and OCA compared with UDCA monotherapy in patients with PBC.. We searched the PubMed, EMBASE, the web of science, and the Cochrane Library databases for English-language studies published before September 2018. Studies were included if they were randomized controlled trials (RCTs) and reported relative risk (RR) estimates with 95% confidence intervals (CIs) or related data for the clinical outcomes of different therapies in patients with PBC.. Of the 1169 titles identified, two studies meeting the inclusion criteria were included in the meta-analysis. Approximately 222 patients with PBC were included in this analysis. The results of this study indicated that combination therapy was significantly superior to monotherapy in reducing serum alanine transaminase (mean difference: -15.63 IU/L; 95% CI, -21.59 to -9.68), aspartate transaminase (mean difference: -6.63 IU/L; 95% CI, -11.03 to -2.24), gamma-glutamyl transpeptidase (mean difference: -131.30 IU/L; 95% CI, -177.52 to -85.08), and C-reactive protein (mean difference = -1.17 mg/L; 95% CI, -2.19 to -0.14), but NS in improving primary endpoints of alkaline phosphatase level with 15.0% reduction from baseline, and equal or higher than the upper limit of normal serum total bilirubin (RR = 2.75; 95% CI, 0.43-17.68), conjugated bilirubin (mean difference = -0.06 mg/dL; 95% CI, -0.28 to 0.15), IgM (mean difference = -41.18 mg/dL; 95% CI, -244.45 to 162.09), and adverse events (P > 0.05).. This meta-analysis demonstrated that combination therapy with UDCA and OCA provided satisfactory clinical outcomes, which may be a promising alternative for patients with PBC who had an inadequate response to UDCA therapy. Therefore, high-quality RCTs on the safety and efficacy of the combination therapy of UDCA and OCA compared with UDCA monotherapy in patients with PBC should be performed in the future.

Topics: Alanine Transaminase; Chenodeoxycholic Acid; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease which on progression causes cirrhosis; various studies also suggested that several diseases can co-exist in patients. In existing depiction of disease PBC, apart from entire use of ursodeoxycholic acid (UDCA), several patients need to step forward to liver-transplantation or death due to resistance or non-responder with UDCA monotherapy.. To overcome this non-respondent treatment, novel bile acid semi-synthetic analogs have been identified which shows their potency against for farnesoid X receptor and transmembrane G protein-coupled receptor-5 which are identified as target for many developing analogs which have desirable pharmacokinetic profiles.. A range of studies suggests that adding semisynthetic analogs in therapeutic regime improves liver biochemistries in patients with suboptimal response to UDCA. Thus, the aspire of this review is to abridge and compare therapeutic value and current markets affirm of various bile acids semi-synthetic analogs which certainly are having promising effects in PBC monotherapy or in pooled treatment with UDCA for PBC.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholic Acids; Humans; Liver Cirrhosis, Biliary; Nitrates; Ursodeoxycholic Acid

Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.

Topics: Antibodies, Antinuclear; Autoimmune Diseases; Chenodeoxycholic Acid; Cholagogues and Choleretics; Congresses as Topic; Female; Humans; Liver; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

This review will summarize the use of obeticholic acid (OCA) in treatment of primary biliary cholangitis (PBC). It seeks to discuss the mechanism of action, evidence for use, appropriate clinical use, and common adverse effects of OCA.. PBC is a chronic, progressive cholestatic liver disease that is a chronic progressive that may lead to end-stage liver disease and need for liver transplantation. Ursodeoxycholic acid (UDCA) has been the mainstay of therapy for PBC for decades. Recent research has led to the discovery that bile acids act as hormones and have many effects, one of which is activating the farnesoid X receptor (FXR). Activation of FXR leads to decreased bile acid synthesis, inflammation, and fibrosis of the liver. OCA is a highly potent FXR agonist.. Several clinical trials demonstrated that OCA treatment in PBC led to a significant decrease in serum alkaline phosphatase, a marker for long-term survival. The US FDA-approved OCA in 2016, which led to incorporation of OCA into current guidelines as a second-line treatment for PBC. The most clinically relevant adverse effect of OCA is dose-related pruritus. We review the role of OCA and current guidelines in treatment of PBC.

Topics: Chenodeoxycholic Acid; Cholesterol, HDL; Dose-Response Relationship, Drug; Drug Labeling; Dyslipidemias; Humans; Liver Cirrhosis, Biliary; Nasopharyngitis; Pruritus; Receptors, Cytoplasmic and Nuclear; Treatment Outcome

For many years the one-size-fits-all approach has been the only one available to manage patients affected by primary biliary cholangitis. The introduction of obeticholic acid in 2016 as a second-line treatment, together with the creation and validation of several biochemically based scores to stratify the risk of progressive disease, has opened up the need to redefine clinical practice by changing the actual paradigm. The precision medicine initiative is a model of patient-centered health care that aims to improve medicine based on genotypic and molecular characteristics that correlate to specific phenotypic, individual characteristics. In summary, the aim of the precision medicine is to define the right treatment for the right person at the right time. The availability of a second-line disease-modifying drug and new molecules in phase 2 or 3 trials makes this an exciting time for the precision medicine initiative in primary biliary cholangitis. In this review we describe the current risk stratification tools and we track a possible path towards the application of precision medicine in clinical daily life.

Topics: Chenodeoxycholic Acid; Disease Progression; Gastrointestinal Agents; Humans; Liver Cirrhosis, Biliary; Precision Medicine

Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic liver disease that progresses slowly to end-stage liver disease. The first Food and Drug Administration (FDA)-approved treatment for PBC was ursodeoxycholic acid (UDCA). This treatment slows the progress of the disease, but approximatively 30-40% of patients fail to respond to UDCA. A number of options are under investigation as second line treatment. Obeticholic acid (OCA), a Farnesoid X Receptor agonist, has been approved in May 2017 by FDA for patients non responders or intolerant to UDCA. The results of a randomized, double blind, phase 3 study of OCA (mg or 10mg) compared to placebo, showed that approximatively 50% of patients reached a significant reduction in serum alkaline phosphatase, a marker predictive of disease progression, liver transplantation or death. Other emerging therapies include: agents targeting fibrosis, inflammation, or immunological response. Indeed, after 30years of UDCA therapy as unique choice for PBC patients, a number of targets, derived from a deeper knowledge of the pathophysiology of the disease, has been discovered and they offer different and new therapeutic approaches that are now under evaluation.

Topics: Budesonide; Chenodeoxycholic Acid; Disease Progression; End Stage Liver Disease; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

For nearly 30 years ursodeoxycholic acid (UDCA) represented the only pharmacological treatment option available for primary biliary cholangitis (PBC). This changed at the end of 2016 when obeticholic acid was licensed in Europe for PBC patients not responding to UDCA. Novel treatment concepts involving the modulation of nuclear receptor signaling in cholestatic and other liver diseases have led to a host of new potential options, studies and drug candidates for the treatment of PBC. The analysis of large multinational cohorts has additionally confirmed the effectiveness of UDCA in slowing PBC progression, and has led to the development of new definitions for the risk assessment of PBC patients under therapy, which will be an asset for clinical decision making. One issue that remains unresolved is the therapeutic management of extrahepatic symptoms associated with PBC, namely fatigue and pruritus, which are the main factors influencing the quality of life of affected individuals. Their pathophysiological basis is poorly understood and treatment remains unsatisfactory.

Topics: Bezafibrate; Budesonide; Chenodeoxycholic Acid; Cohort Studies; Female; Fenofibrate; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Multicenter Studies as Topic; PPAR alpha; Pregnancy; Prognosis; Quality of Life; Receptors, Cytoplasmic and Nuclear; Risk Assessment; Treatment Outcome; Ursodeoxycholic Acid

The name of chronic liver disease: primary biliary cirrhosis, has been changed to: primary biliary cholangitis, primarily because of the stigma associated with the word "cirrhosis", as only a minority of the patients develop cirrhosis. In this review we present data on epidemiology and discuss the current treatments with focus on ursodeoxycholic acid and the newly described effects of the farnesoid receptor agonist obeticholic acid.

Topics: Anti-Inflammatory Agents; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Fibric Acids; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

Topics: Bile Acids and Salts; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Drug Therapy, Combination; Elasticity Imaging Techniques; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

Primary biliary cholangitis is a progressive, autoimmune disease of the interlobular bile ducts, leading to secondary damage of hepatocytes that may progress to cirrhosis and liver failure. Until recently, the only approved treatment was ursodeoxycholic acid. However, 40% of patients do not have an adequate response. Obeticholic acid was approved for treatment as add-on therapy in this group of patients. Off-label use of fibrates has also been reported to be effective. Several new therapies are in development and may further add to the treatment options available to patients with primary biliary cholangitis.

Topics: Alkaline Phosphatase; Bezafibrate; Chenodeoxycholic Acid; Cholagogues and Choleretics; Comorbidity; Drug Therapy, Combination; Fenofibrate; Fibroblast Growth Factors; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Malnutrition; Osteoporosis; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

Primary biliary cholangitis is an archetypal autoimmune disease that causes cholestasis, fibrosis, and liver failure. Ursodeoxycholic acid and obeticholic acid are approved for its treatment. Not all patients respond, some are intolerant, many have ongoing symptoms, and new therapies are required. Herein we describe drugs in development and potential future biological targets. We consider compounds acting on the farnesoid X receptor/fibroblast growth factor 19 pathway, fibrates and other agonists of the peroxisome proliferator-activated receptor family, transmembrane-G-protein-receptor-5 agonists, and several immunological agents. We also consider the roles of bile acid reuptake inhibitors, nalfurafine, and fibrates in pruritus management.

Topics: Abatacept; Acetates; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Bezafibrate; CD40 Antigens; CD40 Ligand; Chalcones; Chemokine CX3CL1; Chenodeoxycholic Acid; Cholic Acids; Drug Development; Fenofibrate; Fibroblast Growth Factors; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Janus Kinase Inhibitors; Liver Cirrhosis, Biliary; Methylamines; Peroxisome Proliferator-Activated Receptors; PPAR alpha; PPAR delta; PPAR gamma; Propionates; Pruritus; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Thiazepines; Triazoles; Ustekinumab

Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic disease characterized by an autoimmune-mediated destruction of small and medium-sized intrahepatic bile ducts. Originally PBC was considered to be rare and almost invariably fatal, mainly because the diagnosis was made in patients presenting with advanced symptomatic disease (jaundice and decompensated cirrhosis). However, the development of a reproducible indirect immunofluorescence assay for antimitochondrial antibody made it possible to diagnose the disease at an earlier stage, and introduction of ursodeoxycholic acid therapy as the first-line therapy for PBC drastically changed PBC-related mortality. At present, patients with an early histological stage have survival rates similar to those of an age- and sex-matched control population. Although 30% of patients treated with ursodeoxycholic acid may exhibit incomplete responses, obeticholic acid and drugs currently in development are expected to be effective for these patients and improve outcomes. Meanwhile, more etiology and immunopathology studies using new technologies and novel animal models are needed to dissect variances of clinical course, treatment response, and outcome in each patient with PBC. Precision medicine that is individualized for each patient on the basis of the cause identified is eagerly awaited.

Topics: Animals; Chenodeoxycholic Acid; Cholagogues and Choleretics; Disease Models, Animal; Drug Design; Fluorescent Antibody Technique, Indirect; Humans; Liver Cirrhosis, Biliary; Precision Medicine; Ursodeoxycholic Acid

Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; End Stage Liver Disease; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by chronic cholestasis. Treatment with the accepted primary therapy ursodeoxycholic acid (UDCA) has been shown to be associated with delayed disease progression probably through reduced impact of cholestatic injury on the target biliary epithelial cells. Patients with inadequate response to UDCA (which can be identified through validated biochemical criteria) are at increased risk of disease progression, need for liver transplantation, and death. Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second-line therapy in PBC and has been recently licensed by the Food and Drug Administration and European Medicines Agency for use in patients showing an inadequate response to UDCA or who are unable to tolerate it. Although evidence for biochemical improvement by OCA is compelling, there is, as yet, no evidence that OCA improves hard clinical outcomes or quality of life. In addition, OCA may not be suitable for PBC patients with pruritus as it can worsen the symptom. Other novel agents currently in clinical development may have better side-effect profile. Fibrates have the potential but currently lack high quality evidence to support their routine clinical use in PBC. Symptom management of PBC is challenging and ASBT inhibitors and rituximab are being evaluated for pruritus and fatigue, respectively.

Topics: Chenodeoxycholic Acid; Cholangitis; Disease Progression; Humans; Liver Cirrhosis, Biliary; Quality of Life; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that may lead to biliary fibrosis, and eventually cirrhosis. The primary treatment for PBC is ursodeoxycholic acid (UDCA), which has favorably altered its natural history. However, up to 40% of patients have an inadequate response to UDCA, and are therefore at high risk of liver-related complications. Obeticholic acid has recently been approved for use in patients with PBC with inadequate response or who are intolerant to UDCA, but improvement in long-term outcomes has not yet been demonstrated. Alternative therapeutic options for PBC are needed. Areas covered: Recent advances in research including epidemiological, genetic and pre-clinical studies in animal models of PBC have yielded numerous agents currently at different stages of development for treatment of patients with PBC; in this review, we cover novel therapies that were recently or are recently being investigated in phase II clinical trials. Expert opinion: Despite the evolving landscape in PBC, the main challenges facing development of novel therapies remain the rarity of the disease and the limitations to design and conduct of controlled clinical trials in PBC, which are needed to determine the long-term effects of novel therapies on the clinical outcomes of PBC.

Topics: Animals; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Disease Progression; Drug Design; Drugs, Investigational; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by chronic inflammation of the intrahepatic bile ducts, causing progressive ductopenia, cholestasis and fibrosis, and leading to liver failure. Ursodeoxycholic acid (UDCA) is the first-line therapy for the treatment of PBC patients. This is effective in majority of patients; however, up to 20 percent of patients have an incomplete response to UDCA therapy and have a reduced prognosis as compared to healthy individuals. Obeticholic acid (OCA) has been recently registered as second-line therapy for patients with incomplete response to UDCA, with plans to demonstrate the long-term clinical efficacy. Areas covered: Recent evolution in our understanding of disease mechanisms is leading to the advent of new and re-purposed therapeutic agents targeting key processes in the etiopathogenesis. Several therapeutic targets have been proposed which can be categorized into three compartments: immune, biliary and fibrosis. In this review we describe the main biological mechanisms underpinning disease development and progression in PBC and the new targeted therapies on the horizon. Expert commentary: Testing new drugs towards hard clinical endpoints is challenging in PBC due to its low prevalence and the slow progression of the disease. Novel promising biomarkers are under study and should be evaluated as surrogate endpoints in clinical trials.

Topics: Autoimmunity; Bile Ducts, Intrahepatic; Chenodeoxycholic Acid; Cholangitis; Fibrosis; Humans; Immunotherapy; Liver; Liver Cirrhosis, Biliary; Molecular Targeted Therapy; Ursodeoxycholic Acid; Ustekinumab

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most frequent chronic cholestatic liver diseases and serve as model diseases to discuss the management of cholestasis in 2017 in the lecture that is summarized in this report. PBC and PSC are characterized by inflammation and fibrosis of small intrahepatic (PBC) or larger intra- and/or extrahepatic (PSC) bile ducts. Bile duct damage leads to cholestasis and can progress to liver fibrosis and even cirrhosis. Various genetic, environmental and endogenous factors may contribute to the development of chronic cholestatic liver diseases, but the exact pathogenesis of PBC and PSC has not been clarified. Ursodeoxycholic acid (UDCA) is the standard treatment of PBC and is used also for other cholestatic conditions including PSC, and it exerts anticholestatic effects at adequate doses. Novel anticholestatic therapeutic options for patients not adequately responding to UDCA are under development or have, like obeticholic acid, already been proven to have efficacy when combined with UDCA in the treatment of PBC. The future role of immunomodulating/immunosuppressive drug regimens must be critically reviewed.

Topics: Bile Acids and Salts; Bile Ducts; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis, Sclerosing; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Humans; Liver Cirrhosis, Biliary

Despite the presumed immunological pathogenesis of primary biliary cholangitis, no clear or even harmful consequences have resulted from treatments designed to modify the immunological condition. Ursodeoxycholic acid (13-16 mg/kg/d) has, however, clear favorable effects that not only improve biochemical cholestasis, but also delay histological progression. Long-term treatment with ursodeoxycholic acid is associated with excellent transplant-free survival in cases showing a biochemical response at 1 year. Data on the effects of obeticholic acid and fibrates are encouraging. Moreover, recent pilot studies evaluating several biological agents targeting immunity such as different monoclonal antibodies and other drugs that modulate cholestasis are under investigation, although with limited results at present.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Disease Progression; Fibric Acids; Gastrointestinal Agents; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Autoimmune liver diseases are a group of abnormal autoimmune-mediated inflammatory hepatobiliary injuries, mainly including autoimmune hepatitis(AIH), primary biliary cholangitis(PBC), and primary sclerosing cholangitis (PSC). The diagnosis and treatment of autoimmune liver diseases, an important type of non-viral liver disease, have become a prominent issue in hepatology. In 2016, many new advances have been achieved in the clinical and basic research on autoimmune liver diseases, including the phase 3 clinical trial of obeticholic acid, the proposal of UK-PBC risk score, and the research on gut microbiota associated with PSC. This article reviews the research advances in the diagnosis and treatment of autoimmune liver diseases in 2016.. 自身免疫性肝病是一组由异常自身免疫介导的肝胆炎症性损伤，主要包括自身免疫性肝炎、原发性胆汁性胆管炎及原发性硬化性胆管炎等。作为非病毒性肝病的重要成员，自身免疫性肝病的诊断与治疗日益成为肝病领域的突出问题之一。2016年，自身免疫性肝病在临床和基础研究方面又有了许多新进展，包括奥贝胆酸的临床III期试验，UK-PBC危险评分的提出，以及原发性硬化性胆管炎相关的肠道微生态研究等。现就自身免疫性肝病2016年的诊疗与研究进展进行介绍。.

Topics: Autoimmune Diseases; Biomedical Research; Chenodeoxycholic Acid; Cholangitis; Cholangitis, Sclerosing; Clinical Trials, Phase III as Topic; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases

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

All patients with primary biliary cirrhosis (PBC) and abnormal liver biochemistry should be considered for specific therapy. Ursodeoxycholic acid (UDCA) is the only FDA-approved drug for treating PBC. Approximately 40% of patients with PBC respond incompletely to treatment with UDCA, thus having increased risk of death or need for liver transplantation. No second-line therapies for patients with inadequate response to UDCA therapy have been approved. This review provides a current perspective on potential new approaches to treatment in PBC, and highlights some of the challenges we face in evaluating and effectively implementing those treatments.

Topics: Abatacept; Anti-Retroviral Agents; Antibodies, Monoclonal, Humanized; Bezafibrate; Chenodeoxycholic Acid; Cholagogues and Choleretics; Fenofibrate; Glucocorticoids; Humans; Hypolipidemic Agents; Immunologic Factors; Liver Cirrhosis, Biliary; Mesenchymal Stem Cell Transplantation; Receptors, Cytoplasmic and Nuclear; Rituximab; Ursodeoxycholic Acid; Ustekinumab

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

Obeticholic acid (Ocaliva(TM)) is a farnesoid-X receptor (FXR) agonist that is being developed by Intercept Pharmaceuticals for the treatment of various liver diseases, and has recently been granted accelerated approval in the USA for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults with an inadequate response to ursodeoxycholic acid, or as monotherapy in adults unable to tolerate ursodeoxycholic acid. The drug is in preregistration for this indication in the EU. This article summarizes the milestones in the development of obeticholic acid leading to this first approval for primary biliary cholangitis.

Topics: Chenodeoxycholic Acid; Drug Approval; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease. Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo.. This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database.. If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.

Topics: Animals; Autoimmune Diseases; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Cholestasis; End Stage Liver Disease; Genome-Wide Association Study; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Topics: Animals; Azepines; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholestasis; Drug Evaluation, Preclinical; Gastrointestinal Agents; Hepatitis, Autoimmune; Humans; Hypertension, Portal; Indoles; Isoxazoles; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Liver Diseases; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

Primary biliary cirrhosis (PBC) is a rare inflammatory liver disease for which ursodeoxycholic acid (UDCA) is the only therapy approved by the U.S. Food and Drug Administration. Patients with a biochemical response to UDCA therapy have a similar survival rate compared to the general population. However, up to 40% of PBC patients do not achieve a complete response to UDCA, have an increased risk of liver-related death and liver transplantation, and represent a persistent medical need for new therapies. Several novel drugs have recently been studied and show potential efficacy in PBC. Obeticholic acid, a farnesoid X receptor agonist, has been tested in phase II trials and initial results after 1 year in a phase III international trial suggest that it may be effective in achieving a biochemical response in approximately 40% of patients who do not completely respond to UDCA. Several small studies on fibrates have suggested that they may have efficacy, but larger studies are needed. Surprisingly, results of immunomodulators and biologics have not yet been able to demonstrate efficacy, but new approaches have shown promise in animal models and their translation to human clinical trials are awaited.

Topics: Biological Factors; Budesonide; Chenodeoxycholic Acid; Clinical Trials as Topic; Fibric Acids; Humans; Liver Cirrhosis, Biliary; Treatment Outcome

Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive.. Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids.. We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.

Topics: Autoimmune Diseases; Bile Acids and Salts; Budesonide; Chenodeoxycholic Acid; End Stage Liver Disease; Female; Fibric Acids; Humans; Liver; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Treatment Failure; Ursodeoxycholic Acid

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of adults. Treatments are needed when patients have incomplete response to ursodeoxycholic acid (UDCA).. Discoveries of the key role played by bile acids (BAs) and nuclear receptors (NRs) in regulating liver and metabolic homeostasis have led to promising therapeutic approaches in liver diseases. A PubMed search for the recent literature on NRs in liver disease was conducted. In particular, obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist that has an important role in the enterohepatic circulation of BAs. Preliminary studies of OCA in patients with PBC have demonstrated marked biochemical improvement when administered in combination with UDCA and alone. Pruritus is the most common side effect, limiting treatment at higher doses. Budesonide is a glucocorticoid receptor/pregnane X receptor (PXR) agonist also involved in BA synthesis, metabolism and transport. Studies with budesonide have shown positive effects of short-term combination therapy in selected patients with early stage disease and overlapping features of autoimmune hepatitis.. Though larger studies are needed, preliminary results of agents targeting FXR and PXR have been encouraging, particularly in subsets of patients with PBC and may mark a new therapeutic era.

Topics: Bile Acids and Salts; Budesonide; Chenodeoxycholic Acid; Humans; Liver Cirrhosis, Biliary; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid

Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease. It is characterized by slow destruction of small intrahepatic bile ducts, impaired biliary secretion and stasis of toxic endogenous bile acids within the liver with progression to liver fibrosis and cirrhosis. It has an increasing prevalence worldwide. It occurs more commonly in women than men at a ratio of 10:1. In most cases, diagnosis relies on a positive antimitochondrial antibody in the context of chronic cholestasis, without the need for a liver biopsy. Ursodeoxycholic acid improves survival even in patients with advanced liver disease. Certain findings such as fatigue, anti-nuclear antibodies, anti-centromere antibodies and the GP210 antinuclear antibody predict a poor outcome. Up to 40% of patients do not respond satisfactorily to ursodeoxycholic acid therapy and should be considered for adjunctive therapies. Several adjunctive and newer therapies are being tested and some appear promising. We provide a review of PBC with a focus on advances in therapies that may impact the management of PBC in the near future.

Topics: Adult; Autoimmune Diseases; Chenodeoxycholic Acid; Cholagogues and Choleretics; Humans; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

This review will provide an overview of the role of nuclear receptors in bile acid homeostasis with a focus on the farnesoid X receptor (FXR) and its potential therapeutic use in cholestatic liver diseases.. Nuclear receptors have emerged as important mediators of a variety of metabolic and transport functions involving the liver. The role of FXR, in particular, has come to light because of its important role in bile acid homeostasis. The use of potent FXR ligands has recently been shown to offer potentially important therapeutic benefits in patients with primary biliary cirrhosis, an important cholestatic liver disease of adults. This recent finding has now opened the door for future therapeutic trials for use of FXR agonists such as obeticholic acid for the treatment of chronic cholestatic liver diseases.. Further understanding of the role of farnesoid X receptor agonists and the potential role of ligands in animal models of other forms of cholestasis will be important to set the stage for future applications to human disease.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Gastrointestinal Agents; Humans; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear

The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls.. Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis.. During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10-0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12-0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03-1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09-1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21-0.85) including hepatic decompensation.. Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.

Topics: Chenodeoxycholic Acid; Humans; Liver Cirrhosis; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor farnesoid X receptor, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA).. Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi, and bile ducts by positron emission tomography of the liver using the conjugated bile acid tracer [N-methyl-. Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of. This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer. Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third.

Topics: Aged; Alkaline Phosphatase; Bile Acids and Salts; Bile Ducts, Intrahepatic; Biological Transport; Chenodeoxycholic Acid; Double-Blind Method; Female; Gastrointestinal Agents; Hepatocytes; Humans; Liver Cirrhosis, Biliary; Middle Aged; Positron-Emission Tomography; Receptors, Cytoplasmic and Nuclear; Treatment Outcome; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by bile duct destruction that can progress to cirrhosis. A liver biopsy substudy was conducted in the PBC obeticholic acid (OCA) International Study of Efficacy (POISE) to determine the long-term effects of OCA on liver damage and fibrosis in patients with PBC. POISE is a phase 3, double-blind, placebo-controlled, randomized trial with a 5-year open-label extension that evaluated 5 to 10 mg OCA daily in patients who were intolerant or unresponsive to ursodeoxycholic acid.. Liver biopsy specimens were collected from 17 patients at time of enrollment in the double-blind phase and after 3 years of OCA treatment. Histologic evaluations were performed by 2 pathologists in a blinded, randomized fashion to determine the effects of OCA on fibrosis and other histologic parameters. Collagen morphometry assessments were performed by automated second harmonic generation and 2-photon excitation microscopy to observe quantitative measures of fibrosis.. From the time of enrollment until 3 years of treatment, most patients had improvements or stabilization in fibrosis (71%), bile duct loss (76%), ductopenia (82%), ductular reaction (82%), interface hepatitis (100%), and lobular hepatitis (94%). Over the 3-year period, we found significant reductions in collagen area ratio (median, -2.1; first quartile, -4.6, third quartile, -0.3; P = .013), collagen fiber density (median, -0.8; first quartile, -2.5; third quartile, 0; P = .021), collagen reticulation index (median, -0.1; first quartile, -0.3; third quartile, 0; P = .008), and fibrosis composite score (median, -1.0; first quartile, -2.5; third quartile, -0.5; P = .002).. A subanalysis of data from the POISE study showed that long-term OCA treatment in patients with PBC is associated with improvements or stabilization of disease features, including ductular injury, fibrosis, and collagen morphometry features (ClinicalTrials.gov no: NCT01473524 and EudraCT no: 2011-004728-36).

Topics: Chenodeoxycholic Acid; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Ursodeoxycholic Acid

Total bilirubin is a predictor of survival in primary biliary cholangitis, with the main elevated component being direct bilirubin. The purpose of this post hoc analysis was to assess the efficacy and safety of obeticholic acid across quartiles of varying baseline levels of direct bilirubin in the phase 3, randomized, placebo-controlled Primary Biliary Cholangitis Obeticholic Acid International Study of Efficacy.. This analysis assessed patients on the basis of their baseline direct bilirubin level (divided by quartile). Biochemistry and safety outcomes were evaluated within each quartile over time.. In the quartile with the highest baseline direct bilirubin (>5.47 µmol/L), there was a significant reduction in both direct and total bilirubin at Month 12 compared with placebo. Least squares mean (standard error) change from baseline in direct bilirubin at Month 12 was 4.17 (1.42) µmol/L for placebo, -3.48 (1.63) µmol/L for obeticholic acid 5-10 mg and -3.66 (1.51) µmol/L for obeticholic acid 10 mg (P < .0001, obeticholic acid vs placebo); the corresponding values for total bilirubin at Month 12 were 4.38 (1.55) µmol/L for placebo, -4.53 (1.83) µmol/L for obeticholic acid 5-10 mg and -5.06 (1.64) µmol/L for obeticholic acid 10 mg (P < .0001, obeticholic acid vs placebo).. Obeticholic acid treatment was associated with significant reductions in total and direct bilirubin, particularly in patients with high baseline direct bilirubin. Because raised direct bilirubin levels, even within the normal range, are predictive of survival in primary biliary cholangitis, these results suggest substantial benefits of obeticholic acid in at-risk patients.

Topics: Bilirubin; Chenodeoxycholic Acid; Cholangitis; Humans; Liver Cirrhosis, Biliary; Liver Function Tests

Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.. AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety.. The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged.. Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.. ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38.. Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.

Topics: Alkaline Phosphatase; Chenodeoxycholic Acid; Cholagogues and Choleretics; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Pruritus; Treatment Outcome

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus.. OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).

Topics: Adult; Alkaline Phosphatase; Chenodeoxycholic Acid; Cholestasis; Double-Blind Method; Female; Follow-Up Studies; Humans; Liver Cirrhosis, Biliary; Male; Middle Aged; Receptors, Cytoplasmic and Nuclear; Treatment Outcome

Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease.. In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level.. Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group.. Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).

Topics: Adult; Aged; Alkaline Phosphatase; Bile Acids and Salts; Bone Density; Chenodeoxycholic Acid; Double-Blind Method; Female; Fibroblast Growth Factors; Humans; Liver Cirrhosis; Liver Cirrhosis, Biliary; Male; Middle Aged; Pruritus

We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy.. We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year.. OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline.. Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.

Topics: Adult; Aged; Alanine Transaminase; Alkaline Phosphatase; Chenodeoxycholic Acid; Cholagogues and Choleretics; Dose-Response Relationship, Drug; Double-Blind Method; Female; gamma-Glutamyltransferase; Humans; Liver Cirrhosis, Biliary; Male; Middle Aged; Pruritus; Treatment Failure; Treatment Outcome; Ursodeoxycholic Acid

Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy.. Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs).. One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA.. An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

Topics: Albumins; Ascites; Bilirubin; Chenodeoxycholic Acid; Humans; Liver Cirrhosis; Liver Cirrhosis, Biliary; Male

Topics: Chenodeoxycholic Acid; Cholangitis; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Topics: Alkaline Phosphatase; Bezafibrate; Bilirubin; Chenodeoxycholic Acid; Cholestasis; Cholesterol; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Female; Humans; Hypolipidemic Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Pruritus; Treatment Outcome

Obeticholic acid (OCA) was recently approved as the only on-label alternative for patients with primary biliary cholangitis (PBC) with intolerance or suboptimal response to ursodeoxycholic acid (UDCA). However, few data are available outside clinical trials.. To assess the effectiveness and safety of OCA in a real-world cohort of patients with non-effective UDCA therapy.. Open-label, prospective, real-world, multicentre study, enrolling consecutive patients who did not meet Paris II criteria, from 18 institutions in Spain and Portugal. Effectiveness was assessed by the changes in GLOBE and UK-PBC scores from baseline. POISE and Paris II criteria were evaluated after 12 months of OCA . Liver fibrosis was evaluated by FIB-4 and AST to platelet ratio index (APRI).. One hundred and twenty patients were eligible, median time since PBC diagnosis 9.3 (4.0-13.8) years, 21.7% had cirrhosis, and 26.7% received had previous or concomitant treatment with fibrates. Seventy-eight patients completed at least 1 year of OCA. The Globe-PBC score decreased to 0.17 (95% CI 0.05 to 0.28; P = 0.005) and the UK-PBC score decreased to 0.81 (95% CI -0.19 to 1.80; P = 0.11). There was a significant decrease in alkaline phosphatase of 81.3 U/L (95% CI 42.5 to 120; P < 0.001), ALT 22.1 U/L (95% CI 10.4 to 33.8; P < 0.001) and bilirubin 0.12 mg/dL (95% CI 0 to 0.24; P = 0.044). FIB-4 and APRI remained stable. According to the POISE criteria, 29.5% (23 out of 78) achieved response. The adverse events rate was 35%; 11.67% discontinued (8.3% due to pruritus).. This study supports data from phase III trials with significant improvement of PBC-Globe continuous prognostic marker score among OCA-treated patients with good tolerability.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Humans; Liver Cirrhosis, Biliary; Prospective Studies; Spain; Ursodeoxycholic Acid

Obeticholic acid (OCA) and fibrates are second-line therapies for patients with primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA).. To know whether OCA and fibrates, administered together in combination with UDCA, have additive beneficial effects in patients with difficult-to-treat PBC.. PBC patients treated for ≥3 months with UDCA, OCA and fibrates (bezafibrate or fenofibrate) due to failure of either second-line therapy were included in a multicentre, uncontrolled retrospective cohort study. Changes in biochemical liver tests and pruritus were analysed using a generalised linear mixed-effect model.. Among 58 patients included, half received OCA as second-line and fibrates as third-line therapy (Group OCA-Fibrate), while the other half had the inverse therapeutic sequence (Group Fibrate-OCA). The mean duration of triple therapy was 11 months (range 3-26). Compared to dual therapy, triple therapy was associated with a significant gain in alkaline phosphatase (ALP) reduction: 22% per first year (95% CI 12%-31%), an effect that was stronger in OCA-Fibrate than in Fibrate-OCA group. Triple therapy was associated with a 3.4 (95% CI 1.4-8.2) odds ratio (OR) of reaching normal ALP and with a significant decrease in gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. The ORs of achieving the Paris-2 and Toronto criteria of adequate biochemical response were 6.8 (95% CI 2.8-16.7) and 9.2 (95% CI 3.4-25.1) respectively. Finally, triple therapy significantly improved pruritus in OCA-Fibrate but not in Fibrate-OCA group.. Triple therapy with UDCA, OCA and fibrates is able to normalise biochemical liver tests and improve pruritus in patients with difficult-to-treat PBC.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Fibric Acids; Humans; Liver Cirrhosis, Biliary; Retrospective Studies; Ursodeoxycholic Acid

Obeticholic acid (OCA) and fibrates therapy results in biochemical improvement in placebo-controlled trials in patients with primary biliary cholangitis and insufficient response to ursodeoxycholic acid. There is scarce information outside of clinical trials. Therefore, we have assessed the effectiveness and adverse events of these treatments.. Data from patients included in the ColHai registry treated with OCA, fibrates, or both were recorded during a year, as well as adverse events and treatment discontinuation.. Eighty-six patients were treated with OCA, 250 with fibrates (81% bezafibrate; 19% fenofibrate), and 15 with OCA plus fibrates. OCA group had baseline significantly higher alkaline phosphatase (ALP) (P = 0.01) and lower platelets (P = 0.03) than fibrates. Both treatments significantly decreased ALP, gamma-glutamyl transferase (GGT), and transaminases and improved Globe score. Albumin and immunoglobulin type M improved in the fibrates group. ALP decrease was higher under fibrates, whereas alanine aminotransferase decline was higher under OCA. Although baseline transaminases and GGT were higher in patients with OCA plus fibrates, significant ALP, GGT, alanine aminotransferase, and Globe score improvement were observed during triple therapy. Adverse events were reported in 14.7% of patients (21.3% OCA; 17.6% fenofibrate; 10.7% bezafibrate), mainly pruritus (10.1% with OCA). Discontinuation was more frequent in fenofibrate treatment mainly because of intolerance or adverse events.. Second-line therapy with OCA or fibrates improves hepatic biochemistry and the GLOBE score in primary biliary cholangitis patients with suboptimal response to ursodeoxycholic acid. Simultaneous treatment with OCA and fibrates improved ALP as well.

Topics: Bezafibrate; Chenodeoxycholic Acid; Female; Fenofibrate; Humans; Liver Cirrhosis, Biliary; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Topics: Aged; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Female; Humans; Liver Cirrhosis, Biliary; Male; Middle Aged

Topics: Chenodeoxycholic Acid; Cholangitis; Humans; Liver Cirrhosis, Biliary

There is no consensus treatment for patients with autoimmune hepatitis (AIH) - primary biliary cholangitis (PBC) overlap syndrome who are not responding to conventional therapy. We present a case of a 43-yr-old woman with AIH-PBC overlap syndrome treated with obeticholic acid (OCA). The patient showed a reduction in liver enzymes and no fibrosis progression during 15 months of follow up.

Topics: Adult; Chenodeoxycholic Acid; Female; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Activation of farnesoid X receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein 4 (BRD4) also has antiinflammatory, antifibrotic effects in mice. We determined the role of BRD4 in FXR function in bile acid (BA) regulation and examined whether the known beneficial effects of OCA are enhanced by inhibiting BRD4 in cholestatic mice. Liver-specific downregulation of BRD4 disrupted BA homeostasis in mice, and FXR-mediated regulation of BA-related genes, including small heterodimer partner and cholesterol 7 alpha-hydroxylase, was BRD4 dependent. In cholestatic mice, JQ1 or OCA treatment ameliorated hepatotoxicity, inflammation, and fibrosis, but surprisingly, was antagonistic in combination. Mechanistically, OCA increased binding of FXR, and the corepressor silencing mediator of retinoid and thyroid hormone receptor (SMRT) decreased NF-κB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of FXR and BRD4 was significantly reduced. In conclusion, BRD4 is a potentially novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. Although BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the antiinflammatory, antifibrotic actions of OCA-activated FXR. Cotreatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.

Topics: Animals; Azepines; Bile Acids and Salts; Cell Cycle Proteins; Chenodeoxycholic Acid; Cholestasis; Cholesterol 7-alpha-Hydroxylase; Disease Models, Animal; Drug Interactions; Gene Knockdown Techniques; Humans; Liver; Liver Cirrhosis, Biliary; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Nuclear Proteins; Nuclear Receptor Co-Repressor 2; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Triazoles

Topics: Antiviral Agents; Blood Coagulation Disorders; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; End Stage Liver Disease; Gastroenterology; Hepatic Encephalopathy; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Diseases; Non-alcoholic Fatty Liver Disease; Palliative Care

Topics: Chenodeoxycholic Acid; Humans; Liver Cirrhosis, Biliary; Pruritus; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholangitis; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

Topics: Alanine Transaminase; Alkaline Phosphatase; Autoantibodies; Bilirubin; Biomarkers; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Disease Progression; Gastroenterology; Humans; Liver Cirrhosis, Biliary; Mitochondria; Predictive Value of Tests; Risk Assessment; Risk Factors; Sensitivity and Specificity; Societies, Medical; Treatment Outcome; United Kingdom; Ursodeoxycholic Acid

Primary Biliary Cholangitis (PBC, formerly cirrhosis), is a chronic cholestatic liver disease which until spring 2016 had a single licensed therapy, Ursodeoxycholic acid (UDCA). Approximately 30% of patients do not respond to UDCA, and are high-risk for progressing to end stage liver disease, transplantation or death. A new era of stratified medicine with second-line therapies to treat high-risk disease is emerging, with the first such second-line agent obeticholic acid recently receiving FDA and EMA approval and entering practice. Recent experience in the USA of inappropriate use and associated deaths has highlighted concerns as to whether clinicians have the knowledge to implement second-line therapies appropriately and safely.. Online survey of knowledge regarding optimal PBC management in Gastroenterologists and Hepatologists in the USA; the first 100 completed responses from each group used for analysis.. 80% of Hepatologists felt they were highly competent in their understanding of the importance of early diagnosis and early UDCA therapy in PBC compared with 65% of gastroenterologists. However, only 36% of Hepatologists and 30% of gastroenterologists felt competent at assessing response to UDCA. Competence in knowledge (mode of action, efficacy, and side effects) of second-line therapies and enrollment into trials was low among both groups.. Significant knowledge gaps in clinicians managing PBC presents a problem in optimizing care. It is perhaps not surprising that knowledge of emerging second-line therapies is low, however more concerning is sub-optimal use of UDCA in real-life practice and the lack of confidence at assessing treatment response which should be a routine part of clinical practice to assess risk of disease progression and will be key in delivering stratified medicine.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Clinical Competence; Disease Progression; Early Diagnosis; Gastroenterologists; Humans; Liver Cirrhosis, Biliary; Risk Factors; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with unknown etiology. The prognosis of patients affected by PBC is heterogeneous, with a relevant improvement achieved after the introduction of ursodeoxycolic acid (UDCA). Since in the last years obeticholic acid (OCA) has been approved for the combined treatment of PBC, in patient non-responders to UDCA or as monotherapy in those intolerant to UDCA, we evaluated the response to UDCA in a cohort of patients with PBC managed in a specialistic setting.. We included 38 UCDA-treated non-cirrhotic, early-PBC patients. Data were retrieved from documents compiled during the annual follow-up. The response to therapy was assessed comparing the parameters of our cohort with the inclusion criteria of the POISE Trial and the Paris I and Paris II criteria.. The cohort included 34/38 female patients and the average age was 65.34±10.69 years. Over 50% of the patients were affected by at least one disease associated to PBC. Using the POISE criteria and the Paris I and Paris II criteria, we identified 5, 2 and 5 non-responders, respectively. All patients with severe fibrosis had a biochemical response to UDCA according to the three different criteria applied. No side effect was reported.. We confirm that UDCA is a safe and effective treatment in patients with PBC. Non-responder patients represent 13% of our population, with high risk of disease progression and complications. In this context, further therapy using OCA should be considered.

Topics: Aged; Chenodeoxycholic Acid; Cholagogues and Choleretics; Female; Humans; Liver Cirrhosis, Biliary; Male; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholangitis; Gastrointestinal Agents; Humans; Liver; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Treatment Outcome

The introduction of ursodeoxycholic acid (UDCA)may well have contributed to some of the improvements in morbidity and mortality of primary biliary cholangitis (PBC). Yet nearly 40% of PBC patients are unresponsive to UDCA. Further the data on UDCA is confounded by the changes in the goepidemiology and particularly the earlier diagnosis of PBC. In this regard we welcome the addition of obeticholic acid (OCA) as an alternative therapeutic option forthe treatment of PBC in those patients refractory to UDCA. However, OCA is intellectually disappointing.There is no data on OCA that reflects dynamic and critical endpoints, for example death or liver transplantation; only surrogate endpoints have been used in the clinical trials. A nested study with liver histology wouldbeanideal surrogate marker,including intensive use of immunohistochemistry to define cellular infiltrates and cytokine/chemokine activity. More importantly, the clinical characteristics of PBCmay vary among patients and progression is not always predictable. We need to identify more appropriate and specific biomarkers that predict the clinical course, and we need to know which therapies are applicable at different stages, since treatmentfor PBC should be individualized. We need to know more about the etiology of PBC,and we want a cure for PBC.

Topics: Biomarkers; Chenodeoxycholic Acid; Cholagogues and Choleretics; Disease Progression; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Recent years have seen a growing interest in PBC within the scientific community, healthcare providers and industries, coupled with great advances in the understanding of the molecular and genetic basis and the natural history of the disease. Several disease-modifying agents targeting the immune-mediated response and bile-acid therapies are at different stages of development, some with promising results. A new drug, obeticholic acid, has been recently registered in the US and Europe as a second-line treatment in refractory PBC. International cohort studies have highlighted a disease heterogeneity, and so the need to provide patients with a more personalised management based on their risk of disease progression. Major challenges remain the development of surrogate endpoints in clinical trials acceptable to regulatory authorities, in a disease with a relatively low rate of events; and the development of clinical tools for patient's risk stratification and selection of those with greatest potential benefit from second-line therapies.

Topics: Biomarkers; Chenodeoxycholic Acid; Disease Progression; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic

In a double-blind, randomized, placebo-controlled study including 217 patients with primary biliary cholangitis, the authors show that obeticholic acid (a potent farnesoid X agonist) administered with ursodeoxycholic acid or as monotherapy significantly decreases serum alkaline phosphatase and bilirubin when compared to placebo. Pruritus (and serious adverse effects) was observed more frequently in obeticholic acid-treated patients than in controls, in spite of a decrease in serum bile acid concentration. These results are encouraging, but more studies are needed on clinical efficacy and safety before obeticholic acid can be widely recommended.

Topics: Chenodeoxycholic Acid; Cholangitis; Double-Blind Method; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Female; Humans; Liver Cirrhosis, Biliary; Male

Topics: Chenodeoxycholic Acid; Cholangitis, Sclerosing; Hope; Humans; Life Expectancy; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid