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The recent phase 3 trials of peroxisome proliferator-activated receptor (PPAR) agonists in primary biliary cholangitis (PBC) patients with incomplete response to ursodeoxycholic acid (UDCA) demonstrated very promising short-term biochemical responses. However, long-term outcomes, crucial in chronic diseases like PBC, remain uncertain. While real-world data (RWD) support surrogate endpoints, there's a need to validate long-term efficacy especially with combination therapies. Bezafibrate, an off-label option with extensive RWD, demonstrated short-term response, reduced patients' pruritus, and improved long-term outcomes. Therefore, the therapeutic choice between new selective PPAR agonists and old bezafibrate poses a challenge. Undoubtedly further investigations into new PPAR agonists in terms of long-term efficacy are warranted, but prospective, randomized trials in post-approval settings are very unlikely to be successfully conducted, necessitating alternative approaches using RWD rather than traditional trial design. Finally, it will be essential to identify patients who may be intolerant and/or unresponsive to PPAR agonists., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Tanaka reports receiving consultant fees from EA Pharma, GlaxoSmithKline, Kowa Company Ltd., Abbvie and Gilead Sciences. Dr. Corpechot reports receiving grants from Arrow Generiques and Intercept France, consulting fees from Intercept France, Ipsen, Cymabay, Calliditas, GlaxoSmithKline and EchoSens, and fees for teaching from Intercept France and GlaxoSmithKline France., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The field of liver transplantation directly or indirectly embodies all liver diseases, in addition to specific ones related to organ rejection (cellular and humoral). The recommended non-invasive methods for determining the indication for liver transplantation are the Model for End-stage Liver Disease score, and the alpha-foetoprotein score in case of hepatocellular carcinoma. Radiological methods are the cornerstones for the diagnosis of vascular and biliary complications after liver transplantation. The possible diseases of the liver graft after transplantation are multiple and often intertwined. Non-invasive diagnostic methods have been poorly evaluated in this context, apart from the recurrence of hepatitis C. Liver biopsy remains the gold standard for evaluating graft lesions in the majority of cases, especially graft rejection., (Copyright © 2021. Published by Elsevier Masson SAS.)

Primary biliary cholangitis (PBC) is a chronic inflammatory disease of the intra-hepatic bile ducts [1]. It is characterised biologically by chronic cholestasis associated with the presence of specific autoantibodies, and histologically by lesions of nonsuppurative destructive cholangitis. If left untreated it can progress to cirrhosis, portal hypertension and liver failure. Diagnosis, staging and follow-up are largely based on non- or minimally-invasive assessment (blood tests, ultrasound, liver stiffness measurement). Histological examination of the liver and upper gastrointestinal endoscopy are sometimes necessary, but their indications remain limited. The purpose of this chapter is to provide the clinicians with what should be known about the non-invasive assessment of PBC and to provide specific recommendations for clinical practice., Competing Interests: Declarations of interest BOURLIÈRE Marc: Abbott, BMS, Boehringer Ingelheim, Gilead, GSK, Idenix, Intercept, Janssen, Merck, Novartis, Roche, Vertex BUREAU Christophe: AbbVie, Gilead, Gore CORPECHOT Christophe: Arrow Génériques, Cymabay, Genkyotex, Intercept, Siemens Healthineers, Biotest, Abbvie, Gilead, GSK DE LÉDINGHEN Victor: AbbVie, Alfasigma, BMS, Diafir, Echosens, Gilead, Indivior, Intercept, Medac, Myr Pharma, Pfizer, Promethera, Spimaco, Supersonic Imagine DECRAECKER Marie: No conflict of interest GANNE-CARRIÉ Nathalie: Bayer, Gilead, Ipsen, Roche, Shionogi HANSLIK Bertrand: AbbVie, Echosens, Gilead, Intercept, MSD HEURGUE Alexandra: No conflict of interest POTIER Pascal: No conflict of interest TANNE Florence: AbbVie, Bayer, Gilead, Ipsen, Mayoli, (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: The aim of this study was to identify predictive criteria of improvement after endoscopic treatment (ET) for severe strictures of extrahepatic bile ducts in patients with primary sclerosing cholangitis (PSC)., Methods: PSC patients who had at least one ET for severe stricture were included. Features of magnetic resonance cholangiography (MRC), performed before ET, were evaluated according to a standard model of interpretation, and a radiologic qualitative score of probability of improvement after ET was built. Score 3 (likely) was given in case of severe common bile duct (CBD) stricture with marked dilatation without severe strictures of upstream ducts, Score 1 (unlikely) was given in case of severe multiple strictures of secondary ducts without biliary dilatation and Score 2 (undeterminate) was given to an intermediate pattern. The response to ET was assessed at 2 months (T2-response) from the last ET and at 12 months (T12-response) from inclusion., Results: Thirty-one patients were included. All had severe stricture (reduction ≥ 75% of the diameter) of CBD and 50% had severe stricture of right and/or left hepatic duct (LHD) at MRC before ET. According to the qualitative score, 16 patients had Score 3, 7 had Score 1 and 9 had Score 2. T12-response was obtained in 50% of patients. In univariate analysis, short LHD strictures, bilirubin, transaminases, pruritus and Score 3 were associated with T12-response. Increased bilirubin and transaminases were independent predictive factors of T12-response (HR 24, 95% CI: 3.4-170.4, P = 0.001 and 23.8, 95% CI: 3.4-169.4, P = 0.002, respectively)., Conclusion: MRC, together with biochemical features, may contribute to identify the PSC patients who are likely to be improved after ET for severe strictures of extrahepatic bile ducts., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background & Aims: In patients with primary sclerosing cholangitis (PSC), ursodeoxycholic acid (UDCA) treatment improves serum liver tests and surrogate markers of prognosis but has no proven effect on survival. Additional therapies are obviously needed. Fibrates, PPAR agonists with anti-cholestatic properties, have a beneficial effect in primary biliary cholangitis. The aim of this study was to evaluate the safety and efficacy of fibrates in PSC patients., Methods: Retrospectively, we investigated PSC patients treated with fibrates (fenofibrate 200mg/day or bezafibrate 400mg/day) for at least 6 months in addition to UDCA, after an incomplete biochemical response (alkaline phosphatase [ALP] ≥1.5×upper limit of normal) to UDCA. Changes in biochemical parameters and clinical features were assessed., Results: Twenty patients were included (fourteen from Paris and six from Barcelona): median age 43.8 years, median liver stiffness 11kPa (≥F3). Upon treatment with fibrates (median duration of 1.56 years), liver tests significantly improved, including a reduction of ALP levels by 41% and pruritus significantly decreased. No serious adverse event attributable to fibrates occurred. Discontinuation of fibrates was followed by a clear rebound of ALP. Despite biochemical improvement, liver stiffness significantly increased., Conclusions: Combining UDCA with fibrates results in a significant biochemical improvement and pruritus decrease in PSC patients with incomplete response to UDCA. These results provide a rationale for larger and prospectively designed studies to establish the efficacy and safety of fibrates in PSC., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background and Aim: Fenofibrate is a potential novel therapy for primary biliary cirrhosis (PBC). We performed a systematic review and a meta-analysis of studies of fenofibrate in PBC., Methods: Electronic database search was performed for relevant studies. A search of abstracts presented in the main scientific meetings in the field and articles in press was also performed. Random effect model was used to pool the effect size across studies for changes in alkaline phosphatase, GGT, bilirubin and IgM levels before and after treatment and the overall rate of complete response to fenofibrate therapy., Results: Six studies with 102 patients met the inclusion criteria. All studies were case series and in all, patients who had no or incomplete response to UDCA had fenofibrate added at a dose of 100-200mg daily. Treatment duration ranged from 8-100weeks. Treatment with fenofibrate was associated with a significant decrease in alkaline phosphatase (-114IU/L, 95% CI: -152 to -76, P<0.0001); a significant decrease in GGT level (-92IU/L, 95% CI: -149 to -43; P=0.0004); significant decrease in total bilirubin (-0.11mg/dL, 95% CI: -0.18 to -0.08; P=0.0008); and a significant decrease in IgM level (-88mg/dL, 95% CI: -119 to -58; P<0.0001). The complete response rate was 69% (95% CI: 53-82%) with an odds ratio of 82.8 (95% CI: 21.6-317.2; P=0.024) while on fenofibrate., Conclusions: Fenofibrate at doses of 100-200mg daily appears to be effective adjunctive therapy in PBC patients who had no or incomplete response to UDCA. There is a critical need for larger scale randomized trials to determine its effect on liver-related morbidity and mortality (or progression towards end-stage disease)., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objective: The aim of this study was to understand better the quality of life (QOL) and illness perception in women with primary biliary cirrhosis (PBC) through a comparison with women having diabetes., Methods: One hundred and ninety-four women took part in this study: 130 with PBC, 64 with type 2 diabetes. They were administered the SF-12 to measure QOL and the Brief Illness Perception Questionnaire to assess representations of their illness. Analysis of covariance with bootstrapping was used to compare QOL and illness perception scores by controlling age and mean disease duration., Results: Physical QOL was significantly worse for women with PBC than for women with diabetes. Women with PBC felt their disease would last longer and reported more symptoms and concerns related to their disease than women with diabetes. Significant differences were also observed for causes: women with PBC mainly reported autoimmune, emotional, unknown/unlucky and medical causes whereas women with diabetes reported mostly lifestyle and hereditary causes. Marginally significant differences were observed regarding consequences on daily life, feeling of control over the disease and emotional responses, which were shown to be worse in PBC. Mental QOL, treatment control and overall understanding of the disease was similar in both groups., Conclusions: This study shows that women with PBC have a worse QOL and somewhat different illness perception than women with diabetes. Further research could help understand PBC specificities better in order to improve patient care, especially if factors such as fatigue or rarity of the disease explain these results., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background and Aims: There is evidence for an association between thrombosis in the hepatic microcirculation and liver fibrosis. The aim of this study was to evaluate the role of daily low-dose aspirin (75 or 100mg, given for prevention of hepatic artery thrombosis) in fibrosis progression to ≥ F2 fibrosis score in liver-transplant recipients with recurrent hepatitis C virus (HCV)., Methods: All HCV-positive patients who had undergone liver transplantation (LT) between 2000 and 2010 were included. Exclusion criteria were negative HCV RNA, previous LT or death within a year of LT. Liver fibrosis was assessed by histological evaluation. Data were censored at the date of the last histological evaluation before starting anti HCV therapy. Progression to fibrosis F ≥ 2 was analyzed with a multistate model with time-dependent covariables., Results: One hundred and eighty-eight patients were included. In univariate analysis, older recipient and donor age, male donor gender, activity score ≥ A2 after LT, number of steroid boluses and aspirin intake (HR: 0.75 [0.57-0.97]; P=0.03) influenced the risk of progression to fibrosis ≥ F2. In multivariate analysis, adjusted on site, older donor age, male donor gender, activity score ≥ A2 and number of steroids boluses, remained independent predictors of fibrosis progression, while younger recipient age and aspirin intake (HR: 0.65 [0.47-0.91]; P=0.01) were associated with a slower fibrosis progression., Conclusion: Low-dose aspirin treatment might be associated with a lower risk of liver fibrosis progression in patients with HCV recurrence after LT., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The dihydroxylated bile acid ursodeoxycholic acid (UDCA) has now been regarded for 20 years as the standard treatment for primary biliary cirrhosis (PBC), a chronic cholestatic immune-mediated condition marked by progressive destruction of small intrahepatic bile ducts, impaired biliary secretion, hepatocellular retention of toxic endogenous bile acids and, ultimately, the development of fibrosis leading to cirrhosis that commonly requires liver transplantation. At first sight, it seems intriguing that a bile acid could be considered for use as a therapeutic agent in a bile-acid secretion disorder. Yet, in addition to its inherently greater hydrophilic nature and competitive effect on endogenous bileacid recycling, UDCA has indeed been demonstrated to be a potent post-transcriptional secretagogue as well as a potential anti-inflammatory and anti-apoptotic agent. While the combined glucocorticoid receptor/pregnane X receptor (PXR) agonist budesonide, in combinaison with UDCA, has been shown to exert additional beneficial effects in PBC, significant progress in understanding the regulatory mechanisms involved in bile-acid homeostasis has led to the identification of nuclear [farnesoid X receptor (FXR), PXR, peroxisome proliferator-activated receptor alpha (PPARα)] and membrane (the membrane G protein-coupled bile acid receptor TGR5) receptors as critical pharmacological targets for future therapeutic approaches. Encouraging data from recent experimental and phase-II studies tend to confirm that the FXR agonist obeticholic acid and the PPARα agonists bezafibrate and fenofibrate may be used as add-on therapies in PBC patients with inadequate responses to UDCA or even as alternative first-line agents. These results could mark the beginning of a new therapeutic era for PBC., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)