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Background and aims: Autoimmune hepatitis (AIH) is a rare indication (

ContextLiver function abnormalities (LFAs) have been described in patients with Turner syndrome (TS). Although a high risk of cirrhosis has been reported, there is a need to assess the severity of liver damage in a large cohort of adult patients with TS.ObjectiveEvaluate the types of LFAs and their respective prevalence, search for their risk factors, and evaluate the severity of liver impairment by using a noninvasive fibrosis marker.MethodsThis was a monocentric retrospective cross-sectional study. Data were collected during a day hospital visit. The main outcome measures were liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase), FIB-4 score, liver ultrasound imaging, elastography, and liver biopsies, when available.Results264 patients with TS were evaluated at a mean age of 31.15 ± 11.48 years. The overall prevalence of LFAs was 42.8%. The risk factors were age, body mass index, insulin resistance, and an X isochromosome (Xq). The mean FIB-4 sore of the entire cohort was 0.67 ± 0.41. Less than 10% of patients were at risk of developing fibrosis. Cirrhosis was observed in 2/19 liver biopsies. There was no significant difference in the prevalence of LFAs between premenopausal patients with natural cycles and those receiving hormone replacement therapy (P = .063). A multivariate analysis adjusted for age showed no statistically significant correlation between hormone replacement therapy and abnormal gamma-glutamyl transferase levels (P = .12).ConclusionPatients with TS have a high prevalence of LFA. However, 10% are at high risk of developing fibrosis. The FIB-4 score is useful and should be part of the routine screening strategy. Longitudinal studies and better interactions with hepatologists should improve our knowledge of liver disease in patients with TS.

Background and aims The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region. Methods Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate. Results One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris). Conclusion We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors.

BACKGROUND: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients. OBJECTIVE: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC. METHODS: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed. RESULTS: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value. CONCLUSION: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients. ispartof: Gastroenterology vol:163 issue:6 pages:1630-1642.e3 ispartof: location:United States status: published

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that, if left untreated or insufficiently treated, inexorably progresses toward cirrhosis and its potentially fatal complications. Alongside with the biochemical response to ursodeoxycholic acid therapy, advanced liver fibrosis and portal hypertension (PH) were shown to be major prognostic determinants in PBC. Therefore, one of the goals of noninvasive PBC evaluation should be to early diagnose compensated advanced disease and/or clinically significant PH. In this article, the main methods of noninvasive assessment of liver fibrosis and PH in PBC, and their clinical relevance, will be reviewed.

A beneficial effect of bezafibrate (BZF) on symptoms and biochemical features of primary biliary cholangitis (PBC) has been reported in patients with an incomplete response to ursodeoxycholic acid (UDCA), but long-term effects on survival remain unknown. In Japan, BZF has been used as a de facto second-line therapy for PBC since 2000. Herein, we compared the survival rates between patients treated with and those without BZF in a large nationwide Japanese PBC cohort.All consecutively registered patients of this cohort who started UDCA therapy from 2000 onwards and had a follow-up ≥1 year were included. Association between BZF exposure and mortality or need for liver transplantation (LT) was assessed using time-dependent, multivariable-and propensity score-adjusted Cox proportional hazards models. Clinical benefit was quantified using the number needed to treat (NNT).Of 3,908 eligible patients, 3,162 (81%) received UDCA only and 746 (19%) UDCA and BZF over 17,360 and 3,932 patient-years, respectively. During follow-up, 183 deaths (89 liver-related) and 21 LT were registered. Exposure to combination therapy was associated with a significant decrease in all-cause and liver-related mortality or need for LT (adjusted hazard ratios: 0.3253, 95% CI 0.1936-0.5466 and 0.2748, 95% CI 0.1336-0.5655, respectively; p0.001 for both). This association was consistent across various risk groups at baseline. The NNTs with combination therapy to prevent 1 additional death or LT over 5, 10, and 15 years were 29 (95% CI 22-46), 14 (10-22), and 8 (6-15), respectively.In a large retrospective cohort study of treatment effects in patients with PBC, the addition of BZF to UDCA was associated with improved prognosis.The long-term efficacy of bezafibrate (BZF) on liver transplantation (LT) - free survival in patients with PBC and an incomplete response to ursodeoxycholic acid (UDCA) remains to be determined. In this Japanese nationwide retrospective cohort study, the use of UDCA-BZF combination therapy, compared to UDCA alone, was associated with a lower risk of all-cause and liver-related mortality or need for LT. These results indicate that BZF is so far the only drug in PBC to have demonstrated efficacy in improving symptoms, biochemical markers, and long-term outcomes.

Liver transplantation (LT) is the treatment of end-stage non-alcoholic liver disease (NAFLD), that is decompensated cirrhosis and/or complicated by hepatocellular carcinoma (HCC). Few data on long-term outcome are available. The aim of this study was to evaluate overall patient and graft survivals and associated predictive factors.This retrospective multicentre study included adult transplant patients for NAFLD cirrhosis between 2000 and 2019 in participating French-speaking centres.A total of 361 patients (69.8% of male) were included in 20 centres. The median age at LT was 62.3 years [57.4-65.9] and the median MELD score was 13.9 [9.1-21.3]; 51.8% of patients had HCC on liver explant. Between 2004 and 2018, the number of LT for NAFLD cirrhosis increased by 720%. A quarter of the patients had cardiovascular history before LT. Median follow-up after LT was 39.1 months [15.8-72.3]. Patient survival at 1, 5 and 10 years after LT was 89.3%, 79.8% and 68.1% respectively. The main causes of death were sepsis (37.5%), malignancies (29.2%) and cardiovascular events (22.2%). In multivariate analysis, three risk factors for overall mortality after LT were recipient pre-LT BMI 32 kg/mSurvival after LT for NAFLD cirrhosis is good at 5 years. Donor and recipient age, and cardiovascular history, are major prognostic factors to consider.

Treatment of primary biliary cholangitis (PBC) can improve the GLOBE score. We aimed to assess the association between changes in the GLOBE score (ΔGLOBE) and liver transplantation (LT)-free survival in patients with PBC who were treated with ursodeoxycholic acid (UDCA).Among UDCA-treated patients within the Global PBC cohort, the association between ΔGLOBE (ΔGLOBE0-1: during the first year of UDCA, ΔGLOBE1-2: during the second year) and the risk of LT or death was assessed through Cox regression analyses.Overall, 3,775 UDCA-treated patients were included; 3,424 (90.7%) were female, the median age was 54.0 (interquartile range [IQR] 45.9-62.4) years, and the median baseline GLOBE score was 0.25 (IQR -0.47 to 0.96). During a median follow-up of 7.2 (IQR 3.7-11.5) years, 730 patients reached the combined end point of LT or death. The median ΔGLOBE0-1 was -0.27 (IQR -0.56 to 0.02). Cox regression analyses, adjusted for pretreatment GLOBE score and ΔGLOBE0-12, showed that ΔGLOBE was associated with LT or death (adjusted hazard ratio 2.28, 95% confidence interval 1.81-2.87, P0.001). The interaction between baseline GLOBE score and ΔGLOBE0-1 was not statistically significant (P = 0.296). The ΔGLOBE1-2 was associated with LT or death (adjusted hazard ratio 2.19, 95% confidence interval 1.67-2.86, P0.001), independently from the baseline GLOBE score and the change in GLOBE score during the first year of UDCA.UDCA-induced changes in the GLOBE score were significantly associated with LT-free survival in patients with PBC. While the relative risk reduction of LT or death was stable, the absolute risk reduction was heavily dependent on the baseline prognosis of the patient.

Background & Aims: Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT. Methods: We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983–2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10–15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models. Results: While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28–0.61; p

INTRODUCTION: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN. DISCUSSION: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.

PRIMARY BILIARY CHOLANGITIS Primary biliary cholangitis (formally primary biliary cirrhosis, PBC) is the most common chronic cholestatic liver disease in humans. It is a presumed autoimmune liver disease, characterized by inflammation and progressive destruction of small bile ducts. Without treatment, PBC progresses towards liver fibrosis and, ultimately, cirrhosis. Women older than 40 are more likely affected. Pruritus and tiredness are the most common symptoms but they are frequently lacking. Diagnosis is made by the association of chronic biochemical features of cholestasis (parallel increase in ALP and GGT) and presence of specific auto-antibodies (particularly M2 anti-mitochondrial antibodies). Ursodeoxycholic acid (UDCA), which is the standard of care treatment for PBC, has dramatically improved the prognosis of the disease. However, 30 % to 40 % of patients have an inadequate biochemical response to UDCA and continue to be at high-risk of complications. In this situation, second-line treatments, including obeticholic acid or fibrates, should be considered in association with UDCA.CHOLANGITE BILIAIRE PRIMITIVE La cholangite biliaire primitive (ou anciennement cirrhose biliaire primitive, CBP) est la maladie cholestatique chronique la plus fréquente. Il s’agit d’une affection présumée auto-immune caractérisée par une inflammation et une destruction progressive des petits canaux biliaires, aboutissant, en l’absence de traitement, à une fibrose hépatique puis à une cirrhose. Elle atteint majoritairement les femmes (90 % des cas) de plus de 40 ans. Les signes cliniques révélateurs (prurit et asthénie) sont inconstants et peu spécifiques. Le diagnostic repose sur l’association d’une cholestase biologique (élévation concomitante des PAL et de la GGT) chronique et la présence d’auto-anticorps spécifiques (en particulier anti-mitochondrie de type 2). Le traitement de référence est l’acide ursodésoxycholique (AUDC) qui a fortement amélioré le pronostic de la CBP. Dans 30 à 40 % des cas, la réponse biologique à l’AUDC est insuffisante et des traitements complémentaires sont nécessaires, parmi lesquels figurent actuellement l’acide obéticholique et les fibrates.

Background & Aims: Machine learning (ML) provides new approaches for prognostication through the identification of novel subgroups of patients. We explored whether ML could support disease sub-phenotyping and risk stratification in primary biliary cholangitis (PBC). Methods: ML was applied to an international dataset of PBC patients. The dataset was split into a derivation cohort (training set) and a validation cohort (validation set), and key clinical features were analysed. The outcome was a composite of liver-related death or liver transplantation. ML and standard survival analysis were performed. Results: The training set was composed of 11,819 subjects, while the validation set was composed of 1,069 subjects. ML identified four clusters of patients characterized by different phenotypes and long-term prognosis. Cluster 1 (n = 3566) included patients with excellent prognosis, whereas Cluster 2 (n = 3966) consisted of individuals at worse prognosis differing from Cluster 1 only for albumin levels around the limit of normal. Cluster 3 (n = 2379) included young patients with florid cholestasis and Cluster 4 (n = 1908) comprised advanced cases. Further sub-analyses on the dynamics of albumin within the normal range revealed that ursodeoxycholic acid-induced increase of albumin >1.2 x lower limit of normal (LLN) is associated with improved transplant-free survival. Conclusions: Unsupervised ML identified four novel groups of PBC patients with different phenotypes and prognosis and highlighted subtle variations of albumin within the normal range. Therapy-induced increase of albumin >1.2 x LLN should be considered a treatment goal.

International audience; Non-invasive diagnosis and follow-up of primary biliary cholangitis Summary Primary biliary cholangitis (PBC) is a chronic inflammatory disease of the intrahepatic 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.

Background and aims The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders. Methods The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing. Results Most patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive-induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population. Conclusions This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.

BACKGROUND & AIMS: The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC. METHODS: This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW). RESULTS: In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1-12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1-81.2) among UDCA-treated patients and 60.7% (95% CI 58.2-63.4) among untreated patients (p

New treatments for primary biliary cholangitis (PBC) are progressively emerging, including first and second generations of farnesoid X receptor and peroxisome proliferator-activated receptors agonists. Even though ursodeoxycholic acid monotherapy remains the standard of care treatment for PBC, these additional therapeutic options, already or soon to be available, lead us to revise our priorities and strategies with respect to future clinical trials. The present article is a personal view of where we currently stand in this field and where and how we should be going to achieve new progress.

Ursodeoxycholic acid (UDCA) is recognized worldwide as the standard of care of primary biliary cholangitis (PBC). Obeticholic acid and fibrates have recently shown the potential to further improve the biochemical markers of PBC. The purpose of this review is to discuss more specifically the role of fibrates in PBC. The BEZURSO trial (Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cholangitis) is the first ever placebo-controlled trial of a fibrate in PBC. In this 24-month study, second-line use of bezafibrate in addition to continued UDCA resulted in a rate of complete biochemical response significantly higher than that achieved with placebo and UDCA. This effect was associated with a parallel improvement in symptoms and surrogate markers of fibrosis. Studies aiming to determine the effect of bezafibrate on long-term outcomes are still needed. Bezafibrate (probably fibrates in general) should be considered as a second-line therapy of PBC in patients with incomplete response to or intolerance of UDCA.

Background & Aims Low-phospholipid-associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, is still poorly understood. We report the results of the largest-ever case-control study of patients with LPAC syndrome aiming to assess the prevalence, clinical features, and comorbidities of the disease. Methods We included all LPAC cases diagnosed between 2001 and 2016 in 11 French centres. Controls consisted of all patients who underwent a cholecystectomy for common gallstone disease in a single non-academic centre over 1 year. A logistic regression analysis was used to identify the clinical features associated with LPAC syndrome across several patient strata with increasing levels of diagnostic confidence. The ratio between the incident cases of LPAC syndrome and the total number of cholecystectomies for gallstones was used to assess the relative prevalence of the disease. Results In this study, 308 cases and 206 controls were included. LPAC syndrome accounted for 0.5–1.9% of all patients admitted with symptomatic gallstone disease. Age at first symptoms, Graphical abstract, Highlights • Low-phospholipid-associated cholelithiasis (LPAC) syndrome affects approximately 1% of adults with symptomatic cholelithiasis. • Normal weight, common bile duct stones, and lack of cholecystitis are clinical features significantly associated with this syndrome. • ABCB4 variants in patients with LPAC may be associated with an increased personal or family risk of hepato-biliary cancer.

Background: Obeticholic acid (OCA) and fibrates are second-line therapies for patients with primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA). Aim: To know whether OCA and fibrates, administered together in combination with UDCA, have additive beneficial effects in patients with difficult-to-treat PBC. Methods: PBC patients treated for ≥3months 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. Results: 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 11months (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. Conclusions: Triple therapy with UDCA, OCA and fibrates is able to normalise biochemical liver tests and improve pruritus in patients with difficult-to-treat PBC.

International audience; GBCA gadolinium-based contrast agent MR magnetic resonance MRC magnetic resonance cholangiography PSC primary sclerosing cholangitis VCTE vibration controlled transient elastography Dear editor, We read with interest the review written by Mahzar and Russo about non-invasive prognostic tests for primary sclerosing cholangitis (PSC) 1. Although rare, PSC is a serious disease, associated with potentially lethal complications, notably cirrhosis and cholangiocarcinoma 2. Liver transplantation is the only curative treatment for PSC and median transplant-free survival is approximately 12-21 years after diagnosis 3. Identification of prognostic factors is essential for tailoring the follow-up strategies and testing new therapeutic modalities in homogeneous groups of PSC patients. As detailed in this review, over the last twenty years, different teams across the world, including ours, have identified several noninvasive prognostic tests for PSC patients 1. First, our team demonstrated in a large retrospective study that liver stiffness measured by vibration-controlled transient elastography (VCTE) was an independent predictive marker of survival in PSC patients 4. Next, we built 2 magnetic resonance (MR) risk scores (with and without gadolinium-based contrast agent (GBCA) administration) 5 , called Anali scores, and showed that they were able to predict adverse outcome-free survival (defined by survival without liver transplantation or cirrhosis

BACKGROUND & AIMS: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC). METHODS: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America. We obtained measurements of serum GGT at baseline and time points after treatment. We used Cox model hazard ratios to evaluate the association between GGT and clinical outcomes, including liver transplantation and liver-related death. RESULTS: Of the 2129 patients included in our analysis, 281 (13%) had a liver-related clinical endpoint. Mean age at diagnosis was 53 years and 91% of patients were female patients. We found a correlation between serum levels of GGT and alkaline phosphatase (ALP) (r = 0.71). Based on data collected at baseline and yearly for up to 5 years, higher serum levels of GGT were associated with lower hazard for transplant-free survival. Serum level of GGT at 12 months after treatment higher than 3.2-fold the upper limit of normal (ULN) identified patients who required liver transplantation or with liver-related death at 10 years with an area under the receiver operating characteristic curve of 0.70. The risk of liver transplantation or liver-related death in patients with serum level of GGT above 3.2-fold the ULN, despite level of ALP lower than 1.5-fold the ULN, was higher compared to patients with level of GGT lower than 3.2-fold the ULN and level of ALP lower than 1.5-fold the ULN (P < .05). Including information on level of GGT increased the prognostic value of the Globe score. CONCLUSIONS: Serum level of GGT can be used to identify patients with PBC at risk for liver transplantation or death, and increase the prognostic value of ALP measurement. Our findings support the use of GGT as primary clinical endpoint in clinical trials. In patients with low serum level of ALP, a high level of GGT identifies those who might require treatment of metabolic disorders or PBC treatment escalation. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:19 issue:8 pages:1688-+ ispartof: location:United States status: published

Low phospholipid-associated cholelithiasis is a rare genetic disorder, characterized by the followings: (1) Biliary symptoms with onset before the age of 40; (2) Recurrence of symptoms after cholecystectomy; (3) Intrahepatic cholelithiasis or intrahepatic hyperechogenic foci; (4) History of intrahepatic lithiasis in first-degree relatives. The genetic defect consists into a mutation of ABCB4 gene which encodes for multidrug resistance protein 3. As consequence of the altered gene product a reduced concentration of phospholipids is present into bile, leading to an impaired cholesterol solubilization. ABCB4 mutations have been described in up to 50% of cases. Ursodeoxycholic acid is the long-term treatment; cholecystectomy is indicated in the case of symptomatic gallstones. Hepato-biliary malignancy is a very rare event. Patients with end-stage liver disease may be candidates for liver transplantation.

BACKGROUND AND AIMS To assess the characteristics, care, treatment response, and outcomes of primary biliary cholangitis (PBC) patients recently followed-up by hepato-gastroenterologists in various French and Belgian healthcare settings. METHODS This retrospective cohort study included patients with PBC who recently visited 79 hepato-gastroenterologists in France and Belgium. Data were collected at the time of diagnosis and at last visit and were compared according to biochemical response (BR) to ursodeoxycholic acid (UDCA) (BR), using Paris I-II criteria, and clinical outcomes. RESULTS A total of 436 patients (mean age at diagnosis 57 years, 88% females, median follow-up 5.2 years) were included. Liver biopsy, transient elastography, or none of these two procedures were performed at baseline in 216 (50%), 194 (45%), and 107 (25%) patients, respectively. Late-stage disease (histological stage III or IV, or transient elastography ≥9.6 kPa, or bilirubin >17 µM and albumin

Primary biliary cholangitis and primary sclerosing cholangitis (PSC) are the two most frequent chronic cholestatic liver diseases in adults. These cholangiopathies are characterized by progressive bile duct destruction, chronic cholestasis, and development of liver fibrosis and cirrhosis. In both the diseases, severe fibrosis and cirrhosis are major determinants of prognosis. The purpose of this chapter is to provide clinicians with a brief overview of what should be known about utility and limitation of elastography-based assessment of both fibrosis and prognosis in PBC and PSC. In brief summary, elastography-based techniques to measure liver stiffness show high performance for the assessment of F3 and F4 fibrosis and prediction of long-term outcomes for both PBC and PSC. In addition, elastography performs better than serum markers. For transient elastography and both diseases, cut-off values for F3 fibrosis and F4 cirrhosis can reasonably be considered as >10 kPa and >15 kPa, respectively, with AUROCs of higher than 0.85 and 0.95, respectively. These techniques should therefore be considered in clinical practice to assess the severity of the disease and its progression. They may be considered as well for risk stratification and definition of surrogate endpoints in clinical trials.

Primary biliary cholangitis (PBC) is an immune-mediated chronic liver disease characterized by biliary epithelial injury, cholestasis, and progressive fibrosis that can lead to cirrhosis and requirement for liver transplantation. All patients with PBC should receive initial treatment with ursodeoxycholic acid (UDCA), and odds for response are based on characteristics at baseline. It is important to have clear definitions of patients at risk for a poor response to therapy, of biochemical markers of an incomplete response, and standardized management. Patients typically are assessed after 12 months of treatment with UDCA for biochemical markers of response. However, evaluation at 6 months has been proposed for patients with more severe disease or symptoms (such as pruritus or fatigue). Markers of response to therapy include reduced serum levels of alkaline phosphatase and bilirubin (Paris-2, Toronto, GLOBE, and so forth); patients with high levels of total and conjugated bilirubin or levels of alkaline phosphatase more than 1.5-fold the upper limit of normal should be considered for second-line therapy. Patients with adequate biochemical responses can continue UDCA monotherapy. Incomplete responders should be considered for second-line therapies with obeticholic acid (licensed) or fibrates (unlicensed) in addition to continued treatment with UDCA. Patients with PBC should be followed up for life.