Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

BACKGROUND AND AIMS: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. APPROACH AND RESULTS: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. CONCLUSIONS: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Dynamics of liver stiffness measurement and clinical course of primary biliary cholangitis.

BACKGROUND & AIMS: In primary biliary cholangitis (PBC), static liver stiffness measurement (LSM) has proven prognostic value. However, the added prognostic value of LSM time course in this disease remains uncertain. METHODS: We conducted an international retrospective cohort study among PBC patients treated with ursodeoxycholic acid (UDCA) and followed by vibration-controlled transient elastography (VCTE) between 2003 and 2022. Using joint modeling, the association of LSM trajectory and the incidence of serious clinical events (SCE), defined as cirrhosis complications, liver transplantation (LT) or death, was quantified using the hazard ratio (HR) and its confidence interval (CI). RESULTS: A total of 6,362 LSMs were performed in 3,078 patients (2,007 on UDCA alone; 13% with cirrhosis), in whom 316 SCE occurred over 14,445 person-years (median follow-up, 4.2 years; incidence rate, 21.9 per 1,000 person-years). LSM progressed in 59% of patients (mean 0.39 kPa/year). After adjusting for prognostic factors at baseline, including LSM, any relative change in LSM was associated with a significant variation in SCE risk (p<0.001). For example, the adjusted HRs (95% CI) associated with a 20% annual variation in LSM were 2.13 (1.89 - 2.45) for the increase and 0.40 (0.33 - 0.46) for the decrease. The association between LSM trajectory and SCE risk persisted regardless of treatment response or duration, when patients with cirrhosis were excluded, and when only death or LT was considered. CONCLUSIONS: Tracking longitudinal changes in LSM using VCTE provides valuable insights into PBC prognosis, offering a robust predictive measure for the risk of SCE. LSM could be used as a clinically relevant surrogate endpoint in PBC clinical trials.

Machine Learning Identifies Key Proteins in Primary Sclerosing Cholangitis Progression and Links High CCL24 to Cirrhosis.

Primary sclerosing cholangitis (PSC) is a rare, progressive disease, characterized by inflammation and fibrosis of the bile ducts, lacking reliable prognostic biomarkers for disease activity. Machine learning applied to broad proteomic profiling of sera allowed for the discovery of markers of disease presence, severity, and cirrhosis and the exploration of the involvement of CCL24, a chemokine with fibro-inflammatory activity. Sera from 30 healthy controls and 45 PSC patients were profiled with proximity extension assay, quantifying the expression of 2870 proteins, and used to train an elastic net model. Proteins that contributed most to the model were tested for correlation to enhanced liver fibrosis (ELF) score and used to perform pathway analysis. Statistical modeling for the presence of cirrhosis was performed with principal component analysis (PCA), and receiver operating characteristics (ROC) curves were used to assess the useability of potential biomarkers. The model successfully predicted the presence of PSC, where the top-ranked proteins were associated with cell adhesion, immune response, and inflammation, and each had an area under receiver operator characteristic (AUROC) curve greater than 0.9 for disease presence and greater than 0.8 for ELF score. Pathway analysis showed enrichment for functions associated with PSC, overlapping with pathways enriched in patients with high levels of CCL24. Patients with cirrhosis showed higher levels of CCL24. This data-driven approach to characterize PSC and its severity highlights potential serum protein biomarkers and the importance of CCL24 in the disease, implying its therapeutic potential in PSC.

Histological evaluation in biliary diseases.

PURPOSE OF REVIEW: This review focuses on recent developments of histopathology in the most common biliary disorders affecting adults. The reader is referred to other sources for the specialized topics on paediatric populations and post liver transplantation. RECENT FINDINGS: Fibrosis stage at diagnosis is an independent predictor of liver transplant-free survival in patients with primary biliary cholangitis. Immunohistochemistry might have an important role in predicting response to treatment. New histological scoring systems with excellent correlation with long-term clinical outcomes are being developed in primary sclerosing cholangitis (PSC). Quantification of fibrosis with collagen proportionate area can improve risk stratification and could be particularly useful to assess treatment response in PSC.Gene sequencing on cytology and intrabiliary biopsy may improve risk stratification for cholangiocarcinoma. Genetic variants of ATP8B1, ABCB11 and ABCB4 are relatively common in adults with cholestatic liver disease. New causes of cholestatic liver injury have recently been described. SUMMARY: Histology is often not necessary for the diagnosis of biliary disease, but can provide important information that may assist the clinician in patients' management. Histopathology remains crucial to confirm a diagnosis of cholangiocarcinoma, and to identify the pattern of biliary injury in immune-mediated cholangiopathies and rarer pathological entities.

Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.

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 <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79-0.87) and 0.92 (0.89-0.95), respectively. Between 5 and 30 kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8 kPa and 15 kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM. CONCLUSIONS: LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials.

Comparison of point-shear wave elastography (ElastPQ) and transient elastography (FibroScan) for liver fibrosis staging in patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: ElastPQ is a point shear wave elastography technique used to non-invasively assess liver fibrosis. We compared liver stiffness measurements (LSM) by ElastPQ and fibroscan transient elastography (F-TE) in a cohort of patients with non-alcoholic fatty liver disease (NAFLD). We further evaluated the performance of ElastPQ in a subgroup of patients with available liver histology. MATERIALS AND METHODS: We included patients with NAFLD who presented in a dedicated multidisciplinary clinic. Anthropometric parameters, blood tests and elastography measurements were obtained using F-TE and ElastPQ as part of routine clinical care. RESULTS: We enrolled 671 patients with NAFLD, mean age 55.8 ± 13 years, body mass index (BMI) 31.5 ± 5.7 kg/m2 , 56.6% males, 41% diabetes, 53.7% hypertension, 68% dyslipidaemia. ElastPQ showed an excellent correlation with F-TE (Spearman's r = 0.80, p < .001), which was better for mild/moderate stages of fibrosis. Independent predictors of a >2 kPa discrepancy between the two techniques were a larger waist circumference and F-TE ≥10 kPa. In the subgroup of 159 patients with available histology, ElastPQ showed similar diagnostic accuracy with F-TE in staging liver fibrosis (ElastPQ area under the curves 0.84, 0.83, 0.86 and 0.95, for F ≥ 1, F ≥ 2, F ≥ 3 and F = 4 respectively). Optimal cut-off values of ElastPQ for individual fibrosis stages were lower than those of F-TE. CONCLUSIONS: ElastPQ shows an excellent correlation with F-TE in patients with NAFLD, which was better for lower LSM. The optimal cut-off values of ElastPQ are lower than those of F-TE for individual stages of fibrosis. ElastPQ has similar diagnostic accuracy to F-TE for all stages of fibrosis.

Cirrhotic Patients with Bacterial Infection and Negative Cultures Have a More Advanced Disease and an Increased Short-Term Mortality Rate.

BACKGROUND: The negative clinical impact of bacterial infections (BI) in patients with cirrhosis is well documented. In cirrhotic patients, failure to isolate the pathogen is a frequent event, occurring in 30-40% of cases. AIM: The aim of this study was to compare the clinical characteristics, early (30-day) and short-term (90-day) mortality rates, in a cohort of cirrhotic patients with BI, between those with positive (C-pos) and those with negative (C-neg) microbiological cultures. METHODS: We retrospectively enrolled 279 consecutive hospitalized cirrhotic patients with BI. Survival and predictors of 30-day and 90-day mortality were assessed by Kaplan-Meier curves and logistic regression analysis, respectively. RESULTS: Cultures tested negative in 108/279 (38.7%) patients. C-neg patients were more frequently males (p = 0.035), had higher Child-Pugh-Turcotte (CPT; p = 0.007) and model for end-stage liver disease-sodium (MELD-Na; p = 0.043) scores, and had more frequently decompensated liver disease (p = 0.04). Mortality rate was higher in C-neg than in C-pos patients, both at 30 days (22.2% versus 11.7%, p = 0.024) and 90 days (46.3% versus 33.3%, p = 0.030). MELD-Na score and non-selective beta-blockers (NSBBs) were independent risk factors for 30-day and 90-day mortality. In particular, the use of NSBBs was independently associated with a lower 30-day and 90-day mortality risk (OR 0.41, CI95% 0.17-0.94, p = 0.040; and OR 0.43, CI95% 0.25-0.75, p = 0.003, respectively). CONCLUSIONS: Cirrhotic patients with BI and negative microbiological cultures have significantly higher mortality compared to those with positive cultures. Early mortality and short-term mortality are mainly influenced by the underlying severity of liver disease. In this contest, therapy with NSBBs has a positive impact on short-term survival.

Collagen proportionate area correlates with histological stage and predicts clinical events in primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease in need of accurate biomarkers for stratification and as surrogates for clinical endpoints in trials. Quantitative liver fibrosis assessment by collagen proportionate area (CPA) measurement has been demonstrated to correlate with clinical outcomes in chronic hepatitis C, alcohol-related and non-alcoholic fatty liver disease. We aimed to investigate the ability of CPA to quantify liver fibrosis and predict clinical events in PSC. METHODS: Biopsies from 101 PSC patients from two European centres were retrospectively assessed by two expert pathologists in tandem, using grading (Ishak and Nakanuma) and staging (Ishak, Nakanuma, Ludwig) systems recently validated to predict clinical events in PSC. CPA was determined by image analysis of picro-Sirius red-stained sections following a standard protocol. We assessed the correlations between CPA, staging and grading and their associations with three outcomes: (1) time to PSC-related death, liver transplant or primary liver cancer; (2) liver transplant-free survival; (3) occurrence of cirrhosis-related clinical manifestations. RESULTS: CPA correlated strongly with histological stage determined by each scoring system (P < .001) and was significantly associated with the three endpoints. Median time to endpoint-1, endpoint-2 and endpoint-3 was shorter in patients with higher CPA, on Kaplan-Meier analyses (P = .011, P = .034 and P = .001, respectively). CONCLUSION: Quantitative fibrosis assessment by CPA has utility in PSC. It correlates with established histological staging systems and predicts clinical events. CPA may be a useful tool for staging fibrosis and for risk stratification in PSC and should be evaluated further within prospective clinical trials.

Establishing Reliability Criteria for Liver ElastPQ Shear Wave Elastography (ElastPQ-SWE): Comparison Between 10, 5 and 3 Measurements.

PURPOSE: ElastPQ is a new elastography technique for non-invasive liver fibrosis staging. However, it does not have validated reliability criteria. We tested the reliability of a different number of measurements in patients with chronic liver disease and explored whether the application of quality criteria improves the diagnostic performance. MATERIALS AND METHODS: All patients underwent liver stiffness assessment (LSM) with ElastPQ and Fibroscan (F-TE). The mean, median, standard deviation (SD) and interquartile range (IQR) of 10, 5 and 3 measurements were retrospectively collected for each patient and compared to each other. Liver histology was available in a subset of patients. RESULTS: Overall, 400 patients met the inclusion criteria. Non-alcoholic fatty liver disease (NAFLD) was the most represented etiology (75 %), followed by primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). The correlation of medians was significantly better between 10 and 5 measurements than between 10 and 3. The difference of medians was significant only in the comparison between 10 and 3 measurements. The correlation between ElastPQ and F-TE was equally good for 10 and 5 measurements and significantly improved after an IQR/median ≤ 30 % was applied. The diagnostic performance of ElastPQ was better with the median value of 10 and 5 measurements and improved if LSM values were obtained with IQR/M ≤ 30 %. CONCLUSION: The median value of 5 valid LSMs suffices for the reliable estimation of liver stiffness using ElastPQ. The quality criterion of IQR/M ≤ 30 % should also be followed when using this technique.

Effects of Tumor Necrosis Factor Antagonists in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Few patients with primary sclerosing cholangitis (PSC) and inflammatory bowel diseases (IBDs) are exposed to tumor necrosis factor (TNF) antagonists because of the often mild symptoms of IBD. We assessed the effects of anti-TNF agents on liver function in patients with PSC and IBD, and their efficacy in treatment of IBD. METHODS: We performed a retrospective analysis of 141 patients with PSC and IBD receiving treatment with anti-TNF agents (infliximab or adalimumab) at 20 sites (mostly tertiary-care centers) in Europe and North America. We collected data on the serum level of alkaline phosphatase (ALP). IBD response was defined as either endoscopic response or, if no endoscopic data were available, clinical response, as determined by the treating clinician or measurements of fecal calprotectin. Remission was defined more stringently as endoscopic mucosal healing. We used linear regression analysis to identify factors associated significantly with level of ALP during anti-TNF therapy. RESULTS: Anti-TNF treatment produced a response of IBD in 48% of patients and remission of IBD in 23%. There was no difference in PSC symptom frequency before or after drug exposure. The most common reasons for anti-TNF discontinuation were primary nonresponse of IBD (17%) and side effects (18%). At 3 months, infliximab-treated patients had a median reduction in serum level of ALP of 4% (interquartile range, reduction of 25% to increase of 19%) compared with a median 15% reduction in ALP in adalimumab-treated patients (interquartile range, reduction of 29% to reduction of 4%; P = .035). Factors associated with lower ALP were normal ALP at baseline (P < .01), treatment with adalimumab (P = .090), and treatment in Europe (P = .083). CONCLUSIONS: In a retrospective analysis of 141 patients with PSC and IBD, anti-TNF agents were moderately effective and were not associated with exacerbation of PSC symptoms or specific side effects. Prospective studies are needed to investigate the association between use of adalimumab and reduced serum levels of ALP further.

Non-Invasive Prediction of High-Risk Varices in Patients with Primary Biliary Cholangitis and Primary Sclerosing Cholangitis.

BACKGROUND: Baveno-VI guidelines recommend that patients with compensated cirrhosis with liver stiffness by transient elastography (LSM-TE) <20 kPa and platelets >150,000/mm(3) do not need an esophagogastroduodenoscopy (EGD) to screen for varices, since the risk of having varices needing treatment (VNT) is <5%. It remains uncertain if this tool can be used in patients with cholestatic liver diseases (ChLDs): primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These patients may have a pre-sinusoidal component of portal hypertension that could affect the performance of this rule. In this study we evaluated the performance of Baveno-VI, expanded Baveno-VI (LSM-TE <25 kPa and platelets >110,000/mm(3)), and other criteria in predicting the absence of VNT. METHODS: This was a multicenter cross-sectional study in four referral hospitals. We retrospectively analyzed data from 227 patients with compensated advanced chronic liver disease (cACLD) due to PBC (n = 147) and PSC (n = 80) that had paired EGD and LSM-TE. We calculated false negative rate (FNR) and number of saved endoscopies for each prediction rule. RESULTS: Prevalence of VNT was 13%. Baveno-VI criteria had a 0% FNR in PBC and PSC, saving 39 and 30% of EGDs, respectively. In PBC the other LSM-TE-based criteria resulted in FNRs >5%. In PSC the expanded Baveno criteria had an adequate performance. In both conditions LSM-TE-independent criteria resulted in an acceptable FNR but saved less EGDs. CONCLUSIONS: Baveno-VI criteria can be applied in patients with cACLD due to ChLDs, which would result in saving 30-40% of EGDs. Expanded criteria in PBC would lead to FNRs >5%.

MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation.

Autoimmune liver diseases (AILDs) are chronic liver pathologies characterized by fibrosis and cirrhosis due to immune-mediated liver damage. In this study, we addressed the question whether mucosal-associated invariant T (MAIT) cells, innate-like T cells, are functionally altered in patients with AILD and whether MAIT cells can promote liver fibrosis through activation of hepatic stellate cells (HSCs). We analyzed the phenotype and function of MAIT cells from AILD patients and healthy controls by multicolor flow cytometry and investigated the interaction between human MAIT cells and primary human hepatic stellate cells (hHSCs). We show that MAIT cells are significantly decreased in peripheral blood and liver tissue of patients with AILD. Notably, MAIT cell frequency tended to decrease with increasing fibrosis stage. MAIT cells from AILD patients showed signs of exhaustion, such as impaired interferon-γ (IFN-γ) production and high ex vivo expression of the activation and exhaustion markers CD38, HLA-DR, and CTLA-4. Mechanistically, this exhausted state could be induced by repetitive stimulation of MAIT cells with the cytokines interleukin (IL)-12 and IL-18, leading to decreased IFN-γ and increased exhaustion marker expression. Of note, repetitive stimulation with IL-12 further resulted in expression of the profibrogenic cytokine IL-17A by otherwise exhausted MAIT cells. Accordingly, MAIT cells from both healthy controls and AILD patients were able to induce an activated, proinflammatory and profibrogenic phenotype in hHSCs in vitro that was partly mediated by IL-17. CONCLUSION: Our data provide evidence that MAIT cells in AILD patients have evolved towards an exhausted, profibrogenic phenotype and can contribute to the development of HSC-mediated liver fibrosis. These findings reveal a cellular and molecular pathway for fibrosis development in AILD that could be exploited for antifibrotic therapy. (Hepatology 2018;68:172-186).

Cholangiocarcinoma is associated with a raised enhanced liver fibrosis score independent of primary sclerosing cholangitis.

BACKGROUND: Cholangiocarcinoma (CCA) complicates primary sclerosing cholangitis (PSC) in 10%-20% of cases, but current tools for prediction of a CCA diagnosis are inadequate. Recently, we demonstrated the utility of the enhanced liver fibrosis (ELF) test to stratify prognosis in PSC. We observed that patients with PSC + CCA had significantly higher ELF score than those with PSC alone. In this study, we aimed to investigate further this association in a larger cohort of PSC patients with CCA compared with patients with PSC or CCA alone. MATERIALS AND METHODS: Stored sera from patients with PSC (n = 119), CCA without known chronic liver disease (n = 36) and PSC + CCA (n = 32) were tested for ELF. ELF score, gender, age, age at disease diagnosis, inflammatory bowel disease, PSC duration and severity, and CCA features were compared amongst the three cohorts. Factors related to an elevated ELF score were investigated. RESULTS: Enhanced liver fibrosis score was significantly higher in patients with CCA without underlying chronic liver disease and in patients with PSC + CCA compared to those with PSC alone (P < 0.001). In multivariate analysis, elevated ELF score was associated with the diagnosis of CCA independently of age and PSC status (P < 0.001). CONCLUSIONS: Enhanced liver fibrosis score was elevated in patients with CCA irrespective of the presence of PSC, and independently of liver disease stage. Our results indicate that the association between high ELF score and CCA may be related to the tumour's desmoplastic nature, independent of background liver fibrosis, suggesting that ELF score could be used to risk stratify for CCA in PSC.

Predictors of Re-bleeding and Mortality Among Patients with Refractory Variceal Bleeding Undergoing Salvage Transjugular Intrahepatic Portosystemic Shunt (TIPS).

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) has proven clinical efficacy as rescue therapy for cirrhotic patients with acute portal hypertensive bleeding who fail endoscopic treatment. AIMS: To investigate predictive factors of 6-week and 1-year mortality in patients undergoing salvage TIPS for refractory portal hypertensive bleeding. METHODS: A total of 144 consecutive patients were retrospectively evaluated. Three logistic regression multivariate models were estimated to individualize prognostic factors for 6-week and 12-month mortality. Log-rank test was used to evaluate survival according to Child-Pugh classes and Bureau's criteria. RESULTS: Mean age 51 ± 10 years, 66% male, mean MELD 18.5 ± 8.3, Child-Pugh A/B/C 8%/38%/54%. TIPS failure occurred in 23(16%) patients and was associated with pre-TIPS portal pressure gradient and pre-TIPS intensive care unit stay. Six-week and 12-month mortality was 36% and 42%, respectively. Pre-TIPS intensive care unit stay, MELD, and Child-Pugh score were independently associated with mortality at 6 weeks. Independent predictors of mortality at 12 months were pre-TIPS intensive care unit stay and Child-Pugh score. CONCLUSIONS: In this large cohort of patients undergoing salvage TIPS, MELD and Child-Pugh scores were predictive of short- and long-term mortality, respectively. Pre-TIPS intensive care unit stay was independently associated with TIPS failure and mortality at 6 weeks and 12 months. Salvage TIPS is futile in patients with Child-Pugh score of 14-15.

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.

Hypergammaglobulinemia is a strong predictor of disease progression, hepatocellular carcinoma, and death in patients with compensated cirrhosis.

BACKGROUND & AIMS: The outcome of compensated cirrhosis may vary considerably and cannot be predicted by routinely performed tests at present. The aim of this study was to evaluate possible predictors of clinical evolution in patients with Child-Pugh (C-P) class A cirrhosis because of untreatable causes by analysing clinical/biochemical/instrumental parameters evaluated at the time of diagnosis and during the subsequent long-lasting follow-up. METHODS: Two hundred and seventy-two consecutive C-P class A cirrhotic patients (155 males; median age 63 years, range 34-81) were analysed. All patients were followed up for a median time of 96 months (range 21-144) through periodically performed clinical/biochemical/ultrasonographic and esophagogastroduodenoscopic examinations. RESULTS: During the follow-up, 97 individuals (36%) were clinically stable, 104 (38%) developed hepatocellular carcinoma (HCC) and 71 (26%) progressed towards C-P class B/C without developing cancer. One hundred and thirty-one patients (48%) died or underwent liver transplantation. Multivariate regression analysis showed that clinical stability was significantly associated with older age (P < .001), the absence of diabetes (P = .04) and of oesophageal varices (P < .001), serum albumin >3.5 gr/dL (P = .01) and gamma globulin <1.8 gr/dL (P = .01). HCC development was significantly associated with younger age (P = .01) and serum gamma globulin values ≥1.8 gr/dL (P < .001). C-P score progression was associated with oesophageal varices (P < .001), lower serum albumin (P = .03) and cholesterol (P = .01) values, and hypergammaglobulinemia (P = .02). Death was associated with younger age (P < .001) and hypergammaglobulinemia (P = .01). Multivariate Cox regression analysis and Kaplan-Meier's survival test confirmed that gammaglobulinemia ≥1.8 g/dL was a significant predictor of death (P < .02, and P < .01 respectively). CONCLUSIONS: Hypergammaglobulinemia identifies C-P class A cirrhotic patients at higher risk of disease progression, HCC development and death.

A combination of different diagnostic tools allows identification of inactive hepatitis B virus carriers at a single time point evaluation.

BACKGROUND & AIMS: Serial evaluation of hepatitis B virus (HBV) DNA and aminotransferase values is required for identification of inactive HBV carriers (ICs). Recently, HBV surface antigen quantification (qHBsAg) and liver stiffness measurement (LSM) have been proposed as diagnostic tools in chronic HBV infection. The aim of this study was to evaluate the efficacy of HBV DNA quantification, qHBsAg and LSM in diagnosing ICs at a single time point. METHODS: Fifty-seven previously characterized ICs and 90 untreated HBsAg-/anti-HBe-positive patients [49 chronic hepatitis (CH), 41 cirrhosis] were enrolled. HBV DNA ≤2000 IU/mL, LSM ≤6.2 kPa and qHBsAg ≤1000 IU/mL were used as cut-offs to evaluate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy (DA). RESULTS: Combined HBV DNA quantification and qHBsAg correctly identified 30/57 (52.6%) ICs showing 94% sensitivity, 96% specificity, 98% PPV, 87% NPV and 95% DA. HBV DNA coupled with LSM identified 40/57 (70.2%) ICs showing 97% sensitivity, 97% specificity, 98% PPV, 95% NPV and 97% DA. Combined LSM and qHBsAg identified 33/57 (57.9%) ICs showing 95% sensitivity, 78% specificity, 89% PPV, 89% NPV and 89% DA. The evaluation of the three parameters altogether allowed the identification of 23/57 (40.3%) ICs showing 100% specificity, 96% sensitivity, 100% PPV, 92% NPV and 97% DA. Similar results were obtained when either CH or cirrhotic patients were excluded from the analysis. CONCLUSIONS: Combined evaluation of HBV DNA amount with LSM and/or qHBsAg is a highly reliable tool allowing the identification of a considerable number of HBV ICs at a single time point evaluation.

Pharmacological interventions for primary biliary cholangitis: an attempted network meta-analysis.

BACKGROUND: Primary biliary cholangitis (previously primary biliary cirrhosis) is a chronic liver disease caused by the destruction of small intra-hepatic bile ducts resulting in stasis of bile (cholestasis), liver fibrosis, and liver cirrhosis. The optimal pharmacological treatment of primary biliary cholangitis remains uncertain. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of primary biliary cholangitis through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to February 2017 to identify randomised clinical trials on pharmacological interventions for primary biliary cholangitis. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with primary biliary cholangitis. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified 74 trials including 5902 participants that met the inclusion criteria of this review. A total of 46 trials (4274 participants) provided information for one or more outcomes. All the trials were at high risk of bias in one or more domains. Overall, all the evidence was low or very low quality. The proportion of participants with symptoms varied from 19.9% to 100% in the trials that reported this information. The proportion of participants who were antimitochondrial antibody (AMA) positive ranged from 80.8% to 100% in the trials that reported this information. It appeared that most trials included participants who had not received previous treatments or included participants regardless of the previous treatments received. The follow-up in the trials ranged from 1 to 96 months.The proportion of people with mortality (maximal follow-up) was higher in the methotrexate group versus the no intervention group (OR 8.83, 95% CI 1.01 to 76.96; 60 participants; 1 trial; low quality evidence). The proportion of people with mortality (maximal follow-up) was lower in the azathioprine group versus the no intervention group (OR 0.56, 95% CI 0.32 to 0.98; 224 participants; 2 trials; I2 = 0%; low quality evidence). However, it has to be noted that a large proportion of participants (25%) was excluded from the trial that contributed most participants to this analysis and the results were not reliable. There was no evidence of a difference in any of the remaining comparisons. The proportion of people with serious adverse events was higher in the D-penicillamine versus no intervention group (OR 28.77, 95% CI 1.57 to 526.67; 52 participants; 1 trial; low quality evidence). The proportion of people with serious adverse events was higher in the obeticholic acid plus ursodeoxycholic acid (UDCA) group versus the UDCA group (OR 3.58, 95% CI 1.02 to 12.51; 216 participants; 1 trial; low quality evidence). There was no evidence of a difference in any of the remaining comparisons for serious adverse events (proportion) or serious adverse events (number of events). None of the trials reported health-related quality of life at any time point. FUNDING: nine trials had no special funding or were funded by hospital or charities; 31 trials were funded by pharmaceutical companies; and 34 trials provided no information on source of funding. AUTHORS' CONCLUSIONS: Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis. However, the follow-up periods in the trials were short and there is significant uncertainty in this issue. Further well-designed randomised clinical trials are necessary. Future randomised clinical trials ought to be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid post-randomisation dropouts or planned cross-overs; should have sufficient follow-up period (e.g. five or 10 years or more); and use clinically important outcomes such as mortality, health-related quality of life, cirrhosis, decompensated cirrhosis, and liver transplantation. Alternatively, very large groups of participants should be randomised to facilitate shorter trial duration.

Pharmacological interventions for primary sclerosing cholangitis: an attempted network meta-analysis.

BACKGROUND: Primary sclerosing cholangitis is a chronic cholestatic liver disease that is associated with both hepatobiliary and colorectal malignancies, which can result in liver cirrhosis and its complications. The optimal pharmacological treatment for patients with primary sclerosing cholangitis remains controversial. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in people with primary sclerosing cholangitis by performing a network meta-analysis, and to generate rankings of available pharmacological interventions according to their safety and efficacy. Given that it was not possible to assess whether potential effect modifiers were similar across comparisons, we did not perform the network meta-analysis but instead used standard Cochrane methods.When trials begin to provide an adequate description of potential effect modifiers, we will attempt to conduct network meta-analysis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index - Expanded, the WHO International Clinical Trials Registry Platform, and randomised controlled trials registers until February 2017 to identify randomised clinical trials (RCT) on pharmacological interventions for primary sclerosing cholangitis. SELECTION CRITERIA: We included only RCTs, irrespective of language, blinding, or publication status, in which participants were given a diagnosis of primary sclerosing cholangitis. We excluded trials that included previously liver-transplanted participants. We considered any of various pharmacological interventions compared with one other or with placebo. We excluded trials that compared different doses of various pharmacological interventions or that reported different treatment durations, except for ursodeoxycholic acid (UDCA). As UDCA is the drug most commonly investigated for primary sclerosing cholangitis, we performed a second analysis in which we stratified the dose of UDCA. DATA COLLECTION AND ANALYSIS: We calculated the odds ratio and the rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified 22 RCTs in which 1211 participants were randomised to 13 different interventions. Most were placebo-controlled trials. Trials had few restrictions apart from an established diagnosis of primary sclerosing cholangitis, evidence of cholestasis, absence of decompensated liver disease, and absence of malignancy. However, some trials included symptomatic participants only, and others included both symptomatic and asymptomatic participants. A total of 11 RCTs (706 participants) provided data for one or more outcomes. The period of follow-up ranged from three months to three years in most trials. Only three trials reported follow-up longer than three years. Investigators found no evidence of differences in important clinical benefits such as reduction in mortality at maximal follow-up and improvement in health-related quality of life. Primary outcomes Mortality: Effect estimates: colchicine versus placebo: odds ratio 0.44, 95% CI 0.04 to 5.07, participants = 84, one trial; penicillamine versus placebo: odds ratio 1.18, 95% CI 0.39 to 3.58, participants = 70, one trial; steroids versus placebo: odds ratio 3.00, 95% CI 0.10 to 90.96, participants = 11, one trial; ursodeoxycholic acid versus placebo: odds ratio 1.51, 95% CI 0.63 to 3.63, participants = 348, two trials, I2 = 0%; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Serious adverse events (proportion): Effect estimates: infliximab versus placebo: odds ratio not estimable (because of zero events in both arms), participants = 7, one trial; steroids versus placebo: odds ratio 20.00, 95% CI 0.93 to 429.90, participants = 11, one trial; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Serious adverse events (number): Effect estimates: infliximab versus placebo: rate ratio 0.80, 95% CI 0.02 to 40.44, participants = 7, one trial; penicillamine versus placebo: rate ratio 13.60, 95% CI 0.78 to 237.83, participants = 70, one trial; steroids versus placebo: rate ratio 3.32, 95% CI 0.71 to 15.62, participants = 11, one trial. Adverse events (proportion): Effect estimates: steroids versus placebo: odds ratio 20.00, 95% CI 0.93 to 429.90, participants = 11, one trial; ursodeoxycholic acid versus placebo: odds ratio 1.22, 95% CI 0.68 to 2.17, participants = 198, one trial; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Adverse events (number): Effect estimates: cyclosporin versus placebo: rate ratio 2.64, 95% CI 0.99 to 7.03, participants = 26, one trial; steroids versus placebo: rate ratio 3.32, 95% CI 0.71 to 15.62, participants = 11, one trial; ursodeoxycholic acid plus metronidazole versus ursodeoxycholic acid: rate ratio 2.36, 95% CI 0.98 to 5.71, participants = 71, one trial. Health-related quality of life: ursodeoxycholic acid versus placebo: mean difference 1.30, 95% CI -5.61 to 8.21, participants = 198, one trial (Short Form (SF)-36 General Health Scale). Secondary outcomes Studies provided no evidence of differences in clinical benefits such as a reduction in the requirement for liver transplantation or a reduction in the incidence proportion of cholangiocarcinoma. One small trial (29 participants) comparing vancomycin versus placebo reported no malignancies, no liver decompensation, and no liver transplantation in either group after a very short follow-up period of 12 weeks after treatment. None of the remaining trials clearly reported other clinical benefits such as decreased development of all malignancies, colorectal cancer, liver decompensation, time to liver decompensation, time to liver transplantation, or requirement for cholecystectomy to allow comparisons between different interventions. SOURCE OF FUNDING: Fifteen trials reported the source of funding; three were funded by parties without vested interest in results of the trial, and 12 were funded in part or in full by drug companies. AUTHORS' CONCLUSIONS: Evidence is currently insufficient to show differences in effectiveness measures such as mortality, health-related quality of life, cirrhosis, or liver transplantation between any active pharmacological intervention and no intervention. However, trials were at high risk of bias and included small numbers of participants, had short follow-up periods, and reported few clinical outcomes. An urgent need exists to identify an effective medical treatment for primary sclerosing cholangitis through well-designed RCTs with adequate follow-up that aim to identify differences in outcomes important to people with primary sclerosing cholangitis.

Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis.

UNLABELLED: There is a need to determine biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC). We evaluated the prognostic utility of the enhanced liver fibrosis (ELF) score in Norwegian PSC patients. Serum samples were available from 305 well-characterized large-duct PSC patients, 96 ulcerative colitis patients, and 100 healthy controls. The PSC patients constituted a derivation panel (recruited 1992-2006 [n = 167]; median age 41 years, 74% male) and a validation panel (recruited 2008-2012 [n = 138]; median age 40 years, 78% male). We used commercial kits to analyze serum levels of hyaluronic acid, tissue inhibitor of metalloproteinases-1, and propeptide of type III procollagen and calculated ELF scores by the previously published algorithm. Results were also validated by analysis of ELF tests using the ADVIA Centaur XP system and its commercially available reagents. We found that PSC patients stratified by ELF score tertiles exhibited significantly different transplant-free survival in both panels (P < 0.001), with higher scores associated with shorter survival, which was confirmed in the validation panel stratified by ELF test tertiles (P = 0.003). The ELF test distinguished between mild and severe disease defined by clinical outcome (transplantation or death) with an area under the curve of 0.81 (95% confidence interval [CI] 0.73-0.87) and optimal cutoff of 10.6 (sensitivity 70.2%, specificity 79.1%). In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI 1.4-2.5, and 1.5, 95% CI 1.1-2.1, respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1-1.6, and 1.6, 95% CI 1.2-2.1, respectively). The ELF test correlated with ultrasound elastography in separate assessments. CONCLUSION: The ELF score is a potent prognostic marker in PSC, independent of the Mayo risk score.