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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: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but this approach lacks applicability. Our aim was to investigate the utility of non-invasive tools for the stratification of stable long-term survivors of LT, according to their immunological risk and need for immunosuppression. METHODS: We conducted a cross-sectional multicentre study of 190 adult LT recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR). RESULTS: In this cohort, 35.8% of patients harboured clinically silent fibro-inflammatory liver lesions (13.7% had mild damage and 22.1% had moderate-to-severe damage). The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSAs), ALT, AST, and liver stiffness measurement (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically significant TCMR. Two multivariable prediction models, integrating ALT+LSM or ALT+class II DSAs, had a high discriminative capacity for classifying patients with or without alloimmune damage. The latter model performed well in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria. CONCLUSION: ALT, class II DSAs and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity who could benefit from minimisation of immunosuppression. LAY SUMMARY: A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate. ispartof: JOURNAL OF HEPATOLOGY vol:75 issue:6 pages:1409-1419 ispartof: location:Netherlands status: published

BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling. ispartof: GASTROENTEROLOGY vol:159 issue:2 pages:534-+ ispartof: location:United States status: published

Background Hepatitis B virus (HBV) immunity is recommended to optimize outcomes after solid organ transplantation (SOT). This study assessed the prevalence and predictors of HBV immunity at the time patients were placed on transplant waiting list over a period from 1997 to 2019 in a low HBV endemic region. Methods Data were obtained from the University Hospitals Leuven transplant database. Minors and patients with past/current HBV infection were excluded. From 1986, Belgian patients are covered by the universal infant vaccination; therefore, birth cohort was stratified in those born >= 1986 vs The study population consisted of 3297 SOT candidates. HBV immunity rate was superior in renal transplant candidates (55.3%), and this number was 21.5%, 15.4% and 16.8% for liver, cardiac and pulmonary transplant candidates, respectively,P < .001. Among liver transplant candidates, HBV immunity rate was 14.8% in decompensated cirrhotic patients and 27.9% in those without advanced cirrhosis (P < .001). The overall immunity rate increased from 19.3% in period 1997-2008 to 32.8% in 2009-2019,P < .001. In multivariable analyses, younger age (odds ratio (OR) 95% confidence interval (CI): 0.97-0.98,P < .001) and birth cohort >= 1986 (OR 95% CI: 1.18-2.66,P = .006) were associated with increased HBV immunity. Conclusion An increase in HBV immunity was observed over a 20-year period related to the introduction of universal infant HBV vaccination. Nevertheless, this study highlights the low overall HBV immunity at the time of listing for organ transplantation and points out the need of an increased awareness and vaccination strategy at an early disease stage. This research is part of the Limburg Clinical Research Center (LCRC) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk, province of Limburg, Flemish government, Hasselt University, Jessa Hospital and Ziekenhuis Oost-Limburg. The authors specially thank Bruno Desschans and Albert Herelixka for the management of the transplant database. Koc, OM (corresponding author), Hasselt Univ, Fac Med & Life Sci, Martelarenlaan 42, B-3500 Hasselt, Belgium. ozgur.koc@uhasselt.be

OBJECTIVE: Therapy for autoimmune hepatitis (AIH) consists of steroid induction therapy, followed by maintenance therapy with azathioprine. However, up to 20% of patients experience either insufficient response or intolerance on first-line therapy. Calcineurin inhibitors (CNIs) are frequently used when first-line therapy fails. Although a number of studies report on efficacy, less is known on the patient trajectory before switch to CNIs. Our aim was to describe the road toward CNI therapy in AIH patients. METHODS: Patients with an AIH diagnosis who used CNIs as either second- or third-line treatment were included in the study. Reason for switch to CNI was assessed as either an insufficient response or intolerance to prior therapy. Efficacy was assessed by normalization of transaminases at last moment of follow-up. RESULTS: Final analysis included 20 patients who were treated with CNIs. Ten patients were treated with tacrolimus and ten patients received cyclosporine. In patients who used CNI treatment as third-line therapy (n = 13), duration of first-line therapy was almost twice as long as duration of second-line therapy (2.58 years vs. 1.33 years; P = 0.67). Patients treated with tacrolimus had relatively high trough levels (7.6 ng/mL) and more (minor) adverse events. Fifty-five percent of patients had normalization of transaminases at last moment of follow-up. CONCLUSION: CNI treatment in AIH as second- or third-line therapy is effective in ~50% of patients. The trajectory before switch varies considerably between patients. ispartof: EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY vol:32 issue:6 pages:727-732 ispartof: location:England status: published

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.

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

ObjectiveAlpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.DesignBaseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.ResultsAmong UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.ConclusionOur study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Telemedicine gained interest in liver transplant patients but focused until now on the early post-operative period. This prospective cohort study assessed feasibility, safety, and clinical beneficial effects of a telemedicine based remote monitoring program (TRMP) for the chronic follow-up of adult liver transplant recipients. Between November 2017 and August 2019, a total of 87 of the 115 selected patients (76%) started the TRMP. Over the 2 years study period, none of the patients switched to standard follow-up: 39/87 (45%) continued to do this autonomously and 48/87 (55%) stopped to report their data personally but communicated their lab values to the nurse. The other 28/115 (11%) patients who did not accept the TRMP continued the standard follow-up. There was no difference in educational level between the three groups. Remote monitoring did not result in an increase in liver graft rejection and need of hospitalization. TRMP was associated with a higher number of tacrolimus level determinations and tacrolimus blood level concentrations could be kept lower. In conclusion, our results show that in patients with a stable clinical condition there is a high willingness to participate in TRMP and that this approach is safe. Remote monitoring allowed a stringent follow-up of tacrolimus levels. ispartof: CLINICAL TRANSPLANTATION vol:36 issue:1 ispartof: location:Denmark status: published

BackgroundThere is currently no systematic screening for hepatitis C (HCV) reinfection in people who inject drugs (PWID) after treatment in Belgium. However, in a recent meta-analysis, the overall HCV reinfection rate was 5.9/100 person-years (PY) among PWID. Accordingly, this study was undertaken to investigate the reinfection rate in former and active PWID who achieved the end of treatment response after direct-acting antiviral (DAA) treatment in Belgium.MethodsThis observational cross-sectional study recruited individuals with a history of injecting drug use who had achieved the end of treatment response to any DAA treatment between 2015 and 2020. Participants were offered a post-treatment HCV RNA test.ResultsEighty-five potential participants were eligible to participate and contacted, of whom 60 participants were enrolled in the study with a median age of 51.0 (IQR 44.3–56.0) years; it was reported that 23.3% continued to inject drugs intravenously after DAA treatment. Liver cirrhosis was present in 12.9%. The majority had genotype 1a (51.7%) or genotype 3 (15.0%) infection. We detected no reinfections in this study population. The total time patients were followed up for reinfection in the study was 78.5 PY (median 1.0 years IQR 0.4–2.0).ConclusionReinfection after successful treatment with DAA initially appears to be very low in Belgian PWID. Therefore, efforts should be made to screen individuals with persistent risk behaviors for reinfection systematically. In addition, a national HCV registry should be established to accurately define the burden of HCV infection and reinfection in Belgium and support the elimination of viral hepatitis C in Europe.Trial registrationclinicaltrials.gov NCT04251572, Registered 5 Feb 2020–Retrospectively registered,https://clinicaltrials.gov/ct2/show/NCT04251572.

BACKGROUND: There is a paucity of data on the prevalence, adequate timing, and outcome of solid organ transplantation after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and the kinetics of immunoglobulin G (IgG) antibodies in these patients. METHODS: SARS-CoV-2 antinucleocapsid (N) IgG and polymerase chain reaction via a nasopharyngeal swab were analyzed in all patients within 24 h before liver or kidney transplantation. Kinetics of IgG antibodies were analyzed and compared with an immunocompetent cohort. RESULTS: Between May 1, 2020, and March 18, 2021, 168 patients underwent liver or kidney transplantation in our center, of which 11 (6.54%) patients with a previous SARS-CoV-2 infection were identified. The median interval between SARS-CoV-2 infection and transplantation was 4.5 mo (range, 0.9-11). After a median posttransplant follow-up of 4.9 mo, 10 out of 11 patients were alive without clinical signs of viral shedding or recurrent or active infection. One patient without symptom resolution at time of transplantation died after combined liver-kidney transplantation. In 9 out of 11 patients with previously polymerase chain reaction-confirmed infection, SARS-CoV-2 anti-N and antispike (S) IgG were detectable at day of transplantation. Absolute levels of anti-N and anti-S IgG were positively correlated, declined over time in all patients, and were significantly lower compared with immunocompetent individuals. All patients remained anti-S IgG positive until the last posttransplant follow-up, whereas 3 patients became anti-N negative. CONCLUSIONS: We observed an uncomplicated course of liver or kidney transplantation after SARS-CoV-2 infection in selected patients. Although having lower absolute IgG antibody levels than immunocompetent individuals, all seroconverted patients remained anti-S IgG positive. These encouraging data need validation in larger studies. ispartof: TRANSPLANTATION vol:106 issue:4 pages:862-868 ispartof: location:United States status: published

Supplemental Digital Content is available in the text., Background. Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3–4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basiliximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). Methods. DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15–0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). Results. Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74.7%. Overall graft survival in patients remaining on PR-T for ≥30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mL/min/1.73 m2, respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had ≥1 adverse drug reaction, considered possibly related to PR-T in 6 patients. Conclusions. In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.

Background & Aims: Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD). Methods: This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3. Results: The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×106 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×106 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF. Conclusions: The treatment of patients with ACLF or AD with up to 2 doses of 1.2×106 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy. Clinical Trials Registration: EudraCT 2016-001177-32. Lay summary: Patients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

INTRODUCTION: Comparative data on scores that predict outcome in primary biliary cholangitis (PBC) are scarce. We aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score in a large international cohort of patients with PBC. METHODS: Ursodeoxycholic acid-treated patients from 7 centers participating in the GLOBAL PBC Study Group were included. The discriminatory performance of the scores was assessed with concordance statistics at yearly intervals up to 5 years. Model for End-stage Liver Disease was included for comparison. Prediction accuracy was assessed by comparing predicted survival and actual survival in Kaplan-Meier analyses. RESULTS: A total of 1,100 ursodeoxycholic acid-treated patients with PBC were included, with a mean (SD) age of 53.6 (12.0) years, of whom 1,003 (91%) were female. During a median follow-up of 7.6 (interquartile range 4.1-11.7) years, 42 patients underwent liver transplantation, and 127 patients died. At 1 year, the concordance statistic for Model for End-stage Liver Disease was 0.68 (95% confidence interval [CI] 0.64-0.72), 0.74 (95% CI 0.67-0.80) for the UK-PBC score, 0.76 (95% CI 0.72-0.81) for the MRS (1989 and 1994), and 0.80 (95% CI 0.76-0.84) for the GLOBE score. The GLOBE score showed superior discriminatory performance, but differences were not statistically different. For all scores, discriminatory performance increased in those with bilirubin >0.6 × ULN and advanced fibrosis estimated with Fibrosis-4. The predicted (median) minus observed 5-year transplant-free survival was +0.4% and +2.5% for the MRS (1989) and GLOBE score, respectively. DISCUSSION: All prognostic scores developed for PBC (GLOBE, UK-PBC, and MRS) demonstrated comparable discriminating performance for liver transplantation or death as well as good prediction accuracy.

BACKGROUND: Transfusion-transmissible infections such as hepatitis B virus (HBV) remain a major concern for the safety of blood transfusion. This cross-sectional study aimed to assess the trend of HBV prevalence and associated risk factors among a first-time donor population in a low endemic country. STUDY DESIGN AND METHODS: Between 2010 and 2018, blood samples were collected from first-time donors presented at donor collection sites of Belgian Red Cross-Flanders. They were tested for hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (anti-HBc), and HBV DNA, HIV and hepatitis virus C (HCV) antibodies and RNA, and syphilis antibodies. RESULTS: A total of 211,331 first-time blood donors (43.7% males, median age 25 years) were analyzed. HBsAg prevalence decreased from 0.06% in 2010 to 0.05% in 2018 (p = .004) and this declining trend was accompanied by an increased number of donors in the HBV vaccinated birth cohort (p

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

Objectives Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) have a major impact on mortality worldwide. Although effective treatments are available for both HBV and HCV infection

SCOPUS: ar.j, info:eu-repo/semantics/published

Three patients with a medical history of breast carcinoma and metastatic carcinomatous liver disease associated with severe portal hypertension and refractory ascites are presented. Transjugular intrahepatic portosystemic shunt creation was considered as a palliative treatment option and a valuable alternative to regular paracenteses in these patients. In 2 of the 3 patients, the refractory ascites was controlled for several months without need for paracentesis, and subsequently transjugular intrahepatic portosystemic shunt may provide valuable palliation and ascites control in patients with refractory ascites due to breast cancer-induced pseudocirrhosis. ispartof: JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY vol:29 issue:12 pages:1713-1716 ispartof: location:United States status: published

Acute graft-versus-host disease (GVHD) after liver transplant (LTx) is a rare complication with a high mortality rate. Recently, monoclonal antibody (mAb) treatment, specifically with anti-interleukin 2 receptor antibodies (IL2RAb) and anti-tumor necrosis factor-α antibodies (TNFAb), has gained increasing interest. However, evidence is mostly limited to case reports and the efficacy remains unclear. Here, we describe 5 patients with LTx-associated GVHD from our center and provide the results of our systematic literature review to evaluate the potential therapeutic benefit of IL2RAb/TNFAb treatment. Of the combined population of 155 patients (5 in our center and 150 through systematic search), 24 were given mAb (15.5%)-4 with TNFAb (2.6%) and 17 with IL2RAb (11%) ("mAb group")-and compared with patients who received other treatments (referred to as "no-mAb group"). Two-sided Fisher exact tests revealed a better survival when comparing treatment with mAb versus no-mAb (11/24 vs 27/131; P = .018), TNFAb versus no-mAb (3/4 vs 27/131; P = .034), and IL2RAb versus no-mAb (8/17 vs 27/131; P = .029). This systematic review suggests a beneficial effect of mAb treatment and a promising role for TNFAb and IL2RAb as a first-line strategy to treat LTx-associated acute GVHD. ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:18 issue:12 pages:3007-3020 ispartof: location:United States status: published

A decrease or normalization of alkaline phosphatase (ALP) and bilirubin levels in patients treated for primary biliary cholangitis (PBC) predicts a better survival. Obeticholic acid (OCA) is the approved second-line therapy if ursodeoxycholic acid (UCDA) fails, but its use may worsen pruritus. Adding bezafibrate to UCDA improved biochemical markers of cholestatic liver injury and decreased pruritus severity. Because normalization of ALP and bilirubin was only achieved in a minority of patients in these studies, we explored whether bezafibrate (off-label drug) could improve the effect of OCA (licensed drug) on cholestasis. ispartof: HEPATOLOGY vol:73 issue:6 pages:2598-2600 ispartof: location:United States status: published

Background Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients. Methods Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed. Results Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls. Conclusion Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.

Objectives: The Belgian population of people living with HIV (PLHIV) has unrestricted access to direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection, since 2017. International literature claims that half of the patients remain untreated in high-income countries with unrestricted access to DAA. This study was initiated to provide an overview of the present situation in Belgium and recommendations for HCV care in PLHIV in other regions. Methods: This was a retrospective, multicenter study of PLHIV in Belgium, from January 1, 2007 to December 31, 2018. The HCV cascade of care was examined. Results: Out of 4607 unique PLHIV, 322 (7.0%) tested positive for HCV antibody and HCV RNA positivity was seen in 289 (6.3%). Of those with a proven HCV infection, 207/289 (71.6%) initiated treatment. Of the 171 (82.6%) persons with a sustained virologic response (SVR), 16 (9.4%) subjects were reinfected. Conclusions: We present a care cascade of 4607 PLHIV in Belgium. Treatment initiation and SVR rates were high compared to other regions. Implementation of a national HCV register to track progress and yearly screening, especially in PLHIV with high-risk behavior, remains crucial. Identifying reasons for not initiating treatment is necessary to achieve elimination of HCV in PLHIV by 2030. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

Supplemental Digital Content is available in the text., Background and Methods. Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24. Results. EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, −1.0%; 95% confidence interval, −5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (−8.37 versus −13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (−12.82 versus −17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels. Conclusions. EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.

Background Obeticholic acid (OCA), a potent farnesoid X receptor agonist, is approved as second-line treatment for primary biliary cholangitis (PBC) in patients with an incomplete response or intolerance to ursodeoxycholic acid. Aims We evaluated the effect of OCA in PBC patients enrolled in the POISE trial, comparing those who did or did not achieve the POISE response criteria. Methods The phase 3, randomized, double-blind, 1-year POISE trial evaluated the efficacy and safety of OCA 5 and 10 mg vs placebo in patients with PBC; a 5-year open-label extension followed in which all patients received OCA. This analysis evaluated longer-term efficacy and safety in patients who achieved the POISE primary endpoint of alkaline phosphatase (ALP) 15% from baseline after 1 year of OCA and in patients who were incomplete responders. Results The analysis included 86 patients who achieved the POISE primary endpoint at year 1 of OCA treatment and 107 incomplete responders (mean baseline ALP, 268 vs 356 U/L, respectively; P Conclusions OCA treatment improved key biochemical markers of PBC, regardless of achieving the POISE primary endpoint after 1 year of OCA treatment. Changes in biochemical parameters over time were often similar between groups. Funding Agencies Intercept Pharmaceuticals

Severe alcoholic hepatitis is the most severe form of alcohol-related liver disease. Corticosteroids remain the first choice of treatment. However, they are only effective in a subset of patients and are associated with an increased infection risk. Furthermore, nonresponders to corticosteroids have a poor prognosis with a mortality of 70% over 6 months. As such, there is a high need for a more personalized use of corticosteroids and the development and identification of alternative therapeutic strategies. In this review, we summarize the recent and ongoing randomized controlled trials concerning the treatment of severe alcoholic hepatitis. ispartof: CURRENT OPINION IN PHARMACOLOGY vol:60 pages:91-101 ispartof: location:England status: published

The development of a polycystic liver is a characteristic of the monogenic disorders: autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic liver disease (ADPLD). Respectively two and one genes mainly cause ADPKD and ARPKD. In contrast, ADPLD is caused by at least six different genes which combined do not even explain the disease development in over half of the ADPLD population. Genetic testing is mainly performed to confirm the likelihood of developing PKD and if renal therapy is essential. However, pure ADPLD patients are frequently not genetically screened as knowledge about the genotype-phenotype correlation is currently limited. This paper will clarify the essence of genetic testing in ADPLD patients. ispartof: EUROPEAN JOURNAL OF MEDICAL GENETICS vol:64 issue:3 ispartof: location:Netherlands status: published

Background: Prophylaxis of HBV recurrence is critical after liver transplantation in HBV patients. Despite new prophylactic schemes, most European LT centres persist on a conservative approach combining hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogues (NA). Aim: This setting prompted the European Liver Intestine Transplantation Association (ELITA) to look for a consensus on the prevention of HBV recurrence. Methods: Based on a 4-round Delphi process, ELITA investigated 16 research questions and established 50 recommendations. Results: Prophylaxis should be driven according to 3 simplified risk groups: Low and high virological risk patients, with undetectable and detectable HBV DNA pre-LT, respectively, and special populations (HDV, HCC, poorly adherent patients). In low-risk patients, short-term (4weeks) combination of third-generation NA+ HBIG, or third generation NA monotherapy can be considered as prophylactic options. In high-risk patients, HBIG can be discontinued once HBV DNA undetectable. Combined therapy for 1year is advised. HBV-HCC patients should be treated according to their virological risk. In HDV/HBV patients, indefinite dual prophylaxis remains the gold standard. Full withdrawal of HBV prophylaxis following or not HBV vaccination should only be attempted in the setting of clinical trials. Organs from HBsAg+ve donors may be considered after assessment of risks, benefits, and patient consent. They should not be used if HDV is present. In poorly adherent patients, dual long-term prophylaxis is recommended. Budget impact analysis should be taken into account to drive prophylactic regimen. Conclusions: These ELITA recommendations should stimulate a more rational and homogeneous approach to HBV prophylaxis across LT programs.

Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes., info:eu-repo/semantics/published

Background and Aims Alcohol‐related liver disease is the most frequent cause of cirrhosis and a major indication for liver transplantation. Several alcohol use biomarkers have been developed in recent years and are already in use in several centers. However, in patients with liver disease their diagnostic performance might be influenced by altered biomarker formation by hepatic damage, altered excretion by kidney dysfunction and diuretics use, and altered deposition in hair and nails. We systematically reviewed studies on the diagnostic accuracy of biomarkers of alcohol use in patients with liver disease and performed a detailed study quality assessment. Methods A structured search in PubMed/Medline/Embase databases was performed for relevant studies, published until April 28, 2019. The risk of bias and applicability concerns was assessed according to the adapted quality assessment of diagnostic accuracy studies‐2 (QUADAS‐2) checklist. Results Twelve out of 6,449 studies met inclusion criteria. Urinary ethyl glucuronide and urinary ethyl sulfate showed high sensitivity (70 to 89 and 73 to 82%, respectively) and specificity (93 to 99 and 86 to 89%, respectively) for assessing any amount of alcohol use in the past days. Serum carbohydrate‐deficient transferrin showed low sensitivity but higher specificity (40 to 79 and 57 to 99%, respectively) to detect excessive alcohol use in the past weeks. Whole blood phosphatidylethanol showed high sensitivity and specificity (73 to 100 and 90 to 96%, respectively) to detect any amount of alcohol use in the previous weeks. Scalp hair ethyl glucuronide showed high sensitivity (85 to 100%) and specificity (97 to 100%) for detecting chronic excessive alcohol use in the past 3 to 6 months. Main limitations of the current evidence are the lack of an absolute gold standard to assess alcohol use, heterogeneous study populations, and the paucity of studies. Conclusions Urinary and scalp hair ethyl glucuronide are currently the most validated alcohol use biomarkers in patients with liver disease with good diagnostic accuracies. Phosphatidylethanol is a highly promising alcohol use biomarker, but so far less validated in liver patients. Alcohol use biomarkers can complement each other regarding diagnostic time window. More validation studies on alcohol use biomarkers in patients with liver disease are needed., Alcohol use biomarkers can be of great benefit, but concerns exist regarding their applicability in patients with liver disease. Arnts, Vanlerberghe et al. provide an in‐depth review of their diagnostic accuracy in liver patients. Urinary and scalp hair ethyl glucuronide are the most validated alcohol use biomarkers. The diagnostic accuracy of phoshatidylethanol is highly promising, but so far less validated in liver patients. Their review aids in the correct application and interpretation of these alcohol use biomarkers in daily practice.

International Variceal Bleeding Observational Study Group and Baveno Cooperation., [Background & Aims] Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis., [Methods] A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization., [Results] A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9)., [Conclusion] Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade., Supported by grants from the Spanish Ministry of Science and Innovation (SAF-2016-75767-R to JC.G-P, SAF 2017-86343-R awarded to A.A, Instituto de Salud Carlos III PIE 15/00027 to JC.G-P, PI17/00398 to V.H.G, PI18/01901 to R.B and PI20/01302 to A.A, and Commissioner for Universities and Research of the Generalitat de Catalunya (AGAUR SGR 2017 awarded to JC.G-P). CIBEREHD is funded by the Instituto de Salud Carlos III with grants cofinanced by the European Development Regional Fund “A way to achieve Europe” (EDRF).

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.

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

Preemptive TIPS Individual Data Metanalysis, International Variceal Bleeding Study and Baveno Cooperation Study groups., [Background & Aims] Compared with drugs plus endoscopy, placement of transjugular portosystemic shunt within 72 hours of admission to the hospital (early or preventive transjugular intrahepatic portosystemic shunt [TIPS], also called preemptive TIPS) increases the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survive for 1 year. However, the benefit of preemptive TIPS is less clear for patients with a Child-Pugh score of B and active bleeding (CP-B+AB). We performed an individual data meta-analysis to assess the efficacy of preemptive TIPS in these patients and identify factors associated with reduced survival of patients receiving preemptive TIPS., [Method] We searched publication databases for randomized controlled trials and observational studies comparing the effects of preemptive TIPS versus endoscopy plus nonselective beta-blockers in the specific population of high-risk patients with cirrhosis and acute variceal bleeding (CP-B+AB or Child-Pugh C, below 14 points), through December 31, 2019. We performed a meta-analysis of data from 7 studies (3 randomized controlled trials and 4 observational studies), comprising 1327 patients (310 received preemptive TIPS and 1017 received drugs plus endoscopy). We built adjusted models to evaluate risk using propensity score for baseline covariates. Multivariate Cox regression models were used to assess the factors associated with survival time. The primary endpoint was effects of preemptive TIPS versus drugs plus endoscopy on 1-year survival in the overall population as well as CP-B+AB and Child-Pugh C patients., [Results] Overall, preemptive TIPS significantly increased the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survived for 1 year, compared with drugs plus endoscopy (hazard ratio [HR] 0.443; 95% CI 0.323–0.607; P < .001). This effect was observed in CP-B+AB patients (HR 0.524; 95% CI 0.307–0.896; P = .018) and in patients with Child-Pugh C scores below 14 points (HR 0.374; 95% CI 0.253–0.553; P < .001). Preemptive TIPS significantly improved control of bleeding and ascites without increasing risk of hepatic encephalopathy in Child-Pugh C and CP-B+AB patients, compared with drugs plus endoscopy. Cox analysis of patients who received preemptive TIPS showed that patients could be classified into 3 categories for risk of death, based on age, serum level of creatinine, and Child-Pugh score. In each of these risk categories, preemptive TIPS increased the proportion of patients who survived for 1 year, compared with drugs plus endoscopy., [Conclusions] In a meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10 and 13 points or CP-B+AB, preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy., Juan Carlos García-Pagán received support in part through grants from the Spanish Ministry of Education and Science (SAF-2016–75767-R and PIE 15/00027) and from the “Commissioner for Universities and Research of the Generalitat de Catalunya” (AGAUR SGR 2017). CIBERehd is funded by the Instituto de Salud Carlos III. Edilmar Alvarado-Tapias and Anna Baiges are recipients of a "Río Hortega" fellowship grant from the Instituto de Salud Carlos III. The study was partially supported by a GORE grant for statistical support.

IntroductionCirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post-TIPS hepatic encephalopathy (HE) is a common (20%–54%) and often severe complication. A prophylactic strategy is lacking.Methods and analysisThe Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial, is a multicentre randomised, double blind, placebo controlled trial. Patients undergoing covered TIPS placement are prescribed either rifaximin 550 mg two times per day and lactulose 25 mL two times per day (starting dose) or placebo 550 mg two times per day and lactulose 25 mL two times per day from 72 hours before and until 3 months after TIPS placement. Primary endpoint is the development of overt HE (OHE) within 3 months (according to West Haven criteria). Secondary endpoints include 90-day mortality; development of a second episode of OHE; time to development of episode(s) of OHE; development of minimal HE; molecular changes in peripheral and portal blood samples; quality of life and cost-effectiveness. The total sample size is 238 patients and recruitment period is 3 years in six hospitals in the Netherlands and one in Belgium.Ethics and disseminationThis study protocol was approved in the Netherlands by the Medical Research Ethics Committee of the Academic Medical Centre, Amsterdam (2018-332), in Belgium by the Ethics Committee Research UZ/KU Leuven (S62577) and competent authorities. This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Study results will be submitted for publication in a peer-reviewed journal.Trial registration numbersClinicalTrials.gov (NCT04073290) and EudraCT database (2018-004323-37).

Background Screening and treatment of hepatitis C virus (HCV) infection in people who use drugs (PWUD) remains insufficient. Reducing the burden of HCV infection in PWUD requires interventions focusing on the different steps of the HCV care cascade. Methods We performed a prospective, multicenter study, evaluating the impact of an HCV care model on the HCV care cascade among PWUD attending an addiction care center in Belgium between 2015 and 2018. Interventions within the care model consisted of pre-test counseling, on-site HCV screening and case management services. A multiple logistic regression model was performed to identify the independent factors influencing the outcomes. Results During the study period, 441 PWUD were registered at the addiction care center, 90% (395/441) were contacted, 88% (349/395) were screened for HCV infection. PWUD were more likely to be screened if they had ever injected drugs (p AOR 6.411 95% CI 3.464–11.864). In 45% (157/349), the HCV antibody (Ab) test was positive, and in 27% (94/349) HCV RNA was positive. Within the Belgian reimbursement criteria (fibrosis stage ≥ F2), 44% (41/94) were treated. Specialist evaluation at the hospital was lower for PWUD receiving decentralized opioid agonist therapy (p = .005; AOR 0.430 95% CI 0.005–0.380), PWUD with unstable housing in the past 6 months before inclusion (p = .015; AOR 0.035 95% CI 0.002–0.517) or if they were recently incarcerated (p = .001; AOR 0.010 95% CI 0.001–0.164). Conclusions This HCV care model demonstrated high screening, linkage to care, and treatment initiation among PWUD in Belgium. Using the cascade of care to guide interventions is easy and necessary to monitor results. This population needs guidance, not only for screening and treatment initiation but also for the long-term follow-up since one in six had cirrhosis and could develop hepatocellular carcinoma. Further interventions are necessary to increase linkage to care and treatment initiation. Universal access to direct-acting antiviral therapy from 2019 will contribute to achieving HCV elimination in the PWUD population. Trial registration Clinical trial registration details: www.clinicaltrials.gov (NCT03106194).

Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male C57BL/6J mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8–9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p

BACKGROUND: Donor hepatectomy and liver implantation time reduce long-term graft and patient survival after liver transplantation. It is not known whether these surgical times influence early outcomes after liver transplantation. METHODS: This single-center study evaluated the effect of donor hepatectomy and implantation time on the risk of nonanastomotic biliary strictures occurring within 1 year and of early allograft dysfunction after deceased-donor solitary liver transplantation, adjusting for other donor, recipient, and surgical factors. RESULTS: Of 917 transplants performed between 1/2000 and 12/2016, 106 (11.56%) developed nonanastomotic biliary strictures and 247 (27%) developed early allograft dysfunction. Donor hepatectomy time (median 35 min, IQR: 26-46) was an independent risk factor of nonanastomotic biliary strictures (adjusted hazard ratio (HR): 1.19, 95% CI: 1.04-1.35, p=0.01). Implantation time (median 80 min, IQR: 69-95) was independently associated with early allograft dysfunction (adjusted odds ratio (OR): 1.15, 95% CI:1.07-1.23, p

BACKGROUND: The role of the microbiome in liver transplantation (LT) outcome has received a growing interest in the past decades. In contrast to bacteria, the role of endogenous viral communities, known as the virome, is poorly described. Here, we applied a viral metagenomic approach to study the dynamic evolution of circulating viruses in the plasma of LT recipients and its effect on the clinical course of patients. METHODS: Patients chronically infected with hepatitis B virus (HBV) that received a LT due to endstage liver disease were included in this study. Longitudinal plasma samples were collected pre- and post-LT. Intact viral particles were isolated and sequenced on an Illumina HiSeq 2500 platform. Short read libraries were analysed with an in-house bioinformatics pipeline. Key endpoints were the dynamics of viral families and post-LT complications. FINDINGS: The initiation of immunosuppression induced a bloom of the Anelloviridae that dominated the post-LT plasma virome. A variety of post-LT complication were observed. Nephrotoxicity was reported in 38% of the patients and was associated with a high abundance of anelloviruses. Besides nephrotoxicity, 16 (67%) patients experienced flares of viral or bacterial infections in post-transplant follow-up. These flares were recognized by an increased burden of anelloviruses (p < 0.05). Interestingly, no mortality was observed in patients infected with human pegivirus. INTERPRETATION: These findings suggest a diagnostic potential for the Anelloviridae family in post-LT complications. Furthermore, the impact of human pegivirus infection on post-transplant survival should be further investigated. FUNDING: This trial was supported by Gilead Sciences grant number BE-2017-000133. ispartof: Ebiomedicine vol:60 ispartof: location:Netherlands status: published

BACKGROUND & AIMS: Hepatocellular adenoma (HCA) is a benign liver tumour that may require resection in select cases. The aim of this study was to the assess growth of residual HCA in the remnant liver and to advise on an evidence-based management strategy. METHOD: This multicentre retrospective cohort study included all patients with HCA who underwent surgery of HCA and had residual HCA in the remnant liver. Growth was defined as an increase of >20% in transverse diameter (RECIST criteria). Data on patient and HCA characteristics, diagnostic work-up, treatment and follow-up were documented and analysed. RESULTS: A total of 134 patients were included, one male. At diagnosis, median age was 38yrs (IQR 30.0-44.0) and median BMI was 29.9 kg/m2 (IQR 24.6-33.3). After resection, median number of residual sites of HCA was 3 (IQR 2-6). Follow-up of residual HCA showed regression in 24.6%, stable HCA in 61.9% and growth of at least one lesion in 11.2%. Three patients (2.2%) developed new HCA that were not visible on imaging prior to surgery. Four patients (3%, one male) underwent an intervention as growth was progressive. No statistically significant differences in clinical characteristics were found between patients with growing residual or new HCA versus those with stable or regressing residual HCA. CONCLUSION: In patients with multiple HCA who undergo resection, growth of residual HCA is not uncommon but interventions are rarely needed as most lesions stabilize and do not show progressive growth. Surveillance is indicated when residual HCA show growth after resection, enabling intervention in case of progressive growth. ispartof: LIVER INTERNATIONAL vol:40 issue:9 pages:2272-2278 ispartof: location:United States status: published

BACKGROUND The increasing rate of liver transplantation (LT) for nonalcoholic fatty liver disease (NAFLD) raises concerns on cardiovascular morbidity and mortality after LT in these patients. METHODS We collected variables regarding the presence of metabolic risk factors, NAFLD recurrence, cardiovascular morbidity, and overall survival at time of listing and after LT of 112 patients with NAFLD and a control group of 120 patients with hepatitis C (HCV). RESULTS Metabolic syndrome and cardiovascular morbidity component rates (24.1% vs 12.5%) at the time of LT listing were higher in patients with NAFLD compared with patients with HCV (for all, P < .0390). Median follow-up after LT was 5.6 years in patients with NAFLD vs 13.5 years in patients with HCV (P = .0009). There was no difference in 6-weeks postoperative mortality (1.7% vs 2.5%) (P =1.0000). Metabolic syndrome components after LT were more frequent in patients with NAFLD than in patients with HCV (for all, P < .0008). The incidence of NAFLD 5 years after LT was higher in patients transplanted for NAFLD compared with HCV (43.5% vs 4.2%) (P < .0001). Patients with recurrent NAFLD more often had myocardial infarction compared with those without recurrence (8.3% vs 0%) (P = .0313). Five years after LT, cardiovascular morbidity was more frequent in the NAFLD group than in the HCV group (12.8% vs 9.3%) (P = .0256), whereas no difference in overall survival was observed. CONCLUSION LT for NAFLD is associated with satisfactory 5-year outcomes; however, our data underscore the need for close monitoring and aggressive management of cardiovascular risk factors in these patients.

BACKGROUND & AIMS: The direct-acting antiviral combination glecaprevir/pibrentasvir has been approved by the Food and Drug Administration for 8 weeks of treatment in treatment-naïve patients with hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis. We performed an integrated analysis of data from trials to evaluate the overall efficacy and safety of 8 weeks of glecaprevir/pibrentasvir in treatment-naïve patients without cirrhosis or with compensated cirrhosis. METHODS: We pooled data from 8 phase 2 or phase 3 trials of treatment-naïve patients with HCV genotype 1 to 6 infections, without cirrhosis or with compensated cirrhosis, who received 8 weeks of glecaprevir/pibrentasvir. RESULTS: Of 1248 patients, 343 (27%) had cirrhosis. Most patients were white (80%) and had HCV genotype 1 infection (47%) or genotype 3 infection (22%); the median age was 54 years. Overall rates of sustained virologic response at post-treatment week 12 were 97.6% (1218 of 1248) in the intention to treat (ITT) and 99.3% (1218 of 1226) in the modified ITT populations. When we excluded patients with genotype 3 infections with compensated cirrhosis (consistent with the European label), rates of sustained virologic response at post-treatment week 12 were 97.6% in the ITT and 99.4% in the modified ITT populations. Eight virologic failures (7 in patients without cirrhosis and 1 in a patient with cirrhosis) occurred in the ITT population. Virologic failure was not associated with markers of advanced liver disease or populations of interest (current alcohol use, opioid substitution therapy, history of injection-drug use, and severe renal impairment). Treatment-emergent adverse events (AEs) occurred in 58% of patients. The most frequent AEs (>10%) were headache (12%) and fatigue (12%). Serious AEs and AEs that led to glecaprevir/pibrentasvir discontinuation were reported in 2% and less than 1% of patients, respectively. CONCLUSIONS: In a pooled analysis of data from 8 trials, we found that 8 weeks of treatment with glecaprevir/pibrentasvir is efficacious and well tolerated in treatment-naïve patients with HCV genotype 1 to 6 infections, with or without cirrhosis. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:18 issue:11 pages:2544-+ ispartof: location:United States status: published

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF., info:eu-repo/semantics/published

BACKGROUND: Guidelines regarding treatment for autoimmune hepatitis (AIH) favour two strategies for azathioprine (AZA) introduction: concurrent with steroids at induction or delayed by 2-4 weeks. The safety and efficacy of both strategies have been unexplored. METHODS: We established a cohort of 900 AIH patients from 12 centres in 7 European countries. There were 631 patients who used AZA as part of the therapeutic regimen. We distinguished two groups: patients with early AZA (

Background & aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date. Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality. Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p

ispartof: LIVER TRANSPLANTATION vol:24 issue:9 pages:1293-1297 ispartof: location:United States status: published