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Coagulation in cirrhosis involves a complex imbalance between procoagulant and anticoagulant factors due to liver dysfunction. This results in a delicate hemostatic equilibrium that increases the risk of both bleeding and thrombosis. To analyze the occurrence of thromboembolic events in a prospective series of patients with liver cirrhosis, and to assess patients' characteristics. We prospectively enrolled 188 patients with cirrhosis admitted to our gastrointestinal ward (December 2021-December 2022). We evaluated general and liver disease-related characteristics as well as the incidence of venous thromboembolism (VTE), and death during the first year following hospital admission. Median age was 63 years, and 72.9% were males. The primary cause of hospitalization was acute decompensation (n=101, 53.7%), followed by hepatocellular carcinoma (n=34, 18.1%) or liver-related elective diagnostic-therapeutic procedures (28, 14.9%). Twenty-five (13.3%) patients were admitted due to non-liver related events. The median length of hospitalization was 9 days (IQR 5-14). Most of patients had decompensated cirrhosis (Child-Pugh B: 41.5%; Child-Pugh C: 26.6%), with median MELD-Na=14, and clinically significant portal-hypertension (CSPH) in 148 (78.7%). Sixty-two (32.9%) patients had hepatocellular carcinoma. Thirty-one patients (16.5%) were on anticoagulants. During a 1-year follow-up, three (1.6%) patients experienced VTE while 26 (13.8%) patients had variceal bleeding. Overall mortality was 42.0% (n=79). Padua and Improve-VTE risk scores, MELD-Na, Child-Pugh class, and presence of CSPH were no different between patients with or without VTE. A competitive-risk model focused on experiencing VTE and risk of death and bleeding as competing events showed no significant association between VTE and use of anticoagulant, Charlson comorbidity index, CSPH, male gender, HCC, length of hospitalization and Improve-VTE, Padua and MELD-Na scores. VTE is a rare event in patients with cirrhosis, occurring in only 1.6% of prospectively evaluated population, and no significant association between VTE and various risk factors was identified. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPIs) are commonly prescribed for gastroesophageal reflux disease (GERD) or prophylaxis of non-steroidal anti-inflammatory drugs and aspirin-induced gastric damage. However, their prolonged use in cirrhotic patients has been linked to complications like spontaneous bacterial peritonitis (SBP) and hepatic encephalopathy (EE). To evaluate the appropriateness of PPI therapy in patients with cirrhosis. We reviewed medical records of 209 cirrhotic patients admitted to our gastrointestinal ward (December 2021-December 2022). Demographics, clinical characteristics, PPI use indications, and incidence of EE and SBP were assessed. The median age was 69 years, and 74.4% were males. Main reasons for hospitalization were hepatocellular carcinoma (n=63, 28.7%), elective diagnostic-therapeutic procedures (n=63, 28.7%), non-liver-related events (n=54, 24.7%), and acute decompensation (n=39, 17.7%). Etiology of liver disease was alcohol in 91 patients (41.6%), virus-related in 77 (35.1%), and metabolic-associated in 30 (13.7%). The median MELD-Na score was 10 (8-14). At admission, 145 patients (66.2%) were on PPIs: of these, 42 patients (29.0%) had confirmed GERD, 12 (8.3%) had esophagitis ≥grade B, and 27 (18.6%) were on aspirin with bleeding risk-factors. Overall, inappropriate PPI use was observed in 74 patients (44.1%). Patients on PPIs were older, with higher MELD-Na and creatinine, and lower hemoglobin and Na compared to those not on PPIs (p<0.05). Multivariate analysis showed that PPI use was independently associated with older age (OR 1.03, IC95% 1.01-1.07) and lower hemoglobin (OR 0.82, IC95% 0.70-0.97). During a median follow-up of 18 months, the incidence of EE and SBP did not differ between PPI users and non-users. A significant proportion of patients with cirrhosis is inappropriately prescribed PPIs. Although this did not correlate with major liver-related events in the short term, proper PPI prescription education is crucial to prevent potential long-term consequences. [ABSTRACT FROM AUTHOR]

Background & Aims: Approximately 40% of patients with Primary Biliary Cholangitis (PBC) show incomplete response to ursodeoxycholic acid, thus needing second-line treatment to prevent disease progression. As no head-to-head comparison study is available, we used a network meta-analysis (NMA) to compare efficacy and safety of available second-line therapies., Methods: We performed a systematic literature review including randomised, placebo-controlled trials of patients with PBC and incomplete response, or intolerance, to ursodeoxycholic acid, and compared relative risks (RRs) for primary (biochemical response at 52-week) and secondary outcomes [incidence of new-onset pruritus and serious adverse events (SAEs)]., Results: The NMA included three studies, each testing obeticholic acid (OCA), seladelpar or elafibranor versus placebo (active therapy/placebo: 379/191 patients). All treatments significantly increased the RR for biochemical response with an advantage of elafibranor versus seladelpar (RR: 4.37, 95% CI: 1.01-18.87). OCA 5-10 mg/10 mg was associated with a higher risk of new-onset pruritus compared to placebo (RR: 1.43; 95% CI: 1.09-1.88/RR: 1.79; 95% CI: 1.37-2.33), while seladelpar decreased this risk (RR: 0.30; 95% CI: 0.12-0.80). Compared to placebo, OCA 5-10 mg/10 mg was associated with an increased risk of SAE (RR: 3.82; 95% CI: 1.46-10.02/RR 2.67; 95% CI: 1.00-7.08)., Conclusions: Among second line therapies for patients with PBC, elafibranor is slightly more effective in obtaining biochemical response than seladelpar that, on the other hand, is the only drug associated with a lower incidence of pruritus. While of similar efficacy, OCA was associated with increased pruritus and SAEs. These findings may help personalise second-line treatment in patients with PBC., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background & Aims: Noninvasive tests (NITs) for ruling-out clinical significant portal hypertension (CSPH) and high-risk varices (HRVs) in patients with primary biliary cholangitis (PBC) and compensated advanced chronic liver disease (cACLD) are lacking. We evaluated NITs in these patients and the influence of cholestasis on their performance., Methods: Consecutive patients from the "Italian PBC registry" and 2 United Kingdom large-volume PBC referral centers with upper endoscopy within 6 months from biochemical evaluation and transient elastography were included. Rete Sicilia Selezione Terapia (RESIST), Baveno VI (BVI), and Expanded Baveno VI (EBVI) criteria for ruling out HRV were assessed according to alkaline phosphatase (ALP) levels (< or ≥1.5 × upper limit of normal). Decision curve analysis was performed. Prevalence of any sized esophageal varices among patients fitting Baveno VII (BVII) criteria was also calculated., Results: The final cohort consisted of 293 patients with cACLD. RESIST criteria were associated with the lowest rate of missed HRV (2.5% vs 9.8% for BVI and 8.9% for EBVI). In patients with ALP levels ≥1.5 × upper limit of normal, BVI and EBVI missed a higher rate of HRV (15.5% and 14.5%, respectively) than RESIST (3.1%). Decision curve analysis demonstrated the highest net benefit of RESIST criteria for ruling out HRV, regardless of ALP levels. Among 75 patients classified as low risk of CSPH according to BVII, 14 (18.7%) showed esophageal varices., Conclusions: Biochemical-based RESIST criteria demonstrate the highest net benefit compared with elastography-based criteria for ruling out HRV. The severity of cholestasis affects NITs performance to rule out HRV and CSPH in patients with PBC and cACLD., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA., Methods: We used data from the Italian RECAPITULATE (N = 441) and the IBER-PBC (N = 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS) or also after 6 months of treatment (ORS+). Multivariable Cox regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (alkaline phosphatase [ALP]/upper limit of normal [ULN]<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or normal range criteria (NR: normal ALP, alanine aminotransferase [ALT], and bilirubin) up to 24 months., Results: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN, and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were 0.75, 0.78, and 0.72 for POISE, ALP/ULN<1.67, and NR response, which raised to 0.83, 0.88, and 0.81 with ORS+, respectively. The respective performances in validation were 0.70, 0.72, and 0.71 for ORS and 0.80, 0.84, and 0.78 for ORS+. Results were consistent across groups with mild/severe disease., Conclusions: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Safety and outcome of atezolizumab/bevacizumab in Child-Pugh B patients with hepatocellular carcinoma (HCC) have not been completely characterized., Objectives: In this study, we aimed at addressing safety and efficacy of atezolizumab/bevacizumab in Child-Pugh B patients by reviewing the available data and analyzing them by meta-analysis., Methods: We compared the safety and efficacy of atezolizumab/becavizumab treatment in patients with unresectable HCC and various degrees of liver dysfunction. A total of 8 retrospective, non-randomized, cohort studies were included in this meta-analysis, for a total of 1,071 Child-Pugh A and 225 Child-Pugh B patients. The albumin-bilirubin (ALBI) grade was also used to assess liver function, when available., Results: Grade ≥3 adverse events were observed in 11.8% of Child-Pugh class A and 26.8% class B patients ( p = 0.0001), with an odds ratio (OR) of 0.43 (confidence interval [CI] 0.21-0.90; p = 0.02). Progression-free survival (PFS) at both 6 months (4.90 ± 2.08 vs. 4.75 ± 2.08 months; p = 0.0004) and 12 months (8.83 ± 2.32 vs. 7.26 ± 2.33 months; p = 0.002) was lower in Child-Pugh class B patients. A trend toward a higher objective response rate (ORR) was observed in Child-Pugh class A patients (219/856, 25.6%) as compared to Child-Pugh class B patients (25/138, 18.1%; p = 0.070), while the probability of obtaining an ORR was significantly greater in Child-Pugh A patients (OR 1.79, CI 1.12-2.86; p = 0.02). Median overall survival (OS) was 16.8 ± 2.0 and 6.8 ± 3.2 months in Child-Pugh A and B patients, respectively (mean difference 9.06 months, CI 7.01-11.1, p < 0.0001). Lastly, OS was longer in patients with ALBI grades 1-2 than in those with grade 3 (8.3 ± 11.4 vs. 3.3 ± 5.0 months, p = 0.0008)., Conclusions: Oncological efficacy of atezolizumab/bevacizumab is moderate in Child-Pugh class B patients, and the shorter PFS and OS associated with the greater likelihood of experiencing treatment-related adverse events observed in these patients suggest great caution and individualization of treatment, possibly with the support of the ALBI grade., Competing Interests: Edoardo G. Giannini has participated in consulting and/or advisory boards for Roche, AstraZeneca, Eisai, MSD. Mario Strazzabosco is an advisor for ENGITIX., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objective: Primary biliary cholangitis (PBC) is a rare chronic autoimmune cholangiopathy, characterized by a variable course and response to treatment. We aimed to describe long-term outcomes of PBC patients referred to three academic centres in Northwest Italy., Methods: This is an ambispective cohort study of PBC patients (retrospective component: diagnosis before 1 January 2019; prospective component: thereafter), including 302 patients: 101 (33%) followed up in Novara, 86 (28%) in Turin, 115 (38%) in Genoa. Clinical features at diagnosis, biochemical response to therapy and survival were analyzed., Results: Among the 302 patients (88% women, median age 55 years, median follow-up 75 months), alkaline phosphatase (ALP) levels significantly decreased during treatment with ursodeoxycholic acid (UDCA, P < 0.0001) and obeticholic acid (P < 0.0001). At multivariate analysis, ALP at diagnosis was predictive of 1-year biochemical response to UDCA [odds ratio 3.57, 95% confidence interval (CI) 1.4-9, P < 0.001]. Estimated median survival free of liver transplantation and hepatic complications was 30 years (95% CI 19-41). Bilirubin level at diagnosis was the only independent risk factor for the combined outcome of death, transplantation or hepatic decompensation (hazard ratio, 1.65, 95% CI 1.66-2.56, P = 0.02). Patients presenting with total bilirubin at diagnosis ≥0.6 times the upper normal limit (ULN) had a significantly lower 10-year survival compared to those with bilirubin <0.6 times ULN (63% vs. 97%, P < 0.0001)., Conclusion: In PBC, both short-term response to UDCA and long-term survival can be predicted by simple conventional biomarkers of disease severity, obtained at diagnosis., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Patients with cirrhosis are considered in a haemostatic balance, though weaker than in normal subjects. In these patients, however, the use of pharmacological prophylaxis for venous thromboembolism (VTE) remains controversial. Therefore, in this study, we aimed to assess the safety and efficacy of VTE prophylaxis in patients with cirrhosis., Methods: We conducted a systematic review of studies reporting the occurrence of bleeding and VTE events in patients with cirrhosis, and controls, undergoing VTE prophylaxis. Meta-regression analysis was conducted to further explore the determinants of heterogeneity in the study of the occurrence of either bleeding or VTE events., Results: In a total of 10 studies, including 5712 patients, of which 2330 undergoing VTE prophylaxis, bleeding (n = 5513) and VTE events occurred in 8.2% and 2.8% patients respectively. A total of 2963 and 3162 patients were included from low-risk of bias studies in bleeding and VTE analysis respectively: while administration of VTE prophylaxis did not seem to reduce VTE (OR = 1.07, CI 0.39-2.96, p = .89), importantly prophylaxis was not associated with increased bleeding risk (OR = 0.56, CI 0.20-1.59, p = .27). Meta-regression analysis showed that no parameter significantly influenced the heterogeneity of data regarding bleeding or VTE events., Conclusions: In patients with cirrhosis, current evidence is insufficient to advise for or against the use of VTE prophylaxis, mainly due to lack of quality and homogeneity of available data. However, its use does not appear to be associated with a significant bleeding risk. Adequately designed studies are required to provide a measure of its overall utility., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Introduction: Hepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE., Methods: We prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT)., Results: During follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01-1.06), HE (HR 1.67, 95% CI 1.08-2.56), ascites (HR 2.56, 95% CI 1.55-4.23), and sodium levels (HR 0.94, 95% CI 0.90-0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39-18.49) and BMI (HR 0.86, 95% CI 0.75-0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission., Conclusion: In patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Riggio, Celsa, Calvaruso, Merli, Caraceni, Montagnese, Mora, Milana, Saracco, Raimondo, Benedetti, Burra, Sacco, Persico, Schepis, Villa, Colecchia, Fagiuoli, Pirisi, Barone, Azzaroli, Soardo, Russello, Morisco, Labanca, Fracanzani, Pietrangelo, Di Maria, Nardelli, Ridola, Gasbarrini and Cammà.)

Background: Since liver fibrosis is one of the most accurate predictors of prognosis in hepatopatic patients, its accurate assessment and staging is a major public health issue. Transient elastography (TE) (Fibroscan, Echosens, Paris, France) and shear wave elastography (SWE) represent the gold standard techniques among non-invasive methods to assess liver fibrosis. Contrast-enhanced ultrasound (CEUS) is increasingly used to diagnose the nature of liver lesions and is often performed together with TE and SWE. In this study we evaluated the effect of CEUS on liver stiffness measurements obtained by TE and SWE., Methods: A retrospective analysis of ultrasound (US) exams performed by an expert operator was carried out. TE and SWE were performed 30 seconds before and after the execution of CEUS. Statistical analysis was carried out using the statistical software R. Kolmogorov-Smirnov analysis was performed to test the normality of continuous variables. The pre- and post-CEUS liver stiffness values were compared using the Wilcoxon's Test., Results: Ninety-six patients were enrolled. While the measurements were comparable when performed with TE, those obtained by SWE decreased by 6% after administration of the contrast agent (P=0.0005). Fibrosis stage deviated between pre- and post-CEUS in 16 (17%) patients with Fibroscan and 22 (23%) patients with SWE. Among the latter, in 9 cases (10%) a deviation from absent-low (F0-F2) to high-fibrosis (F3, F4), or vice versa, occurred., Conclusions: Our study, the first to assess the effects of CEUS on US elastography, shows that the contrast agent (Sonovue, Bracco Suisse SA, Cadempino, Switzerland) does not significantly affect liver stiffness measurements obtained by TE, whereas the accuracy decreases when performed by SWE.

Background & Aims: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy., Methods: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs)., Results: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA., Conclusions: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

An important tool to explore personal experience of symptoms, treatment and clinical outcome is stratification of illness perception in patients affected by PBC., Aim: To assess the perception of illness in a cohort of Italian patients with PBC., Methods: Between June and December 2019, a specific questionnaire was administered to a pool of 210 patients from 7 tertiary Italian centers, in order to identify and assess the patient's past history, symptoms and their impact on the quality of life, follow-up, treatment and perceived satisfaction of patients toward the provided care., Results: Fatigue, pruritus, and abdominal discomfort and sicca syndrome were present in 50.4%, 45%, 30.4% and 28.5% of patients, fatigue having the most impacting the daily-life. After a consultation with a specialist, the diagnosis of PBC was met within 18 months for 143 patients. Patients were mostly concerned about possible health problems that occur and in 25% of cases, symptoms had a negative impact on their life. Eighty percent of patients said they were satisfied with efficacy and tolerability of treatment, while 26% requested an improvement in the relationship with the specialist., Conclusions: The results highlight the importance of both promoting timely referral to the specialist and facilitating communication between healthcare professionals and patients., Competing Interests: Declaration of Competing Interest M. Scaffidi received a Bursary grant for this study by FIRE (Italian Foundation for Research in Hepatology. All the remaining authors declares no conflict of interest that pertain to this work., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Comprehensive and contemporary data pertaining large populations of patients with Primary Biliary Cholangitis (PBC) and hepatocellular carcinoma (HCC) are missing., Aim: To describe main characteristics and outcome of PBC patients with HCC diagnosed in the new millennium., Methods: Analysing the Italian Liver Cancer registry we identified 80 PBC patients with HCC diagnosed after the year 2000, and described their clinical characteristics, access to treatment and survival., Results: Median age of patients was 71 years and 50.0% were males. Cirrhosis was present in 86.3% of patients, being well-compensated in 58.0%. Median HCC diameter was smaller in patients under surveillance (2.6 vs 4.0 cm, P = 0.007). Curative treatment, feasible in 50.0% of patients, was associated with improved survival compared to palliative and supportive care (42 vs 33 vs 6 months, P<0.0001). Surveillance was associated with a non-significant improved survival (36 vs 23 months), likely due to similar rate of curative treatment in patients under (51.4%) and outside surveillance (42.6%)., Conclusions: PBC patients with HCC are often elderly males with well-preserved liver function. Feasibility of curative treatment is high and associated with improved prognosis. Description of these patients may help focus surveillance to identify earlier tumours, increase their curability, and improve prognosis., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disease characterized by hypoalphalipoproteinemia, mixed hyperlipemia, and fatty liver (FL) due to mutations in LIPAse A, lysosomal acid type (LIPA) gene. The rs1051338 single-nucleotide polymorphism (SNP) in LIPA gene, in vitro, could adversely affect the LAL activity (LAL-A). Nonalcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome, and the diagnosis requires the exclusion of excess of alcohol intake and other causes of hepatic disease. The aim of the study was to evaluate the impact of rs1051338 rare allele on lipid phenotype, severity of FL, and LAL-A in patients suffering from dyslipidemia associated with NAFLD. We selected 74 subjects with hypoalphalipoproteinemia or mixed hyperlipemia and evaluated transaminases, liver assessment with controlled attenuation parameter (CAP), LAL-A, rs1051338 SNP genotype. The presence of rare allele caused higher levels of triglycerides and hepatic transaminase and lower levels of high-density lipoprotein cholesterol (HDL-C). Multivariate analysis highlighted independent association between rare allele and FL severity in subjects with NAFLD. The rs1051338 SNP may modulate FL severity and atherogenic dyslipidemia in patients suffering from NAFLD., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background and Aims: Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Noninvasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis (AF) at disease presentation in PBC., Approach and Results: We collected data from 167 consecutive treatment-naïve PBC patients who underwent liver biopsy (LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to the Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for AF (Ludwig stage ≥III). Effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. The derivation cohort consisted of 126 patients with valid LSM and LB; VCTE identified patients with AF with an AUROC of 0.89. LSM cutoffs ≤6.5 and >11.0 kPa enabled to exclude and confirm, respectively, AF (negative predictive value [NPV] = 0.94; positive predictive value [PPV] = 0.89; error rate = 5.6%). These values were externally validated in an independent cohort of 91 PBC patients (NPV = 0.93; PPV = 0.89; error rate = 8.6%). Multivariable analysis found that the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry., Conclusions: In a multicenter study of treatment-naïve PBC patients, we identified two cutoffs (LSM ≤6.5 and >11.0 kPa) able to discriminate at diagnosis the absence or presence, respectively, of AF in PBC patients, with external validation. In patients with LSM between these two cutoffs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

The aim of this study was to identify a method for staging hepatic fibrosis using a non-invasive, rapid and inexpensive technique based on ultrasound morphologic hepatic features. A total of 215 patients with different liver diseases underwent B-mode (2-D brightness mode) ultrasonography, vibration-controlled transient elastography, 2-D shear wave elastography and measurement of the controlled attenuation parameter with transient elastography. B-Mode images of the anterior margin of the left lobe were obtained and processed with automatic Genoa Line Quantification (GLQ) software based on a neural network for staging liver fibrosis. The accuracy of GLQ was 90.6% during model training and 78.9% in 38 different patients with concordant elastometric measures. Receiver operating characteristic curve analysis of GLQ performance using vibration-controlled transient elastography as a reference yielded areas under the curves of 0.851 for F ≥ F1, 0.793 for F ≥ F2, 0.784 for F ≥ F3 and 0.789 for F ≥ F4. GLQ has the potential to be a rapid, easy-to-perform and tolerable method in the staging of liver fibrosis., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions., Methods: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria ; the secondary endpoint was the biochemical response according to normal range criteria , defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed., Results: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria , and 11% by normal range criteria . Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p  = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p  = 0.004), although with similar ALP reduction (29.4% vs. 34%, p  = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p  = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p  = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%)., Conclusions: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC., Lay Summary: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis., Competing Interests: The authors have no conflicts of interest to declare related to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)

Introduction: The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin's Lymphomas (NHL) is well established. Antiviral therapy (AVT) is the first-line treatment for HCV-related indolent NHL whereas diffuse large B-cell lymphoma (DLBCL) requires immediate start of chemoimmunotherapy (CIT), usually deferring AVT. However, an early HCV elimination may reduce the risk of CIT-induced liver toxicity and consequent CIT interruption or withdrawal. To date few data are available on safety and efficacy of concomitant administration of direct-acting antivirals (DAA) and CIT in HCV-associated DLBCL., Methods: 7 consecutive patients (5 males, median age 65 years) with HCV infection (four genotype 2a/2c, two genotype 1b, one genotype 4; one patient with compensated cirrhosis) and DLBCL received different DAA regimens concurrently with CIT., Results: All patients completed the scheduled AVT and CIT with neither interruption nor withdrawal of the latter. One case of neutropenia was observed during concomitant therapy, no liver toxicity occurred. All patients achieved sustained virological response and complete DLBCL response (median follow-up of 12 months)., Conclusions: Concomitant administration of DAA and CIT for HCV-associated DLBCL is safe and may prevent CIT-induced liver toxicity. Large, prospective studies are needed to confirm these preliminary data and to assess prognostic implications., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction., Methods: A total of 103 TDF-treated patients were included as follows: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFR MDRD ) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4 months thereafter., Results: During 46 (4-115) months of ETV treatment, all patients' renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dL (P < 0.0001), eGFR MDRD from 54 to 65 mL/min (P = 0.002), P from 2.2 to 2.6 mg/dL (P < 0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (P < 0.0001). Thirteen patients (52%) improved their eGFR MDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naïve patients, and 11% in LMV-R patients (P = 0.018)., Conclusions: Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Backgound: A significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non-Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation., Aims: We wanted to assess efficacy and safety of lamivudine (LMV) prophylaxis to prevent this complication., Methods: Eighty-five consecutive HBsAg negative/anti-HBc positive NHL patients (71 years, 100% serum HBV DNA undetectable, 74% anti-HBs positive) received LMV coadministered with R-CT and for 18 months after the end of R-CT. Serum ALT, HBsAg, anti-HBs and HBV DNA were assessed every 4 months during and after end of LMV., Results: During 39 (2-108) months of study period, including 21 months of LMV and 27 additional months after LMV discontinuation, one patient (2%) had HBV reactivation, 31 months after stopping LMV and during administration of new immunosuppressive regimens, without LMV prophylaxis, owing to incomplete oncological response. A 50% decline of anti-HBs titers occurred in 22/63 (35%) patients, including 12 who became anti-HBs seronegative. Five (6%) patients had ALT increase during R-CT but none required R-CT discontinuation. Seventeen (20%) patients died, all for tumour progression., Conclusion: LMV prophylaxis is safe and effective in preventing HBV reactivation in HBsAg negative/anti-HBc positive NHL patients receiving R-CT., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P = 0.033 and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.