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Obeticholic acid (OCA) is the only licensed second-line therapy for PBC patients non-responders/intolerant to UDCA. Real-world experiences on OCA therapy are somehow limited by reduced sample sizes and short follow-up. Aim of the RECAPITULATE study is to provide long-term real-world data on OCA therapy in a large Italian cohort of patients with PBC. Data on patients in OCA therapy from centres belonging to "Italian PBC registry", "CLEO/AIGO", "Sicilian PBC Network" and "PBC Project Piemonte-Liguria-Valle-D'Aosta" were captured. Cumulative incidences of OCA response and discontinuation were evaluated through Aalen-Johansen (taking into account the competing risk of discontinuation) and Kaplan-Meier estimators, respectively. 441 PBC patients (median age 58, women 88%) on OCA therapy for at least 6 months were enrolled from 50 Italian centres, with a median time on OCA therapy of 24 months (IQR 12-36, max 48). Cirrhotics were 152 (34%), PBC/autoimmune hepatitis (AIH) overlap were 59 (13%). According to POISE, response probabilities were 37.5/43.5/47.2% at 12/24/36 months. Discontinuation probabilities were 12.8/17.7/22.9% at 12/24/36 months, with pruritus (41 patients, 48%) and hepatic events (18 patients, 21%) as leading causes. In cirrhotics, probabilities of response were lower (25.9/27.7/34.8% at 12/24/36 months; p<0.01 Vs non-cirrhotics), due to higher discontinuation rates (19.9/27.6/34.6% at 12/24/36 months; p<0.01 Vs non-cirrhotics), while patients with PBC/AIH overlap did not show significantly different probabilities of response and discontinuation (p=0.20). Results of Vibration-Controlled-Transient-Elastography (VCTE) were available from 309/114/69 patients at 0/12/24 months. Liver stiffness measurement (LSM) was stable at 12 months in both OCA responders and non-responders, while a significant reduction was observed at 24 months only in responders (p=0.01). Our results confirm long-term efficacy and safety of OCA therapy in a large real-world cohort of PBC patients. These first results concerning LSM variation over time under OCA treatment need to be confirmed in a larger subgroup of patients. [ABSTRACT FROM AUTHOR]

non-invasive assessment of advanced fibrosis in Non-Alcoholic Fatty Liver Disease (NAFLD) is crucial for the identification of patients at greatest risk of progression. Among non-invasive tests, AGILE 3+ and AGILE 4 have been recently proposed, combining liver stiffness measurement (LSM) by vibration-controlled transient elastography (FibroScan) with clinical-biochemical variables. we aimed to assess the accuracy of AGILE 3+ and AGILE 4 for the identification of advanced fibrosis (F3-F4) and cirrhosis (F4), respectively, against LSM in individuals with biopsy-proven NAFLD. we retrospectively included 315 biopsy-proven NAFLD patients. No clinical, radiological or biochemical signs of cirrhosis were present at inclusion. Clinical-biochemical data and LSM were collected at time of the biopsy. median age was 48 (IQR 38-47) years, 62% were male. Median LSM was 7.5 kPa (IQR 5.8-10.1). Advanced fibrosis was present in 28%, cirrhosis in 10% and NASH in 28% of cases. Eighty subjects had type 2 diabetes. At Area Under the Curve (AUC) analysis, LSM had a value of 0.807 (Se 70%, Sp 80%) for advanced fibrosis and 0.877 (Se 88%, Sp 76%) for cirrhosis. AGILE 3+ had AUC of 0.77 for advanced fibrosis (cut-off by Youden index 0.30, Se 68%, Sp 78%), while AGILE 4 had AUC of 0.78 for cirrhosis (cut-off by Youden index 0.11, Se 55%, Sp 89%). Comparison of AUC showed that AGILE 3+ was similar to LSM for identifying advanced fibrosis (DeLong p= 0.254). Similarly, AUC comparison between LSM and AGILE 4 for cirrhosis was not different (DeLong p =0.739). when compared to LSM, AGILE 3+ and AGILE 4 had similar accuracy for the detection of advanced fibrosis and cirrhosis in NAFLD patients. This research was supported by the Italian MIUR "Dipartimenti di Eccellenza 2018-2022" D15D18000410001 and by Horizon 2020, no.777377, LITMUS. [ABSTRACT FROM AUTHOR]

The Patatin-like phospholipase domain–containing 3 (PNPLA3) rs738409 single nucleotide polymorphism (SNP) is one of the major genetic determinant of NAFLD and is strongly regulated by changes in energy balance and dietary factors. The aim of this study was to investigate the association between the PNPLA3 rs738409 SNP, nutrient intake and NAFLD severity. PNPLA3 -rs738409 genetic variant was genotyped in 181 patients with hepatic steatosis who completed the EPIC Food Frequency Questionnaire. Liver steatosis was evaluated by Controlled Attenuation Parameter (CAP) (Fibroscan®530). According to the established cut-off, a CAP value ≥300 was used to identify steatosis (S3). Subsequently, a validation analysis was performed in 47 biopsy-proven NAFLD where significant steatosis was classified as steatosis ≥ 33% and advance fibrosis as ≥F3 according to Kleinert score. Anthropometric, clinical and biochemical parameters were collected at the time of enrolment. Overall, median age was 53 years (IQR 44;62) and 60.22% of patients were male. 102 subjects (56.35%) had severe steatosis and showed increased liver stiffness (p <0.001), AST (p =0.003) and ALT levels (p <0.001) compared to those with CAP<300. At logistic regression analyses we found that the interaction between carbohydrates intake and the carriers of the PNPLA3 G risk allele was significantly associated with severe steatosis (p =0.001). The same result was confirmed in a subgroup of patients who underwent liver biopsy, were the interaction between carbohydrate intake and PNPLA3 SNP was significantly associated with steatosis ≥33% and advanced fibrosis (≥F3) (p =0.017 and p =0.050, respectively) The intake of greater than or equal to 48% carbohydrate carrying the CG/GG allele of PNPLA3 rs738409 may increase the risk of steatosis and fibrosis in patients with NAFLD. This work has received support from EU/EFPIA/IM2 Joint Undertaking (LITMUS grant no.777377) and Italian Ministry for Education, University and Research (MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022" n.D15D18000410001. [ABSTRACT FROM AUTHOR]

Obeticholic acid (OCA) is the approved second-line treatment for patients with primary biliary cholangitis (PBC). Biochemical response by POISE criteria is achieved in ∼40% of patients, according to registrative and post-marketing studies. To derive the OCA response score (ORS) for predicting response to OCA at 12 and 24 months, according to the POISE (alkaline phosphatase(ALP)/upper limit of normal(ULN) <1.67 with a reduction of at least 15%, and a normal bilirubin) and ALP/ULN<1.67 criteria. We used the Italian RECAPITULATE database including centers from Italian PBC Registry, the Sicilian PBC Network, the PBC Project Piemonte-Liguria-Valle D'Aosta and CLEO/AIGO PBC study group. Multivariable Cox's regressions with backward selection method were applied to obtain parsimonious predictive models, including pre-treatment variables and/or the change of ALP/ULN and total bilirubin after 6 months' therapy. Discrimination and calibration were evaluated by c-statistics and comparing observed and predicted probabilities, and internally validated with bootstrap resampling procedure. 441 PBC patients (median age 58, women 88%, cirrhosis 34%, median follow-up 24 months) with at least 6 months' observation after of OCA prescription, were included for ORS derivation. The observed 12 and 24 months' response probabilities were 38% , 47% for POISE and 58%, 67% for ALP/ULN<1.67 criteria. A score including age, pre-treatment pruritus, cirrhosis, ALP/ULN, GGT/ULN and bilirubin (ORS), and one that includes also the relative change of ALP/ULN and total bilirubin after 6 months (ORS+), showed good discrimination for response by POISE (c-statistics=0.76 and 0.84, for ORS and ORS+, respectively) and by ALP/ULN<1.67 (c-statistics=0.78 and 0.89, for ORS and ORS+, respectively). Bootstrap validation evidenced modest overfitting (slopes>0.90) and consistent discriminative performance. Mean absolute errors <0.04 were observed for prediction of POISE and ALP/ULN<1.67 response at 24 months according to ORS and ORS+. The ORS accurately predicts OCA response at 12 and 24 months. This will enable to enhance allocation of second-line therapies in PBC with a personalised medicine approach. [ABSTRACT FROM AUTHOR]

Individuals with Non-Alcoholic Fatty Liver Disease (NAFLD) have abnormal myocardial energy metabolism and reduced coronary functional capacity, even in the absence of risk factors for cardiovascular disease (CVD). We aimed to evaluate diastolic and systolic function in NAFLD individuals with preserved ejection fraction without overt CVD. We prospectively included 95 patients (median age 53.0 [IQR 44.5-62.5] years, male sex 44.6%) with ultrasound-diagnosed NAFLD undergoing echocardiographic evaluation, which included speckle tracking analysis with left ventricular global longitudinal strain (GLS) measurement (Philips, Andover, US). Diastolic dysfunction was defined by mitral E/E'>9 and systolic dysfunction was defined by GLS >-18. Significant liver fibrosis (SLF) was defined by Fibrosis-4 (FIB-4) score>1.3. Obesity, type 2 diabetes (T2D), arterial hypertension and dyslipidemia were present in 43.3%, 21.1%, 46.2% and 57.8% of cases, while median FIB-4 was 0.97 [0.67-1.24]. SLF, diastolic and systolic dysfunction were found in 20%, 17% and 18.3% of the total. Higher FIB-4 levels were found in both diastolic and systolic dysfunction (p=0.003 and p=0.001). SLF was associated with diastolic dysfunction (OR 6.8 [95%CI 1.8-25.5], p=0.004), showing an Area Under the Curve of 0.76 (Se 76.9%, Sp 72.2%, PPV 33.3%, NPV 94.5%). In a multiple stepwise logistic regression model including T2D, obesity, arterial hypertension, dyslipidemia, male sex and SLF, both SLF and T2D were significantly and independently associated with diastolic dysfunction (aOR of SLF 6.2 [95%CI 1.5-25.1, p=0.011). In the same regression model for systolic dysfunction, only T2D showed a significant association (aOR 4.6 [95%CI 1.3-16.8], p=0.021). In NAFLD patients with preserved ejection fraction, SLF by FIB-4 is associated with diastolic dysfunction independently of major risk factors for CVD. Screening echocardiography may be recommended in this population. Funding: the Italian Ministry for Education, University and Research (MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022" Project code D15D18000410001. [ABSTRACT FROM AUTHOR]

The discrepancy in a person's sleep pattern between working days and days off is called Social Jetlag (SJL). The aim of this work was to investigate the potential impact of Mediterranean Diet (MedDiet) on the risk of significant liver fibrosis (F≥2) in individuals with non-alcoholic fatty liver disease (NAFLD), according to SJL. A total of 148 patients diagnosed with NAFLD by ultrasound underwent assessment of liver stiffness + controlled attenuation parameter (CAP) (FibroScan® 530). F≥2 was defined by liver stiffness values ≥7.1kPa. The adherence to the MedDiet was assessed by the Mediterranean diet score questionnaire; low and high adherence were defined by the median value of the score. SJL was defined by the Munich Chronotype Questionnaire as the absolute difference between mid-sleep on free days and mid-sleep on workdays. According to the median value, we defined small and large SJL. The median age was 52 (42-61.5) years and the main comorbidities were type-2 diabetes mellitus (T2DM) (26.35%), arterial hypertension (49.3%), dyslipidemia (64.9%), obstructive sleep apnea (OSAS) (5.4%), and depression (6.1%). Median liver stiffness and CAP values were 5.1kPa (F≥2; 13.5%) and 301db/m, respectively. The prevalence of large SJL was significantly higher in patients with F≤2 compared to those with F≥2 (57.46% vs. 28.57%, p=0.039), while no significant difference was found in the adherence to MedDiet between groups. At multivariate logistic regression analysis adjusted for sex, age, BMI, T2DM, OSAS, arterial hypertension, dyslipidemia, and depression, we found that the interaction between a large SJL and a high adherence to MedDiet was significantly associated to F≥2 (OR=0.02, p=0.049). Models integrating diet and SJL/sleep pattern characteristics may unveil potential pathogenetic mechanisms associated to liver fibrosis risk in patients with NAFLD. Italian Ministry for Education, University and Research (MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022" n.D15D18000410001 [ABSTRACT FROM AUTHOR]

Low adherence to the Mediterranean Diet (MedDiet) has been associated with an increased risk of metabolic associated fatty liver disease (MAFLD), a clinical condition characterized by low grade chronic inflammation. The aim of this study was to assess whether the adherence to the Mediterranean diet is associated with biomarkers of inflammation in patients with MAFLD. A total of 40 patients with MAFLD were evaluated. Liver fibrosis was assessed by transient electrography (Fibroscan®530). Anthropometric, clinical and biochemical parameters were collected at enrolment. We measured the soluble CD163 (sCD163) levels by ELISA as indirect biomarker of both hepatic inflammation and fibrosis. Adherence to the MedDiet was assessed using a validated 14-item Mediterranean diet adherence questionnaire; low and high adherence were defined by the median value of the final score. Overall, the median age was 51 years (IQR 44;62), 52.00% of subjects were female and 32.00% had diabetes. Median liver stiffness was 6.6 (IQR 4.9;8.8), while sCD163 levels were 657 (IQR 553.5;813.5). Consistently, liver stiffness was significantly correlated to both MedDiet adherence and sCD163 concentrations (MedDiet: r= -0.38, p =0.006; sCD163: r=0.66, p <0.001, respectively). In addition, in patients with a low adherence to MedDiet significantly higher levels of sCD163 were observed (771.3 vs. 629.0, p =0.035). Interestingly, at multiple regression analysis, both low adherence to MedDiet adherence and sCD163 values (750-1303 ng/mL) were significantly associated with liver stiffness independently of age, sex, body mass index and diabetes. In conclusion, in subjects with MAFLD low adherence to MedDiet is associated to a pro-inflammatory profile and is associated with the degree of hepatic fibrosis. This work has received support from the EU/EFPIA Innovative Medicines Initiaive 2 Joint Undertaking (LITMUS grant no. 777377). [ABSTRACT FROM AUTHOR]

Hepatocellular Carcinoma (HCC) represents a major clinical event in the cirrhotic population, leading to a significant incidence of morbidity and mortality. To assess the prognostic value of simple non-invasive tests (NITs) for the stratification of the risk of HCC development in a Non-Alcoholic Fatty Liver Disease (NAFLD) cirrhotic population on long-term follow-up (FU). A total of 122 patients with NAFLD-cirrhosis (median age: 62 years; males 52.5%; median BMI 30.5 kg/m2; prevalence of type-2 diabetes: 57.4%) were retrospectively analyzed. Cirrhosis diagnosis was achieved by either liver histology, instrumental findings and/or clinical evidence of portal hypertension. Clinical and biochemical data were collected at the time of diagnosis; the following NITs were calculated: FIB-4, AST to Platelet Ratio Index (APRI) gamma-glutamyl transpeptidase-to-platelet ratio (GPR), BARD. During a median FU of 6 (IQR 3.2-9.3) years, 13 (10.7%) patients developed HCC. Baseline FIB-4 (HR=1.27, 95%CI 1.03–1.58, p=0.027) and GPR (HR=1.44, 95%CI 1.11–1.85, p=0.005) values resulted significantly associated to HCC occurrence. Conversely, no association was observed for APRI and BARD. Conventional FIB-4 cut-off values allowed a proper patients' stratification into 3 risk categories with different HCC incidence: FIB-4<1.3 = 0/18 (0%), FIB-4 between 1.3–3.25 = 7/73 (9.6%), and FIB-4>3.25 = 6/31 (19.4%) (Log-rank test: p=0.009). Likewise, the cumulative HCC incidence according to GPR tertiles risk groups was: 3/41 (7.3%), 4/40 (10.0%) and 6/41 (14.6%) (Log-rank test: p=0.041). Baseline FIB-4 could stratify patients with NAFLD-cirrhosis on long-term FU according to their individual risk of HCC development. In such patients, this simple NIT may be useful to optimize tailored HCC surveillance strategies. [ABSTRACT FROM AUTHOR]

In the setting of non-alcoholic fatty liver disease(NAFLD), liver fibrosis(LF) is the most relevant prognostic factor. Several non-invasive tests have been proposed to assess LF; among them, Magnetic resonance elastography(MRE) is so far the most accurate. Compared to the traditional magnetic resonance(MR), MRE requires an additional hardware with increasing procedure costs, with limited application in clinical practice. Quantitative T1-MR imaging is an emerging tool for the evaluation of LF,but its potential use has not yet been fully investigated. We aimed to explore the correlations between T1 measured on vendor specific(vendor-T1) and LivermultiScan MOLLI(LMS-T1) sequences, with MRE and vibration controlled transient elastography(VCTE) parameters, in a cohort of NAFLD patients. Between June 2021 and October 2022, we prospectively enrolled 24 NAFLD patients who underwent concomitant MR and VCTE. We extracted the following MR data(Philips Achieva 1,5T): from MRE, stiffness measured on FFE and EPI sequences; from multiparametric liver MR, T1 with vendor specific and LMS sequences, T2, proton-density-fat-fraction(PDFF); from VCTE(Fibroscan,Echosense), stiffness and controlled attenuation parameter(CAP). Median age was 54 years(interquartile range[IQR], 45-63) and 52% of the cases were males. Median liver stiffness value by VCTE was 5.9 kPa(IQR 4.4-8.4), while median CAP value was 313 dB/m(IQR 290-334). MRE-EPI stiffness showed significant correlation with MRE-FFE stiffness(r= 0.84, p<0.001), VCTE stiffness(r= 0.71, p<0.001),T1(r= 0.61, p<0.005) and T2(r= 0.42, p<0.05). LMS-T1 correlated to MRE-FFE stiffness(r=0.537, p < 0.02), while T1 correlated to MRE-EPI stiffness(r=0.616, p< 0.005). At multivariate regression analysis adjusted for T2 and PDFF, both vendor-T1 and LMS-T1 were significantly and independently associated with MRE-EPI stiffness(t=3.64, p=0.002 and t=2.4, p=0.027, respectively). In NAFLD patients, T1 sequences may be used for the non-invasive assessment of LF. Further data from larger cohorts are needed to assess its potential use in clinical practice. Supporting grants: Italian MIUR"Dipartimenti di Eccellenza 2018-2022"D15D18000410001 and Horizon2020,no.777377,LITMUS. [ABSTRACT FROM AUTHOR]