Background: Over the last two decades, a fair number of echocardiographic studies have investigated the influence of metabolic dysfunction-associated steatotic liver disease (MASLD) on myocardial strain and strain rate parameters assessed by speckle tracking echocardiography (STE) in individuals without overt heart disease, reporting not univocal results. We aimed at analyzing the main findings of these studies. Methods: All studies examining conventional echoDoppler parameters by transthoracic echocardiography (TTE) and left ventricular (LV) mechanics [LV-global longitudinal strain (GLS), LV-global strain rate in systole (GSRs), in early diastole (GSRe) and late diastole (GSRl)] by STE in MASLD patients without known heart disease vs. healthy individuals, were searched on PubMed, Embase and Scopus databases. The primary endpoint was to quantify the effect of MASLD on LV-GLS in individuals without overt cardiac disease. Continuous data [LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and left ventricular ejection fraction (LVEF)] were pooled as the standardized mean difference (SMD) comparing MASLD cohorts with healthy controls. Results: A total of 11 studies were included, totaling 1348 MASLD patients and 6098 healthy controls. Overall, MASLD showed a medium effect on LV-GLS (SMD −0.6894; 95%CI −0.895, −0.472, p < 0.001) and LV-GLSRs (SMD −0.753; 95%CI −1.501, −0.006, p = 0.048), a large effect on LV-GLSRe (SMD −0.837; 95%CI −1.662, −0.012, p = 0.047) and a small and not statistically significant effect on LV-GLSRl (SMD −0.375; 95%CI −1.113, 0.363, p = 0.319) and LVEF (SMD −0.134; 95%CI −0.285, 0.017, p = 0.083). The overall I² statistic was 86.4%, 89.4%, 90.9%, 89.6% and 72.5% for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, indicating high between-study heterogeneity. Egger’s test for LV-GLS studies gave a p value of 0.11, 0.26, 0.40, 0.32 and 0.42 for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, thus excluding publication bias. Meta-regression analysis excluded any correlation between potential confounders and LV-GLS in MASLD individuals (all p > 0.05). Sensitivity analysis confirmed the robustness of study results. Conclusions: MASLD has a medium effect on LV-GLS, independently of demographics, anthropometrics and the cardiovascular disease burden. STE analysis may allow early detection of subclinical LV systolic dysfunction in MASLD patients, potentially identifying those who may develop heart failure later in life.

Porto-sinusoidal vascular disorder (PSVD) is a group of vascular disorders characterized by lesions involving portal venules and sinusoids, irrespective of the presence of portal hypertension. Liver biopsy is essential for diagnosis. In a single-center study, we demonstrated high rates of PSVD in patients with persistently elevated gamma-glutamyltransferase (GGT). This multicenter study aims to establish PSVD prevalence in a larger dataset of individuals with persistent and unexplained GGT elevation, and to identify associated risk factors. The study included all patients who underwent liver biopsy for persistent and unexplained GGT elevation in five Italian hepatology units between March 2015 and December 2021. A total of 144 patients met the inclusion criteria. The majority were males (76/144, 52.8%) and mean age was 51.9 years (range 19-74). Only 12 (8.3%) had liver stiffness measurements (LSM) >10 kPa, while 7 (4.8%) had ultrasound evidence of portal hypertension. Histological findings were consistent with PSVD in 96 patients (67%). Alternative diagnoses were steatohepatitis in 13 (9%), sarcoidosis in 3 (2%) and congenital hepatic fibrosis in 3 (2%) patients. Histological findings were non-specific in 29 (20%) patients. PSVD was associated with male sex (odds ratio [OR] 2.60, 95% CI 1.13-5.99), LSM <10 kPa (OR 11.05, 95% CI 2.16-56.66) and GGT <200 U/L (OR 2.69, 95% CI 1.22-5.98). PSVD was the main cause of persistent and unexplained elevation of GGT3. Male sex, LSM <10 kPa and GGT <200 U/L were associated with PSVD. These findings highlight the role of liver biopsy in elucidating the underlying pathology and aiding in the diagnosis of patients with persistent and unexplained GGT elevation. In outpatient settings, it is common to encounter individuals with persistent and unexplained gamma-glutamyltransferase elevations. This study reveals, for the first time, a non-negligible prevalence of porto-sinusoidal vascular disorder among these individuals when they undergo liver biopsy. Male sex, liver stiffness measurement <10 kPa, and gamma-glutamyltransferase <200 IU/L predict this histological finding. These results may raise awareness of clinically relevant conditions that may be present in patients with persistent liver enzyme changes, even in the absence of signs of advanced chronic liver disease or portal hypertension. Additionally, the data may encourage further studies in the field of porto-sinusoidal vascular disorder, particularly to define its clinical evolution in patients without signs of portal hypertension at diagnosis.

Several studies have assessed the short-term effectiveness and safety of obeticholic acid (OCA) in the real-world setting. We aimed to extend knowledge on the real-world effectiveness and safety of OCA treatment by expanding sample size and follow-up, and by exploring changes in liver stiffness measurement (LSM) over time. The RECAPITULATE project involves centres belonging to the “Italian PBC registry” and/or the “Club Epatologi Ospedalieri” PBC working group. Effectiveness was evaluated as biochemical response according to POISE and normal range (NR) criteria (normal alkaline phosphatase/alanine aminotransferase/bilirubin). Safety was assessed as the incidence of de novo/worsening pruritus and discontinuation rate/causes. Available LSMs were also captured. We included 747 patients from 66 Italian centres: mean age 58 years; female/male 88%/14%; median follow-up 24 months [IQR 12-42]; 28% with cirrhosis, and 14% with autoimmune hepatitis (AIH)/PBC overlap syndrome. Probabilities of POISE and NR response increased from baseline to 57% and 20%, respectively, by the 42^nd month. The probabilities of response were lower in patients with cirrhosis (p = 0.02 and p = 0.004 for POISE and NR), but not different between patients with AIH/PBC and pure PBC (p = 0.8). Overall, 130 patients (17%) discontinued treatment, mainly due to pruritus (36.9%), while 28.5% did so after developing hepatic events. The discontinuation rate was higher in patients with cirrhosis (p <0.001). LSM was available in 573 patients (∼77%), of whom 255 had multiple measurements. LSM variation over time differed based on the attainment of POISE biochemical response (expected mean annual variation -0.48 [-0.78, -0.19] in responders vs. +0.33 [-0.07, 0.73] in non-responders, respectively, p <0.001). Our findings confirm the effectiveness and safety profiles of OCA in the medium/long term and demonstrate that biochemical response is associated with the change in LSM over time. After the conditional approval of OCA for the treatment of PBC, the main confirmatory study failed to demonstrate OCA's ability to reduce liver-related events, leading the EMA to revoke the drug's marketing authorization. The ensuing scientific debate highlights an urgent need for further evidence from real-world practice. In the largest real-world series of patients treated with OCA to date, we confirm that the drug's effectiveness and safety profiles are maintained over a medium-to-long follow-up period. Valuable data for the management of the drug in relevant subgroups of patients, such as those with cirrhosis and autoimmune hepatitis/PBC overlap syndrome, are also provided. Our original results on liver stiffness measurement variation over time suggest a favourable impact of OCA on fibrosis progression, particularly in patients achieving a biochemical response to the drug. Overall, these data provide important insights for clinicians managing patients with PBC and contribute to the ongoing scientific debate about the effectiveness/safety profile of this drug.

The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan–Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23–0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16–0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02–2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk.

Background & Aim: Sustained‐virological‐response (SVR) after direct‐acting‐antiviral (DAA) therapy improves outcomes in patients with HCV‐related compensated‐advanced‐chronic‐liver‐disease (cACLD). However, it remains unclear whether absolute post‐SVR LSM or LSM reduction better predicts prognosis after SVR. This study evaluated the prognostic performance of absolute‐values‐LSM versus dynamic‐change for predicting liver‐related‐events after SVR. Methods: We retrospectively analysed patients with HCV‐related cACLD treated with DAA between December 2014 and March 2022. Baseline and post‐SVR non‐invasive tests (LSM, FIB‐4 and APRI) were assessed. Predictive performance for liver‐related events was evaluated using time‐dependent receiver operating characteristic analysis. Associations between Baveno‐VII criteria for clinically significant LSM improvement and clinical outcomes were assessed using Fine–Grey competing‐risk models. Results: During a median of 60 months (95%; CI 52–69), 11/135 patients (8%) developed liver‐related events. Patients who developed events had higher baseline LSM than those who remained event‐free (24 vs. 18 kPa, p = 0.049), and higher follow‐up LSM values (20 vs. 12 kPa, p = 0.043). Follow‐up LSM showed good discriminative ability for liver‐related events within the first 3 years after SVR (tAUC at 2 years: 0.86 [95% CI 0.75–0.97]; tAUC at 3 years: 0.82 [0.71–0.93]). Follow‐up LSM was significantly superior to ΔLSM and percentage ΔLSM at both 2 and 3 years (all p ≤ 0.028). In competing‐risk analysis, only follow‐up LSM > 20 kPa was significantly associated with liver‐related events (subdistribution hazard ratio 5.61, p = 0.007), whereas Baveno‐VII criteria for LSM regression were not (SHR 0.33, p = 0.097). Conclusions: Absolute post‐treatment‐LSM provides stronger prognostic information than dynamic changes from baseline. These findings support repeated post‐SVR LSM assessment for risk stratification suggesting the relevance of residual liver disease in predicting liver‐related outcomes.