Frequency of and reasons behind non-listing in adult patients referred for liver transplantation: Results from a retrospective study.

BACKGROUND: Few studies have evaluated the frequency of and the reasons behind the refusal of listing liver transplantation candidates. AIM: To assess the ineligibility rate for liver transplantation and its motivations. METHODS: A single-center retrospective study was conducted on adult patients which entailed a formal multidisciplinary assessment for liver transplantation eligibility. The predictors for listing were evaluated using multivariable logistic regression. RESULTS: In our center, 314 patients underwent multidisciplinary work-up before liver transplantation enlisting over a three-year period. The most frequent reasons for transplant evaluation were decompensated cirrhosis (51.6%) and hepatocellular carcinoma (35.7%). The non-listing rate was 53.8% and the transplant rate was 34.4% for the whole cohort. Two hundred and five motivations for ineligibility were collected. The most common contraindications were psychological (9.3%), cardiovascular (6.8%), and surgical (5.9%). Inappropriate or premature referral accounted for 76 (37.1%) cases. On multivariable analysis, a referral from another hospital (OR: 2.113; 95%CI: 1.259-3.548) served as an independent predictor of non-listing. CONCLUSION: A non-listing decision occurred in half of our cohort and was based on an inappropriate or premature referral in one case out of three. The referral from another hospital was taken as a strong predictor of non-listing.

Serum-free light chains as a dependable biomarker for stratifying patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Adaptive immunity is gaining a significant role in progression of metabolic dysfunction-associated steatotic liver disease (MASLD). B-cell activity can be assessed by serum-free light chains (sFLCs) k and λ levels. The objective of the present investigation is to examine the utility of sFLCs as non-invasive biomarkers for the stratification of MASLD. METHODS: We enrolled a consecutive cohort from an outpatient liver unit. Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) was made with liver biopsy according to current guidelines. Compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) were defined according to Baveno VII criteria. sFLCs were measured by turbidimetry using an immunoassay. RESULTS: We evaluated 254 patients, 162/254 (63.8%) were male. Median age was 54 years old, and the median body mass index was 28.4 kg/m2. A total of 157/254 (61.8%) subjects underwent liver biopsy: 88 had histological diagnosis of MASH, 89 were considered as simple metabolic dysfunction-associated steatotic liver (MASL) and 77/254 (30.3%) patients with compensated metabolic dysfunction-associated cirrhosis. By using Baveno VII criteria, 101/254 (39.7%) patients had cACLD; among them, 45/101 (44.5%) had CSPH. Patients with cACLD showed higher sFLC levels compared with patients without cACLD (p < .01), and patients with CSPH showed higher sFLC levels than patients without CSPH (p < .01). At multivariable analysis, sFLCs were associated with cACLD (p < .05) independently from γ-globulins and other known dysmetabolic risk factors. κFLC was associated with CSPH (p < .05) independently from γ-globulins and other known dysmetabolic risk factors. CONCLUSION: sFLCs could be a simple biomarker for stratification of cACLD in MASLD patients.

Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV).

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.

Hug sign in intraprocedural cone-beam-CT to predict short-term response to combined treatment of hepatocellular carcinoma.

OBJECTIVES: Combined treatment of ablation and chemoembolization for hepatocellular carcinoma represents a promising therapy to increase treatment efficacy and improve patient survival. The "hug sign" is a recently introduced radiological sign consisting in deposition of beads/contrast agent during transarterial chemoembolization in the hyperemic area surrounding the post-ablation volume, seen during intraprocedural unenhanced cone-beam CT, that may indicate intraprocedural success. Aim of our retrospective study was to analyze the usefulness of the "hug sign" at the intraprocedural unenhanced cone-beam CT as an early predictor of response to combined treatment, based on the hug sign angle. MATERIALS AND METHODS: Between January 2017 and September 2021 all patients with hepatocellular carcinoma which underwent a combined treatment of thermal ablation followed by chemoembolization were enrolled. All treated patients underwent immediate post-procedural unenhanced cone-beam CT to evaluate the deposition of contrast agent, lipiodol or radiopaque beads and to assess the percentage of coverage of the ablated area with the contrast agent (hug sign angle). Patients with missing pre-procedural, intra-procedural and/or post-procedural data/imaging, or with poor-quality post-procedural cone-beam CT images were excluded. RESULTS: 128 patients (mean age, 69.3 years ± 1.1 [standard deviation]; 87 men) were evaluated. Our study evidenced that 84.4% (81/85) of patients with a hug sign angle of 360° had no residual tumor at the first 1-/3-months follow-up examination. A hug sign angle of 360° also showed to be an independent protective factor against residual tumor at multivariate analysis. CONCLUSION: Unenhanced cone-beam CT performed at the end of a combined treatment with ablation plus chemoembolization can effectively predict an early treatment response on radiological images, when a hug sign angle of 360° was detected.

Predicting de-novo portal vein thrombosis after HCV eradication: A long-term competing risk analysis in the ongoing PITER cohort.

BACKGROUND & AIMS: Sustained virological response (SVR) by direct-acting antivirals (DAAs) may reverse the hypercoagulable state of HCV cirrhosis and the portal vein thrombosis (PVT) risk. We evaluated the incidence and predictive factors of de novo, non-tumoral PVT in patients with cirrhosis after HCV eradication. METHODS: Patients with HCV-related cirrhosis, consecutively enrolled in the multi-center ongoing PITER cohort, who achieved the SVR using DAAs, were prospectively evaluated. Kaplan-Meier and competing risk regression analyses were performed. RESULTS: During a median time of 38.3 months (IQR: 25.1-48.7 months) after the end of treatment (EOT), among 1609 SVR patients, 32 (2.0%) developed de novo PVT. A platelet count ≤120,000/µL, albumin levels ≤3.5 mg/dL, bilirubin >1.1 mg/dL, a previous liver decompensation, ALBI, Baveno, FIB-4, and RESIST scores were significantly different (p < 0.001), among patients who developed PVT versus those who did not. Considering death and liver transplantation as competing risk events, esophageal varices (subHR: 10.40; CI 95% 4.33-24.99) and pre-treatment ALBI grade ≥2 (subHR: 4.32; CI 95% 1.36-13.74) were independent predictors of PVT. After HCV eradication, a significant variation in PLT count, albumin, and bilirubin (p < 0.001) versus pre-treatment values was observed in patients who did not develop PVT, whereas no significant differences were observed in those who developed PVT (p > 0.05). After the EOT, esophageal varices and ALBI grade ≥2, remained associated with de novo PVT (subHR: 9.32; CI 95% 3.16-27.53 and subHR: 5.50; CI 95% 1.67-18.13, respectively). CONCLUSIONS: In patients with HCV-related cirrhosis, a more advanced liver disease and significant portal hypertension are independently associated with the de novo PVT risk after SVR.

Therapeutic Approach to Post-Transplant Recurrence of Hepatocellular Carcinoma: Certainties and Open Issues.

Hepatocellular carcinoma (HCC) is a growing indication for liver transplantation (LT). Careful candidate selection is a prerequisite to keep post-LT recurrence rates within acceptable percentages. In the pre-LT period, various types of locoregional treatments and/or systemic therapies can be used for bridging or downstaging purposes. In this context, one of the factors limiting the possibility of treatment is the degree of functional liver impairment. In the LT subject, no widely accepted indications are available to guide treatment of disease recurrence and heterogeneity exists between transplant centers. Improved liver function post LT makes multiple therapeutic strategies theoretically feasible, but patient management is complicated by the need to adjust immunosuppressive therapy and to assess potential toxicities and drug-drug interactions. Finally, there is controversy and uncertainty about the use of recently introduced immunotherapeutic drugs, mainly due to the risk of organ rejection. In this paper, we will review the most recent available literature on the management of post-transplant HCC recurrence, discussing evidence and controversies.

Early-Stage HCC Percutaneous Locoregional Management: East versus West Perspectives.

Hepatocellular carcinoma represents an important cause of death worldwide. Early-stage hepatocellular carcinoma patients not suitable for surgery can be treated with a variety of minimally invasive locoregional interventional oncology techniques. Various guidelines in different countries address the treatment of hepatocellular carcinoma, but the actual treatment is usually discussed by a multidisciplinary tumor board in a personalized manner, leading to potential treatment differences based on Western and Eastern perspectives. The aim of this paper is to integrate literature evidence with the eminent experiences collected during a focused session at the Mediterranean Interventional Oncology (MIO) Live Congress 2023.

Contrast-Enhanced Imaging in the Management of Intrahepatic Cholangiocarcinoma: State of Art and Future Perspectives.

Intrahepatic cholangiocarcinoma (iCCA) represents the second most common liver cancer after hepatocellular carcinoma, accounting for 15% of primary liver neoplasms. Its incidence and mortality rate have been rising during the last years, and total new cases are expected to increase up to 10-fold during the next two or three decades. Considering iCCA's poor prognosis and rapid spread, early diagnosis is still a crucial issue and can be very challenging due to the heterogeneity of tumor presentation at imaging exams and the need to assess a correct differential diagnosis with other liver lesions. Abdominal contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) plays an irreplaceable role in the evaluation of liver masses. iCCA's most typical imaging patterns are well-described, but atypical features are not uncommon at both CT and MRI; on the other hand, contrast-enhanced ultrasound (CEUS) has shown a great diagnostic value, with the interesting advantage of lower costs and no renal toxicity, but there is still no agreement regarding the most accurate contrastographic patterns for iCCA detection. Besides diagnostic accuracy, all these imaging techniques play a pivotal role in the choice of the therapeutic approach and eligibility for surgery, and there is an increasing interest in the specific imaging features which can predict tumor behavior or histologic subtypes. Further prognostic information may also be provided by the extraction of quantitative data through radiomic analysis, creating prognostic multi-parametric models, including clinical and serological parameters. In this review, we aim to summarize the role of contrast-enhanced imaging in the diagnosis and management of iCCA, from the actual issues in the differential diagnosis of liver masses to the newest prognostic implications.

The Role of Transabdominal Ultrasound Elastography in Gastrointestinal Non-Liver Diseases: Current Application and Future Prospectives.

Ultrasound imaging is the first-line investigation for patients with abdominal symptoms, as it effectively depicts the gastrointestinal tract and enables the diagnosis of multiple pathological conditions. Among different recent ultrasound technological advancements, elastography enables the evaluation of various tissue characteristics, such as neoplastic transformation or fibroinflammatory status. In recent years, ultrasound elastography has been utilized extensively for the study of liver diseases and in numerous other clinical settings, including gastrointestinal diseases. Current guidelines suggest the use of transabdominal ultrasound elastography to characterize bowel wall lesions, to assess gastrointestinal contractility, to diagnose and grade chronic pancreatitis; however, no specific indications are provided. In the present paper, we summarize the evidence concerning the application of different ultrasound elastography modalities in gastrointestinal non-liver diseases.

Gut Microbiota and Neuroinflammation in Acute Liver Failure and Chronic Liver Disease.

Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut-liver-brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting.

Molecular and Clinical Features of Hepatocellular Carcinoma in Patients with HBV-HDV Infection.

Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.

Multiparametric Dynamic Ultrasound Approach for Differential Diagnosis of Primary Liver Tumors.

A correct differentiation between hepatocellular carcinoma (HCC) and intracellular cholangiocarcinoma (ICC) is essential for clinical management and prognostic prediction. However, non-invasive differential diagnosis between HCC and ICC remains highly challenging. Dynamic contrast-enhanced ultrasound (D-CEUS) with standardized software is a valuable tool in the diagnostic approach to focal liver lesions and could improve accuracy in the evaluation of tumor perfusion. Moreover, the measurement of tissue stiffness could add more information concerning tumoral environment. To explore the diagnostic performance of multiparametric ultrasound (MP-US) in differentiating ICC from HCC. Our secondary aim was to develop an US score for distinguishing ICC and HCC. Between January 2021 and September 2022 consecutive patients with histologically confirmed HCC and ICC were enrolled in this prospective monocentric study. A complete US evaluation including B mode, D-CEUS and shear wave elastography (SWE) was performed in all patients and the corresponding features were compared between the tumor entities. For better inter-individual comparability, the blood volume-related D-CEUS parameters were analyzed as a ratio between lesions and surrounding liver parenchyma. Univariate and multivariate regression analysis was performed to select the most useful independent variables for the differential diagnosis between HCC and ICC and to establish an US score for non-invasive diagnosis. Finally, the diagnostic performance of the score was evaluated by receiver operating characteristic (ROC) curve analysis. A total of 82 patients (mean age ± SD, 68 ± 11 years, 55 men) were enrolled, including 44 ICC and 38 HCC. No statistically significant differences in basal US features were found between HCC and ICC. Concerning D-CEUS, blood volume parameters (peak intensity, PE; area under the curve, AUC; and wash-in rate, WiR) showed significantly higher values in the HCC group, but PE was the only independent feature associated with HCC diagnosis at multivariate analysis (p = 0.02). The other two independent predictors of histological diagnosis were liver cirrhosis (p < 0.01) and SWE (p = 0.01). A score based on those variables was highly accurate for the differential diagnosis of primary liver tumors, with an area under the ROC curve of 0.836 and the optimal cut-off values of 0.81 and 0.20 to rule in or rule out ICC respectively. MP-US seems to be a useful tool for non-invasive discrimination between ICC and HCC and could prevent the need for liver biopsy at least in a subgroup of patients.

Dynamics of liver stiffness predicts complications in patients with HCV related cirrhosis treated with direct-acting antivirals.

BACKGROUND: Direct acting antivirals(DAAs) are effective in reducing inflammatory ant fibrotic markers in patients with chronic hepatitis C virus(HCV) infection and to prevent liver-related complications. Two-dimensional shear wave elastography(2D-SWE) is an effective technique for the assessment of liver fibrosis. AIM: To evaluate changes in liver stiffness(LS) in HCV cirrhotic patients undergoing DAA therapy and to identify non-invasive parameters that predict the occurrence of liver-related events. METHODS: We enrolled 229 patients who received DAAs between January 2015 and October 2018. Ultrasound parameters and laboratory data were assessed before treatment and 24(T1) and 48(T2) weeks after end of treatment. Patients were followed up every 6 months to evaluate the development of HCC and other liver related complications. Multiple Cox regression analysis was used to determine parameters associated with the development of complications. RESULTS: Model for End-stage Liver Disease(MELD) score(HR 1.16; CI 95% 1.01-1.33; p = 0.026) and a change in LS at T2(1-year Delta LS) < 20%(HR 2.98; CI 95% 1.01-8.1; p = 0.03) were independently associated with HCC risk. One-year Delta-LS <20% was independently associated with the development of ascites(HR 5.08; CI 95% 1.03 - 25.14; p = 0.04). CONCLUSIONS: Dynamic changes of 2D-SWE-measured LS after DAA therapy may be a useful tool to identify patients who are at higher risk of liver related complications.

The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study.

BACKGROUND: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. METHODS: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. RESULTS: Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ2 = 50.97; p < 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status. CONCLUSIONS: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'.

Correlation between a New Point-Shear Wave Elastography Device (X+pSWE) with Liver Histology and 2D-SWE (SSI) for Liver Stiffness Quantification in Chronic Liver Disease.

BACKGROUND: The aim of this study was to investigate the feasibility, the correlation with previously validated 2D-SWE by supersonic imagine (SSI), and the accuracy in fibrosis-staging of a novel point shear-wave elastography device (X+pSWE) in patients with chronic liver disease. METHODS: This prospective study included 253 patients with chronic liver diseases, without comorbidities potentially affecting liver stiffness. All patients underwent X+pSWE and 2D-SWE with SSI. Among them 122 patients also underwent liver biopsy and were classified according to histologic fibrosis. Agreement between the equipment was assessed with Pearson coefficient and Bland-Altman analysis, while receiver operator characteristic curve (ROC) analysis with Youden index was used to establish thresholds for fibrosis staging. RESULTS: A very good correlation was found between X+pSWE and 2D-SWE with SSI (r2 = 0.94; p < 0.001), with X+pSWE average liver stiffness values 0.24 kPa lower than those obtained with SSI. AUROC of X+pSWE for the staging of significant fibrosis (F2), severe fibrosis (F3) and cirrhosis (F4) using SSI as a reference standard was 0.96 (95% CI, 0.93-0.99), 0.98 (95% CI, 0.97-1) and 0.99 (95% CI, 0.98-1), respectively. The best cut-off values for diagnosing fibrosis ≥F2, ≥F3 and F4 were, respectively, 6.9, 8.5 and 12 for X+pSWE. According to histologic classification, X+pSWE correctly identified 93 out of 113 patients (82%) for F ≥ 2 and 101 out of 113 patients (89%) for F ≥ 3 using the aforementioned cut-off values. CONCLUSION: X+pSWE is a useful novel non-invasive technique for staging liver fibrosis in patients with chronic liver disease.

Interventional Oncology and Immuno-Oncology: Current Challenges and Future Trends.

Personalized cancer treatments help to deliver tailored and biologically driven therapies for cancer patients. Interventional oncology techniques are able to treat malignancies in a locoregional fashion, with a variety of mechanisms of action leading to tumor necrosis. Tumor destruction determines a great availability of tumor antigens that can be recognized by the immune system, potentially triggering an immune response. The advent of immunotherapy in cancer care, with the introduction of specific immune checkpoint inhibitors, has led to the investigation of the synergy of these drugs when used in combination with interventional oncology treatments. The aim of this paper is to review the most recent advances in the field of interventional oncology locoregional treatments and their interactions with immunotherapy.

Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial.

BACKGROUND: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial. METHODS: We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365. FINDINGS: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management. INTERPRETATION: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH. FUNDING: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.

Gut microbiota modulation in patients with non-alcoholic fatty liver disease: Effects of current treatments and future strategies.

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with metabolic disorders, being highly prevalent in obese and diabetic patients. Many concomitant factors that promote systemic and liver inflammation are involved in NAFLD pathogenesis, with a growing body of evidence highlighting the key role of the gut microbiota. Indeed, the gut-liver axis has a strong impact in the promotion of NAFLD and in the progression of the wide spectrum of its manifestations, claiming efforts to find effective strategies for gut microbiota modulation. Diet is among the most powerful tools; Western diet negatively affects intestinal permeability and the gut microbiota composition and function, selecting pathobionts, whereas Mediterranean diet fosters health-promoting bacteria, with a favorable impact on lipid and glucose metabolism and liver inflammation. Antibiotics and probiotics have been used to improve NAFLD features, with mixed results. More interestingly, medications used to treat NAFLD-associated comorbidities may also modulate the gut microbiota. Drugs for the treatment of type 2 diabetes mellitus (T2DM), such as metformin, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose cotransporter (SGLT) inhibitors, are not only effective in the regulation of glucose homeostasis, but also in the reduction of liver fat content and inflammation, and they are associated with a shift in the gut microbiota composition towards a healthy phenotype. Even bariatric surgery significantly changes the gut microbiota, mostly due to the modification of the gastrointestinal anatomy, with a parallel improvement in histological features of NAFLD. Other options with promising effects in reprogramming the gut-liver axis, such as fecal microbial transplantation (FMT) and next-generation probiotics deserve further investigation for future inclusion in the therapeutic armamentarium of NAFLD.

Profiling the risk of hepatocellular carcinoma after long-term HCV eradication in patients with liver cirrhosis in the PITER cohort.

BACKGROUND AND AIMS: Severe liver disease markers assessed before HCV eradication are acknowledged to usually improve after the SVR. We prospectively evaluated, in the PITER cohort, the long-term HCC risk profile based on predictors monitored after HCV eradication by direct-acting antivirals in patients with cirrhosis. METHODS: HCC occurrence was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the post-treatment variables associated with de-novo HCC; their predictive power was presented in a nomogram. RESULTS: After the end of therapy (median follow-up:28.47 months), among 2064 SVR patients, 119 (5.8%) developed de-novo HCC. The HCC incidence was 1.90%, 4.21%, 6.47% at 12-, 24- and 36-months from end-of-therapy, respectively (incidence rate 2.45/100 person-years). Age, genotype 3, diabetes, platelets (PLT)≤120,000/µl and albumin ≤3.5g/dl levels were identified as pre-treatment HCC independent predictors. Adjusting for age, the post-treatment PLT≤120,000/µl (AdjHR 1.92; 95%CI:1.06-3.45) and albumin≤3.5g/dl (AdjHR 4.38; 95%CI 2.48-7.75) values were independently associated with HCC occurrence. Two different risk profiles were identified by combining long-term post-therapy evaluation of PLT ≤ vs. >120,000/µl and albumin ≤ vs. >3.5g/dl showing a significant different HCC incidence rate of 1.35 vs. 3.77/100 p-y, respectively. CONCLUSIONS: The nomogram score based on age, PLT and albumin levels after SVR showed an accurate prediction capability and may support the customizing management for early HCC detection.