Safety and Efficacy of Atezolizumab/Bevacizumab in Patients with Hepatocellular Carcinoma and Impaired Liver Function: A Systematic Review and Meta-Analysis.

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.

Characteristics and outcome of anti-hepatitis D virus positive patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Chronic hepatitis D virus (HDV) often leads to end-stage liver disease and hepatocellular carcinoma (HCC). Comprehensive data pertaining to large populations with HDV and HCC are missing, therefore we sought to assess the characteristics, management, and outcome of these patients, comparing them to patients with hepatitis B virus (HBV) infection. METHODS: We analysed the Italian Liver Cancer database focusing on patients with positivity for HBV surface antigen and anti-HDV antibodies (HBV/HDV, n = 107) and patients with HBV infection alone (n = 588). Clinical and oncological characteristics, treatment, and survival were compared in the two groups. RESULTS: Patients with HBV/HDV had worse liver function [Model for End-stage Liver Disease score: 11 vs. 9, p < .0001; Child-Turcotte-Pugh score: 7 vs. 5, p < .0001] than patients with HBV. HCC was more frequently diagnosed during surveillance (72.9% vs. 52.4%, p = .0002), and the oncological stage was more frequently Milan-in (67.3% vs. 52.7%, p = .005) in patients with HBV/HDV. Liver transplantation was more frequently performed in HBV/HDV than in HBV patients (36.4% vs. 9.5%), while the opposite was observed for resection (8.4% vs. 20.1%, p < .0001), and in a competing risk analysis, HBV/HDV patients had a higher probability of receiving transplantation, independently of liver function and oncological stage. A trend towards longer survival was observed in patients with HBV/HDV (50.4 vs. 44.4 months, p = .106). CONCLUSIONS: In patients with HBV/HDV, HCC is diagnosed more frequently during surveillance, resulting in a less advanced cancer stage in patients with more deranged liver function than HBV alone. Patients with HBV/HDV have a heightened benefit from liver transplantation, positively influencing survival.

Food Intolerances, Food Allergies and IBS: Lights and Shadows.

This narrative review delves into the intricate relationship between irritable bowel syndrome (IBS) and food intolerances. IBS, a chronic functional gastrointestinal disorder, is characterized by symptoms like abdominal pain and altered bowel habits. The prevalence of IBS has increased globally, especially among young adults. Food and dietary habits play a crucial role in IBS management. About 85-90% of IBS patients report symptom exacerbation linked to specific food consumption, highlighting the strong connection between food intolerances and IBS. Food intolerances often exhibit a dose-dependent pattern, posing a challenge in identifying trigger foods. This issue is further complicated by the complex nature of gastrointestinal physiology and varying food compositions. This review discusses various dietary patterns and their impact on IBS, including the low-FODMAP diet, gluten-free diet, and Mediterranean diet. It highlights the importance of a personalized approach in dietary management, considering individual symptom variability and dietary history. In conclusion, this review emphasizes the need for accurate diagnosis and holistic management of IBS, considering the complex interplay between dietary factors and gastrointestinal pathophysiology. It underlines the importance of patient education and adherence to treatment plans, acknowledging the challenges posed by the variability in dietary triggers and the psychological impact of dietary restrictions.

Albumin-bilirubin score in non-malignant liver diseases should be properly validated.

The albumin-bilirubin (ALBI) score to assess the risk of decompensation in patients with initially compensated cirrhosis may improve their prognostic evaluation. This letter critically evaluates the research, which utilizes the ALBI score to forecast decompensation in cirrhosis patients over a three-year period. This score was initially developed to assess liver function in hepatocellular carcinoma, its prognostic utility for non-malignant liver diseases has now been explored, recognizing decompensation as a pivotal event that significantly affects patient's survival. Some concerns regarding the methodology of this research may be raised, particularly the exclusive use of radiological diagnosis, potentially including patients without definite cirrhosis and thus skewing the decompensation risk assessment. The reported predominance of variceal bleeding as a decompensating event conflicts with established literature, that often reports ascites as the initial decompensation manifestation. The letter highlights the absence of details on esophageal varices and their management, which could introduce bias in evaluating the ALBI score's predictive power. Furthermore, the letter points out the small sample size of patients with high-risk ALBI grades, potentially compromising the score's validity in this context. We suggest prospective future research to investigate the dynamic changes in the ALBI score over time to reinforce the validity of the ALBI score as a predictor of decompensation in non-malignant liver disease.

Health-related Quality of Life in Patients With Nonalcoholic Fatty Liver Disease: A Prospective Multi-center UK Study.

BACKGROUND & AIMS: It is unclear whether health-related quality of life (HRQoL) is impaired in patients with nonalcoholic fatty liver disease (NAFLD) without advanced fibrosis and how this compares with the general population. We aimed to assess HRQoL in patients with NAFLD in comparison to the general population and any associations of fibrosis severity and metabolic comorbidities with impairments in HRQoL. METHODS: We prospectively enrolled 513 consecutive patients with NAFLD who completed the EuroQol 5-dimensional questionnaire (EQ-5D) and Chronic Liver Disease Questionnaires (CLDQ). Demographic and clinical information, liver biopsy results, and/or liver stiffness (LS) by transient elastography were recorded. A general population sub-cohort of the Health Survey for England 2018 was used as a comparator (n = 5483), and a 1:1 propensity-score (PS) matching was performed, according to age, sex, body mass index, and type 2 diabetes mellitus (T2DM). RESULTS: EQ-5D-5L utility was significantly lower in 466 PS-matched patients with NAFLD compared with PS-matched controls (0.77 ± 0.27 vs 0.84 ± 0.19; P < .001), even in those without advanced fibrosis (F ≤2 or LS <8kPa) (0.80 ± 0.24 vs 0.84 ± 0.19; P = .024). HRQoL measures (EQ-5D-5L, EQ-VAS, CLDQ) did not differ between patients with NAFLD with and without advanced fibrosis. LS was independently associated with lower EQ-5D-5L in all patients with NAFLD but not in those without advanced fibrosis. In the latter, lower EQ-5D-5L was associated with female sex, T2DM, and depression. CONCLUSIONS: Patients with NAFLD, even those without advanced fibrosis, have worse HRQoL compared with the general population. In patients with NAFLD without advanced fibrosis, HRQoL is independently associated with non-liver comorbidities but not LS. Multi-disciplinary management is therefore required in NAFLD, irrespective of fibrosis severity.

Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma.

Background & Aims: HIV-seropositivity shortens survival in patients with hepatocellular carcinoma (HCC). Although risk factors for HCC including HCV infection can influence T cell phenotype, it is unknown whether HIV can influence functional characteristics of the T cell infiltrate. Methods: From the Liver Cancer in HIV biorepository, we derived 129 samples of transplanted (76%) or resected (20%) HCC in eight European and North American centres. We profiled intra- and peritumoural tissue to evaluate regulatory CD4+/FOXP3+ and immune-exhausted CD8+/PD1+ T cells in HIV+ (n = 66) and HIV- (n = 63) samples. We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples evaluated in relationship with HIV status. We correlated immunopathologic features with patients' characteristics including markers of HIV infection. Results: Of the 66 HIV+ patients, 83% were HCV coinfected with an undetectable HIV viral load (51%) and a median blood CD4+ cell count of 430 cells/mm3 (range 15-908). Patients who were HIV+ were compared with HIV- controls with similar staging characteristics including Barcelona Clinic Liver Cancer (BCLC) stage A-B (86% vs. 83%, p = 0.16), <3 nodules (90% vs. 83%, p = 0.3) and median alpha-foetoprotein values (10.9 vs. 12.8 ng/ml, p = 0.72). HIV+ samples had higher PD-L1 expression rates in tumour tissue (51% vs. 8% p <0.0001) and displayed denser intratumoural CD4+/FOXP3+ (p <0.0001), CD8+/PD1+ (p <0.0001), with lower total peritumoural CD4+ (p <0.0001) and higher peritumoural CD8+/PD1+ (p <0.0001). Gene set analysis revealed HIV+ cases to have evidence of dysregulated adaptive and innate immunity. Tumour-infiltrating lymphocyte clonality was not influenced by HIV status. Conclusions: HIV-associated HCC harbours a profoundly immune-exhausted tumour microenvironment, warranting prospective testing of immunotherapy in this treatment-deprived patient population. Impact and Implications: Hepatocellular carcinoma is a non-AIDS defining malignancy characterised by poor survival. The programmed cell death (PD-1) pathway governs antiviral and anticancer immune exhaustion and is a therapeutic target in HCC. This study highlights how HIV infection is associated with significantly higher PD-L1 expression in HCC cells and in the surrounding microenvironment, leading to changes in cytotoxic and regulatory T cell function and dysregulation of proinflammatory pathways. Taken together, our results suggest dysfunctional T cell immunity as a mechanism of worse outcome in these patients and suggest clinical testing of checkpoint inhibitors in HIV-associated HCC.

Safety and efficacy of venous thromboembolism prophylaxis in patients with cirrhosis: A systematic review and meta-analysis.

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.

Immune checkpoint inhibitors in malignancies after liver transplantation: A systematic review and pooled analysis.

BACKGROUND AND AIMS: Treatment of de novo malignancies and recurrent hepatocellular carcinoma with immune checkpoint inhibitors (ICI) in liver transplant recipients (LT) is an attractive strategy that is infrequently pursued because of the lack of strong evidence regarding their safety and efficacy. In this systematic review with pooled analysis, we aimed to assess safety and efficacy of ICI therapy following LT. METHODS: We performed a systematic search of case reports and series published until January 2022. We included 31 publications reporting a total of 52 patients treated with ICIs after LT and assessed in a pooled analysis the risk of graft rejection and the outcome of ICI therapy. RESULTS: Acute graft rejection occurred in 15 patients (28.8%) and 7 patients (13.4% of the total cohort) died because of graft loss. Rejection was associated with shorter overall survival (OS) (17.2 months, confidence interval [CI] 12.1-22.2 vs. 3.5 months, CI 1.6-5.4, p < 0.001). Disease control rate was 44.2% (n = 23), and in these patients, OS was longer than in non-responders (26.4 months, CI 20.8-32.0 vs. 3.4 months, CI 2.1-4.7, p < 0.001). CONCLUSIONS: Observational, off-label experience suggests that treatment with ICI for advanced malignancies in LT recipients might not be discarded a priori. This notwithstanding, ICI treatment in these patients is associated with a substantial risk of graft rejection and mortality. Prospective studies are needed to provide adequate safety and efficacy figures of ICI treatment in this fragile population.

Characteristics and survival of patients with primary biliary cholangitis and hepatocellular carcinoma.

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.

Diabetes medications and risk of HCC.

Type 2 diabetes mellitus is a recognized risk factor for HCC in patients with liver disease, independent from the etiology of their liver disease. Hence, prevention and treatment of type 2 diabetes mellitus and its underlying cause, insulin resistance, should be considered a treatment target for patients with liver disease. The drug armamentarium for diabetes is wide and consists of agents with insulin-sensitizing activity, agents that stimulate insulin secretion, insulin itself, and agents that reduce gastrointestinal and urinary glucose absorption. From an endocrinology perspective, the main goal of treatment is the achievement of euglycemia; however, in patients at risk of, or with known underlying liver disease, the choice of diabetic medication as it relates to potential hepatic carcinogenesis remains complex and should be carefully considered. In the last decade, increasing evidence has suggested that metformin may reduce the risk of HCC, whereas evidence for other classes of diabetic medications, particularly some of the newer agents including the sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, is fewer and often inconsistent. In this review, we aim to summarize the current evidence on the potential effects of the most widely used diabetic agents on liver cancer tumorigenesis.

Is there an 'ideal' diet for patients with NAFLD?

Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic that encompasses three distinct clinical phenotypes: uncomplicated fatty liver, nonalcoholic steatohepatitis (NASH) and NASH-related cirrhosis with its complications, including hepatocellular carcinoma. To date, no pharmacological treatments have been approved and lifestyle modifications including reduced caloric intake targeting a 7%-10% weight loss from baseline assessment represent the standard approach. Mediterranean diet has been recommended as the best dietary pattern since it is easy to follow and, independently of caloric intake its nutritional components have beneficial metabolic effects that not only improve steatosis but also risk factors for cardiovascular events, the leading cause of morbidity/mortality in individuals with NAFLD. Other dietary patterns such as ketogenic diet and Dietary Approach to Stop Hypertension (DASH) diet can be used in patients with NAFLD. Recently, intermittent fasting diets have gained popularity among healthy individuals and have been proposed as a safe and effective treatment for the metabolic syndrome in experimental and in a few human studies. In this narrative review, we aim to summarize the evidence for the available dietary approaches for patients with NAFLD.

Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors and Applicability of First-Line Atezolizumab/Bevacizumab in a Real-Life Setting.

Immune checkpoint inhibitors (ICIs) are the new frontier for the treatment of advanced hepatocellular carcinoma (HCC). Since the first trial with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 inhibitor, increasing evidence has confirmed that these drugs can significantly extend the survival of patients with advanced hepatocellular carcinoma (HCC). As a matter of fact, the overall survival and objective response rates reported in patients with advanced HCC treated with ICIs are the highest ever reported in the second-line setting and, most recently, the combination of the anti-programmed death ligand protein-1 atezolizumab with bevacizumab-an anti-vascular endothelial growth factor monoclonal antibody-demonstrated superiority to sorafenib in a Phase III randomized clinical trial. Therefore, this regimen has been approved in several countries as first-line treatment for advanced HCC and is soon expected to be widely used in clinical practice. However, despite the promising results of trials exploring ICIs alone or in combination with other agents, there are still some critical issues to deal with to optimize the prognosis of advanced HCC patients. For instance, the actual proportion of patients who are deemed eligible for ICIs in the real-life ranges from 10% to 20% in the first-line setting, and is even lower in the second-line scenario. Moreover, long-term data regarding the safety of ICIs in the population of patients with cirrhosis and impaired liver function are lacking. Lastly, no biomarkers have been identified to predict response, and thus to help clinicians to individually tailor treatment. This review aimed to summarize the state of the art immunotherapy in HCC and, by analyzing a large, multicenter cohort of Italian patients with HCC, to assess the potential applicability of the combination of atezolizumab/bevacizumab in the real-life setting.

Management and Treatment of Hepatitis C: Are There Still Unsolved Problems and Unique Populations?

Direct-acting antivirals (DAA) have revolutionized the treatment of patients with chronic hepatitis C virus (HCV) infection, possibly leading to HCV elimination by 2030 as endorsed by the World Health Organization (WHO). However, some patients belonging to the so-called unique or special populations are referred to as difficult-to-treat due to unreached sustained virological response, potential drug side effects or interactions or co-morbidities. Several years after the DAA introduction and on the basis of excellent findings in terms of efficacy and safety, some doubts arise around the exact meaning of the special population designation and whether this group of patients actually exists. The aim of this review is to discuss and analyze current evidence on the management and treatment of the so-called "unique populations". We placed particular emphasis on patients with decompensated cirrhosis, chronic kidney disease (CKD), coinfections, rare genotypes, and previous treatment failure, in order to provide physicians with an updated overview of the actual problems and needs in the current scenario.

Primary prevention of variceal bleeding in people with oesophageal varices due to liver cirrhosis: a network meta-analysis.

BACKGROUND: Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years. There are several different treatments to prevent bleeding, including: beta-blockers, endoscopic sclerotherapy, and variceal band ligation. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES: To compare the benefits and harms of different treatments for prevention of first variceal bleeding from oesophageal varices in adults with liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for prevention of first variceal bleeding from oesophageal varices according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to December 2019 to identify randomised clinical trials in people with cirrhosis and oesophageal varices with no history of bleeding. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and oesophageal varices with no history of bleeding. We excluded randomised clinical trials in which participants had previous bleeding from oesophageal varices and those who had previously undergone liver transplantation or previously received prophylactic treatment for oesophageal varices. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR), and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute for Health and Care Excellence Decision Support Unit guidance. We performed the direct comparisons from randomised clinical trials using the same codes and the same technical details. MAIN RESULTS: We included 66 randomised clinical trials (6653 participants) in the review. Sixty trials (6212 participants) provided data for one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those at high risk of bleeding from oesophageal varices. The follow-up in the trials that reported outcomes ranged from 6 months to 60 months. All but one of the trials were at high risk of bias. The interventions compared included beta-blockers, no active intervention, variceal band ligation, sclerotherapy, beta-blockers plus variceal band ligation, beta-blockers plus nitrates, nitrates, beta-blockers plus sclerotherapy, and portocaval shunt. Overall, 21.2% of participants who received non-selective beta-blockers ('beta-blockers') - the reference treatment (chosen because this was the most common treatment compared in the trials) - died during 8-month to 60-month follow-up. Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates all had lower mortality versus no active intervention (beta-blockers: HR 0.49, 95% CrI 0.36 to 0.67; direct comparison HR: 0.59, 95% CrI 0.42 to 0.83; 10 trials, 1200 participants; variceal band ligation: HR 0.51, 95% CrI 0.35 to 0.74; direct comparison HR 0.49, 95% CrI 0.12 to 2.14; 3 trials, 355 participants; sclerotherapy: HR 0.66, 95% CrI 0.51 to 0.85; direct comparison HR 0.61, 95% CrI 0.41 to 0.90; 18 trials, 1666 participants; beta-blockers plus nitrates: HR 0.41, 95% CrI 0.20 to 0.85; no direct comparison). No trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation had a higher number of serious adverse events (number of events) than beta-blockers (rate ratio 10.49, 95% CrI 2.83 to 60.64; 1 trial, 168 participants). Based on low-certainty evidence, beta-blockers plus nitrates had a higher number of 'any adverse events (number of participants)' than beta-blockers alone (OR 3.41, 95% CrI 1.11 to 11.28; 1 trial, 57 participants). Based on low-certainty evidence, adverse events (number of events) were higher in sclerotherapy than in beta-blockers (rate ratio 2.49, 95% CrI 1.53 to 4.22; direct comparison rate ratio 2.47, 95% CrI 1.27 to 5.06; 2 trials, 90 participants), and in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison rate ratio 1.72, 95% CrI 1.08 to 2.76; 1 trial, 140 participants). Based on low-certainty evidence, any variceal bleed was lower in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison HR 0.21, 95% CrI 0.04 to 0.71; 1 trial, 173 participants). Based on low-certainty evidence, any variceal bleed was higher in nitrates than beta-blockers (direct comparison HR 6.40, 95% CrI 1.58 to 47.42; 1 trial, 52 participants). The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates may decrease mortality compared to no intervention in people with high-risk oesophageal varices in people with cirrhosis and no previous history of bleeding. Based on low-certainty evidence, variceal band ligation may result in a higher number of serious adverse events than beta-blockers. The evidence indicates considerable uncertainty about the effect of beta-blockers versus variceal band ligation on variceal bleeding. The evidence also indicates considerable uncertainty about the effect of the interventions in most of the remaining comparisons.

Secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis: a network meta-analysis.

BACKGROUND: Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years of diagnosis. Several different treatments are available, which include endoscopic sclerotherapy, variceal band ligation, beta-blockers, transjugular intrahepatic portosystemic shunt (TIPS), and surgical portocaval shunts, among others. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES: To compare the benefits and harms of different initial treatments for secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for secondary prevention according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until December 2019 to identify randomised clinical trials in people with cirrhosis and a previous history of bleeding from oesophageal varices. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and previous history of bleeding from oesophageal varices. We excluded randomised clinical trials in which participants had no previous history of bleeding from oesophageal varices, previous history of bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those who had acute bleeding at the time of treatment, and those who had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 48 randomised clinical trials (3526 participants) in the review. Forty-six trials (3442 participants) were included in one or more comparisons. The trials that provided the information included people with cirrhosis due to varied aetiologies. The follow-up ranged from two months to 61 months. All the trials were at high risk of bias. A total of 12 interventions were compared in these trials (sclerotherapy, beta-blockers, variceal band ligation, beta-blockers plus sclerotherapy, no active intervention, TIPS (transjugular intrahepatic portosystemic shunt), beta-blockers plus nitrates, portocaval shunt, sclerotherapy plus variceal band ligation, beta-blockers plus nitrates plus variceal band ligation, beta-blockers plus variceal band ligation, sclerotherapy plus nitrates). Overall, 22.5% of the trial participants who received the reference treatment (chosen because this was the commonest treatment compared in the trials) of sclerotherapy died during the follow-up period ranging from two months to 61 months. There was considerable uncertainty in the effects of interventions on mortality. Accordingly, none of the interventions showed superiority over another. None of the trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation may result in fewer serious adverse events (number of people) than sclerotherapy (OR 0.19; 95% CrI 0.06 to 0.54; 1 trial; 100 participants). Based on low or very low-certainty evidence, the adverse events (number of participants) and adverse events (number of events) may be different across many comparisons; however, these differences are due to very small trials at high risk of bias showing large differences in some comparisons leading to many differences despite absence of direct evidence. Based on low-certainty evidence, TIPS may result in large decrease in symptomatic rebleed than variceal band ligation (HR 0.12; 95% CrI 0.03 to 0.41; 1 trial; 58 participants). Based on moderate-certainty evidence, any variceal rebleed was probably lower in sclerotherapy than in no active intervention (HR 0.62; 95% CrI 0.35 to 0.99, direct comparison HR 0.66; 95% CrI 0.11 to 3.13; 3 trials; 296 participants), beta-blockers plus sclerotherapy than sclerotherapy alone (HR 0.60; 95% CrI 0.37 to 0.95; direct comparison HR 0.50; 95% CrI 0.07 to 2.96; 4 trials; 231 participants); TIPS than sclerotherapy (HR 0.18; 95% CrI 0.08 to 0.38; direct comparison HR 0.22; 95% CrI 0.01 to 7.51; 2 trials; 109 participants), and in portocaval shunt than sclerotherapy (HR 0.21; 95% CrI 0.05 to 0.77; no direct comparison) groups. Based on low-certainty evidence, beta-blockers alone and TIPS might result in more, other compensation, events than sclerotherapy (rate ratio 2.37; 95% CrI 1.35 to 4.67; 1 trial; 65 participants and rate ratio 2.30; 95% CrI 1.20 to 4.65; 2 trials; 109 participants; low-certainty evidence). The evidence indicates considerable uncertainty about the effect of the interventions including those related to beta-blockers plus variceal band ligation in the remaining comparisons. AUTHORS' CONCLUSIONS: The evidence indicates considerable uncertainty about the effect of the interventions on mortality. Variceal band ligation might result in fewer serious adverse events than sclerotherapy. TIPS might result in a large decrease in symptomatic rebleed than variceal band ligation. Sclerotherapy probably results in fewer 'any' variceal rebleeding than no active intervention. Beta-blockers plus sclerotherapy and TIPS probably result in fewer 'any' variceal rebleeding than sclerotherapy. Beta-blockers alone and TIPS might result in more other compensation events than sclerotherapy. The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Accordingly, high-quality randomised comparative clinical trials are needed.

Nuts and Non-Alcoholic Fatty Liver Disease: Are Nuts Safe for Patients with Fatty Liver Disease?

Diet and lifestyle interventions are the recommended treatment for patients with non-alcoholic fatty liver disease (NAFLD), with the aim of achieving a 7-10% weight loss. Several dietary patterns have been suggested for this purpose, however, to date, the best one is represented by the Mediterranean diet (MD) as it is rich in macro- and micro- nutrients known for their effectiveness in health-promotion and cardio-vascular disease prevention. Moreover, MD is characterized by the inclusion of nuts. These foods have shown potential benefits in health-promotion as they are rich in fibers, which have lipid-lowering effects, rich in mono- and poly-unsaturated fatty acids, which help reduce insulin-resistance and serum cholesterol, and contain anti-oxidants which reduce oxidative stress and inflammation. Additionally, nuts are associated with a better control, or reduction, of Body Mass Index (BMI). All these effects are useful targets to achieve in NAFLD, so that nuts have been proposed as a suitable dietary treatment supplement for weight and metabolic control in these patients. In recent years, health authorities raised an alert on nuts consumption as these may be at high risk of aflatoxin (AF) contamination, for which controls and legislations are different among countries. AF is a well-known cancerogenic agent and a recognized risk factor for hepatocellular carcinoma. Patients with NAFLD have an overall, inherent sevenfold increased risk of developing hepatocellular carcinoma as compared with the general population. In this context, one could argue that recommending the inclusion of nuts in the diet of NAFLD patients has to be balanced with the risk of potential chronic exposure to AF, and every effort should be pursued to assure the safety of these nutrients. In this review, we aim to summarize the benefits of nuts consumption, the evidence for AF contamination of nuts and the consequent potential risks in patients with NAFLD.

Appropriateness of proton pump inhibitors treatment in clinical practice: Prospective evaluation in outpatients and perspective assessment of drug optimisation.

BACKGROUND: High rates of inappropriate proton pump inhibitor (PPI) prescriptions have been reported in retrospective database analyses. Assessing the appropriateness of long-term PPIs in outpatients, with a proactive approach at drug optimisation may enhance treatment adequacy. AIMS: To describe the characteristics of outpatients who are on long-term PPIs, to assess the magnitude of inappropriate PPI prescriptions, and to evaluate the rate of drug optimisation following specialist recommendations. METHODS: Appropriateness of long-term (>8weeks) PPI prescription was prospectively assessed in 249 consecutive patients referred to a Gastroenterology outpatient clinic. We recorded reason for prescription, dose, modality, duration of therapy, and attempts at PPI optimisation. RESULTS: PPIs were inappropriately prescribed in 96/249 patients (38.6%). Gastro-oesophageal reflux disease (50/143, 35.0%) and prophylaxis of anti-platelet/non-steroidal anti-inflammatory drugs (5/49, 10.2%) were the most common PPI indications and those with the lowest rate of inappropriateness, while the highest rates were observed for treatment of dyspepsia (10/12, 83.3%) and anti-coagulant therapy (21/21, 100%). PPI treatment was optimised in 112 patients (45.0%). CONCLUSIONS: PPIs are inappropriately used in about 40% of outpatients, reflecting scant attention to guidelines. A proactive approach may improve therapeutic adequacy in approximately half of patients. Educational efforts to guide PPI prescription should be further pursued.