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Background & Aims: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. Methods: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. Results: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p

Renal dysfunction often complicates the course of liver disease, resulting in higher morbidity and mortality. The accurate assessment of kidney function in these patients is essential to early identify, stage and treat renal impairment as well as to better predict the prognosis, prioritize the patients for liver transplantation and decide whether to opt for simultaneous liver-kidney transplants. This review analyses the available tools for direct or indirect assessment of glomerular filtration rate, focusing on the flaws and strengths of each method in the specific setting of cirrhosis. The aim is to deliver a clear-cut view on this complex issue, trying to point out which strategies to prefer in this context, especially in the peculiar setting of liver transplantation. Moreover, a glance is given at future promising tools for glomerular filtration rate assessment, including new biomarkers and new equations specifically modelled for the cirrhotic population.

Clinical trials; Liver transplant; Quality of life Ensayos clínicos; Trasplante de hígado; Calidad de vida Assaigs clínics; Trasplantament de fetge; Qualitat de vida Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.

BACKGROUND AND AIMS Transjugular intrahepatic porto-systemic shunt (TIPS) ameliorates renal function in type-2 hepatorenal syndrome (HRS). Available evidence is based on 'old' HRS diagnostic criteria, and not on the current definition of HRS - chronic kidney disease (HRS-CKD). Among patients who underwent TIPS for refractory ascites over the last 12 years, we investigated clinical and renal function evolution of those with HRS-CKD. METHODS among 212 patients, 41 with HRS-CKD were included. Renal function was evaluated for 12 months after TIPS, along with management of ascites and transplant-free survival (TFS). RESULTS renal function significantly improved already one week after TIPS [serum creatinine (sCr): 1.37 ± 0.23 vs 1.94 ± 0.54 mg/dl, p< 0.001]; the amelioration was maintained during the whole follow-up and was observed in every CKD stage, defined according to baseline estimated Glomerular Filtration Rate (eGFR). sCr and eGFR became comparable between different CKD stages after only one week, whilst significantly different at baseline. TIPS led to a remarkable improvement in the control of ascites in all CKD stages and no significant differences in TFS were recorded. CONCLUSIONS TIPS led to an early, substantial and persistent improvement in renal function in patients with HRS-CKD, irrespective of their baseline CKD stage.

Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes., info:eu-repo/semantics/published

Background Adult-onset Still's Disease (AOSD) is a systemic inflammatory condition, mainly characterized by high spiking fevers, leukocytosis, skin rash, arthralgia and myalgia. Liver involvement is a frequent feature, usually presenting with hepatomegaly and mild liver enzymes abnormalities, which usually normalize after treatment with anti-inflammatory or immunomodulatory drugs given for AOSD. Although uncommon, the onset of severe acute hepatitis and even of life-threatening liver failure is possible and requires a prompt diagnosis and an aggressive therapy and, in some cases, an emergency liver transplantation. The differential diagnosis of the cause of the liver injury can be very challenging in these patients. Methods We reviewed the charts of all consecutive patients admitted for acute hepatitis, between January 2019 and December 2019, to the unit of Gastroenterology and Hepatology, Molinette Hospital, Turin, Northern Italy, searching for episodes AOSD-related. Results In this period, 21 cases of acute hepatitis were recorded with one among them diagnosed as due to AOSD. The incidence was 5% (1/21). This patient was a woman with a recent diagnosis of AOSD who developed a severe acute seronegative biopsy-proven autoimmune hepatitis. She was successfully treated with high-dose methylprednisolone, with a full and stable recovery from the liver injury. Conclusions We discuss the incidence, etiology, pathophysiology, diagnosis, and standard of treatment in the clinical management of AOSD with a special attention and a systematic review on the available therapies for severe liver involvement associated with AOSD.

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF., info:eu-repo/semantics/published

Summary Background Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. Methods We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. Findings The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST −14 IU/L [–91 to 64; p=0·728] and for ALT −8 IU/L [–49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [–804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study. Interpretation Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis. Funding Horizon 20/20 European programme.

Background & Aims: The ANSWER study reported that long-term albumin administration in patients with cirrhosis and uncomplicated ascites improves survival. During treatment, serum albumin increased within a month and remained stable thereafter. In this post hoc analysis, we aimed to determine whether on-treatment serum albumin levels could guide therapy. Methods: Logistic regression was used to assess the association between baseline serum albumin and mortality, as well as to determine on-treatment factors associated with mortality and to predict the achievement of a given on-treatment serum albumin level. Survival was assessed by Kaplan-Meier estimates and second-order polynomial regression. Patients whose on-treatment serum albumin remained below normal were compared with a subset of patients from the control arm matched by principal score. Results: Baseline serum albumin was closely associated with 18-month mortality in untreated patients; albumin treatment almost effaced this relationship. On-treatment serum albumin and MELD-Na at month 1 were the sole independent variables associated with mortality. Second-order polynomial regression revealed that survival improved in parallel with increased 1-month on-treatment serum albumin. Kaplan-Meier estimations showed that any value of 1-month on-treatment serum albumin (0.1 g/dl intervals) in the range 2.5–4.5 g/dl discriminated patient survival. In the normal range of serum albumin, the best discriminant value was 4.0 g/dl. Compared to untreated patients, survival even improved in patients whose on-treatment serum albumin remained below normal. Conclusion: Baseline serum albumin per se should not guide the decision to start albumin therapy. Conversely, 1-month on-treatment serum albumin levels are strongly associated with outcomes and could guide the use of albumin – 4.0 g/dl being the target threshold. However, even patients whose serum albumin remains below normal benefit from long-term albumin administration. Lay summary: The ANSWER study has shown that long-term albumin administration improves survival and prevents the occurrence of major complications in patients with cirrhosis and ascites. This study shows that the achievement of these beneficial effects is related to a significant increase in serum albumin concentration. Even though the best results follow the achievement of a serum albumin concentration of 4 g/dl, a survival benefit is also achieved in patients who fail to normalise serum albumin.

Objectives A correlation between autism spectrum disorders (ASDs) and gastrointestinal (GI) problems, and a possible link between gluten consumption and ASD have been increasingly reported. Gluten/casein-free diet (GCFD) is often undertaken, with conflicting results. This study aimed at evaluating the distribution of human leukocyte antigen (HLA)-DQ2/DQ8 typing among patients with ASD with GI symptoms, together with its correlation with duodenal histology and response to GCFD. Methods Between 2002 and 2015 all patients with ASD with GI symptoms referred to our outpatient clinic, displaying clinical, laboratory, or ultrasound findings suggestive of organic disease, underwent endoscopy, celiac disease (CD) serum antibodies testing and HLA-DQ2/DQ8 genotyping. Patients were prescribed a 6-month GCFD, and then clinically reassessed. Results Among 151 enrolled patients, 134 (89%) were negative for CD-specific antibodies; 72 (48%) were positive for HLA-DQ2/DQ8; and 56 (37%) showed duodenal microscopic inflammation. Clinical improvement was observed in non-CD patients irrespective of the rigorous or partial adherence to the diet, being the difference nonstatistically significant. Response to diet was related to the presence of histological duodenal alterations at baseline (odds ratio 11.323, 95% confidence interval 1.386-92.549 for Marsh 2 pattern), but not to HLA-DQ2/DQ8 positivity (odds ratio 1.120, 95% confidence interval 0.462-2.716). Conclusions Our data suggest that children with ASD with GI symptoms have a high prevalence of duodenal intraepithelial lymphocytic infiltration, which seems to be linked to a mechanism other than autoimmune response to gluten consumption. Alteration of duodenal histology, but not the HLA-DQ2/DQ8 status, was associated with clinical response to the diet.

Background & Aims: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). Methods: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. Results: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). Conclusions: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279., SCOPUS: ar.j, info:eu-repo/semantics/published

Hepatic encephalopathy (HE) is a common and serious neuropsychiatric complication of cirrhosis, acute liver failure, and porto-systemic shunting. HE largely contributes to the morbidity of patients with liver disease, severely affecting the quality of life of both patients and their relatives and being associated with poor prognosis. Its presentation is largely variable, manifesting with a broad spectrum of cognitive abnormalities ranging from subtle cognitive impairment to coma. The pathogenesis of HE is complex and has historically been linked with hyperammonemia. However, in the last years, it has become evident that the interplay of multiple actors, such as intestinal dysbiosis, gut hyperpermeability, and neuroinflammation, is of crucial importance in its genesis. Therefore, HE can be considered a result of a dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as non-absorbable disaccharides, non-absorbable antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. In this context dietary modifications, by modulating the intestinal milieu, can also provide significant benefit to cirrhotic patients with HE. This review will provide a comprehensive insight into the mechanisms responsible for gut-liver-brain axis dysregulation leading to HE in cirrhosis. Furthermore, it will explore the currently available therapies and the most promising future treatments for the management of patients with HE, with a special focus on the dietary approach.

Autism spectrum disorder (ASD) defines a set of neurodevelopmental disorders characterized by persistent deficits in social communication and interaction, along with repetitive patterns of behavior. Symptoms generally appear in the early developmental period and cause significant impairment in individual and social functioning. In recent years the increased prevalence of ASD, along with the evidence of a significant link between autism and gastrointestinal (GI) disturbances, raised a special interest in exploring the reciprocal influences between gut and brain. Investigators highlighted the existence of a so-called "gut-brain axis," empowering the hypothesis that GI abnormalities could trigger neuropsychiatric symptoms in ASD. Intestinal microbiota is thought to play a pivotal role in gut and systemic homeostasis, in central nervous system development, as well as in behavioral modulation and recurrent microbial imbalances have been shown in gut microbiota of autistic people. In this review we analyze current knowledge about intestinal microbiota and the relevance and role of dysbiosis in ASD. The most accredited theories about gut-brain interaction will be reviewed, along with current scientific evidence supporting the relationship between microbial imbalances and impairment of neurodevelopment. Finally, we will focus on the results of different therapeutic approaches in this context: administration of pre- and probiotics, antibiotics, fecal microbiota transplantation and special diets and dietary supplements.

The number and the proportion of older people in the world have both increased substantially in recent years in most countries, and the growth is projected to accelerate in the coming decades. It is thus important to gain a better understanding of the most frequent diseases in people living to advanced old age. Although the aging process has clinically significant effects on oropharyngeal and upper esophageal motility, colonic function and gastrointestinal (GI) immunity, no specific GI disease of the aged population is known. Nevertheless, the prevalence of GI symptoms and signs have increased, due to aging processes and to the superimposed effects of comorbidities and environmental exposure (medications, alcohol, tobacco). As a consequence, GI morbidity in the elderly represents an increasingly relevant burden for public health systems. This review focuses on the most frequent GI disorders of the elderly, describing their epidemiological, pathophysiological and clinical implications. The main benign diseases, symptoms or signs involving the GI tract are discussed, debating the potential role of a multidisciplinary approach when appropriate. Finally, it is highlighted that age-related physiologic changes in most systems, including the GI tract, affect diagnostic test interpretation and response to treatments, and may be difficult to differentiate from disease. This should be considered together with the fact that, with multiple coexisting diseases, there is a less consistent relationship between disease and clinical manifestations in the elderly.

Stereotactic ablative radiotherapy (SABR) is a safe treatment approach for hepatocellular carcinoma (HCC) with comparable results to other local therapies. For lesions larger than 3 cm, no definitive standard treatment is present and several options are available. We retrospectively review local control (LC) and survival results of SABR in patients with HCC lesions >3 cm. Between 2012 and 2015, we treated 29 patients (39 lesions) having histological or radiological diagnosis of HCC and at least one lesion sized >3 cm. Patients were prescribed 36–48 Gy in 3–5 fractions (mainly 16 Gy × 3 fractions or 8 Gy × 5 fractions), in 3–5 consecutive days. A total of 15 lesions (52 %) had complete, while 10 (34 %) had partial remission; 3 (11 %) had a stable disease. Mean time for CR achievement was 5.8 months (range 1–17). One- and two-year actuarial LC was 100 %. Moreover, 1- and 2-year progression-free (PFS), cancer-specific and overall survival were 57.9 % [standard error (SE) 0.09; 95 % CI 36.9–74.2] and 41.2 % (SE 0.12; 95 % CI 17.7–63.5), 80.7 % (SE 0.08; 95 % CI 59.6–91.5) and 63.3 % (SE 0.11; 95 % CI 38.4–80.3), 71.7 % (SE 0.08; 95 % CI 51.2–84.7) and 56.2 % (SE 0.10; 95 % CI 33.8–73.6). On multivariate analysis, achieving a CR within the target lesion had a borderline significance with respect to PFS (HR 0.83; SE = 0.014; z −1.15; p = 0.095; 95 % CI 0.71–7.45). Time between HCC diagnosis and SABR delivery ( 12 months) was significantly correlated with OS (HR 16.5; SE 21.5; z = 2.14; p = 0.032; 95 % CI 1.27–213.3) as CLIP score (score: 0–1 vs 2) (HR 5.6; SE 4.6; z = 2.10; p = 0.036; 95 % CI 1.11–27.8). A total of 6 major toxic events (G3–G4) were recorded (20 %). In 2 patients (6 %), a radiation-induced liver disease was seen. In conclusion, SABR provided LC and survival rates comparable to other local therapies for patients with HCC lesion sized >3 cm, with acceptable toxicity profile.

Background & Aims We elaborate a non-invasive score system for liver fibrosis (NISF), exploring its diagnostic performance and comparing its accuracy to FibroScan in patients with chronic viral hepatitis (CH) and non-alcoholic fatty liver disease (NAFLD). Methods Clinical, biochemical, elastographic and ultrasound parameters derived from patients with CH (n = 83) or NAFLD (n = 58), undergoing liver biopsy for fibrosis assessment, were prospectively collected as potential predictors of fibrosis. Each parameter was evaluated for its correlation with the liver biopsy (Gold Standard). Candidate predictors with good interobserver agreement and correlation with histological stages were combined into two algorithms (NISF) to predict fibrosis in chronic viral hepatitis and NAFLD. Results The CH-NISF included six parameters: bluntness of liver edges, irregularity of left lobe surface, diameter of segment 4, liver stiffness measurement, platelet count and ALT values. The ability of the model to discriminate F3–F4 vs F0–F1 stages and F2 vs F0-F1 was high (AUROC of 0.95 and 0.83 respectively) and better than FibroScan alone, especially in intermediate stages (F2 vs F0-F1), AUROC 0.83 vs 0.57 (P = 0.003). The resulting algorithm is available as mathematical formula, nomogram or free online link. [http://health.mafservizi.it/NISF_Calculator/liver.htm] The NAFLD-NISF included liver stiffness, platelet count and AST levels, had good ability to discriminate F0–F1 vs F2–F3–F4 stages (AUROC 0.86), however, not significantly higher than FibroScan. Conclusions CH-NISF can be proposed as preliminary and easily available staging tool, superior to FibroScan alone in predicting histological fibrosis, especially in intermediate stages. Further validations are needed to improve NISF accuracy in NAFLD.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterised by hepatic steatosis, which may be benign (NAFL) or which may progress via inflammation and fibrosis to nonalcoholic steatohepatitis (NASH) and then to cirrhosis and liver failure. Liver biopsy is the standard diagnostic approach for NAFL/NASH. However it has limitations due to sampling site variability, cost and procedure-related morbidity. Appropriate NAFLD-specific circulating biomarkers may enable diagnosis, staging and monitoring of NAFL/NASH with fewer biopsies. Circulating fragments of cytokeratin-18 (K18), a marker of hepatocyte death, have been shown in several studies to indicate the transition from benign fatty liver to NASH, with a risk of fibrosis, in patients with NAFLD. Our goal was to develop a highly specific serum K-18 assay to monitor hepatic disease severity in patients with different stages of NAFLD. Methods: An assay to measure K18 fragments in serum using electrochemiluminescence (ECL) technology was developed using proprietary K18 fragment-specific antibodies: one labelled with an ECL-active ruthenium chelate reporter and a second antibody bound to paramagnetic beads. Results: Thirty known NAFL and NASH patient serums with assigned NAS scores were evaluated. K18 fragment concentrations in biopsy-proven NASH were elevated compared to NAFL (1232U/L and 345U/L respectively). The results also demonstrated good correlation with the M30 antibody assay. Conclusions: An ECL-based assay has been developed for the quantitation of serum K18 fragments. This new diagnostic test may enable routine monitoring in both central laboratories and physician’s offices of disease severity and progression in patients with NAFLD.