Search

Background and Aims: Patients with hepatitis C virus (HCV)-related cirrhosis with sustained virological response (SVR) to direct-acting antivirals (DAA) remain at risk of developing hepatocellular carcinoma (HCC). Recently, serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) has shown promising results as an HCC-predictive biomarker. We aimed to develop and validate a PIVKA-II-based model for HCC risk stratification in cirrhotic patients with SVR to DAA., Methods: A total of 1220 consecutive patients (Turin, n = 531; Pisa, n = 335; Milan, n = 354) with HCV-related cirrhosis treated with DAA were included in the study. Patients were retrospectively allocated to the training cohort (Turin+Pisa; median follow-up [FU] 39, 22-55 months; incident HCC: 93 [10.7%]) and validation cohort (Milan; median FU 49.0, 35.0-52.0 months; incident HCC: 19 [5.4%]). Serum PIVKA-II levels were measured using the LumipulseG system (Fujirebio, Japan) at SVR12 (Turin and Pisa cohorts) or the end of treatment (Milan cohort)., Results: Using Cox regression analysis, a model including PIVKA-II combined with age, sex, ALT, AST, γGT, platelet count, albumin and total bilirubin was derived from the training cohort (C-index = 0.72). In the validation cohort, the model showed a C-index of 0.71 with an area under the curve of 0.84 for identifying patients who developed HCC during the first 12 months of FU. When patients were grouped into three risk categories, the cumulative incidence of HCC was 2.7%, 4.0% and 14.3% in the low-, medium- and high-risk groups, respectively (p < 0.001). Notably, no HCC occurred within 3 years of FU in the low-risk group., Conclusions: Our PIVKA-II-based model showed satisfactory accuracy for HCC risk stratification and may represent a valuable tool for implementing risk-based surveillance protocols in patients with HCV-related cirrhosis with SVR to DAA., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Micro-RNAs (miRNAs) are involved in the modulation of viral replication and host immune antiviral response. Using next-generation sequencing, we investigated the miRNome profile of circulating extracellular vesicles in 20 patients with chronic hepatitis D virus (HDV) infection undergoing pegylated interferon alpha (Peg-IFNα) treatment. Circulating miRNAs' expression was analysed according to virologic response (i.e., HDV RNA clearance maintained at least 6 months after the end of therapy). Overall, 8 patients (40%) achieved a virologic response to Peg-IFNα treatment. At baseline, 14 miRNAs were differentially expressed between responders and non-responders; after 6 months of Peg-IFNα treatment, 7 miRNAs (miR-155-5p, miR-1246, miR-423-3p, miR-760, miR-744-5p, miR-1307-3p and miR-146a-5p) were consistently de-regulated. Among de-regulated miRNAs, miR-155-5p showed an inverse correlation with HDV RNA (at baseline: r s  = -0.39, p = 0.092; at 6 months: r s  = -0.53, p = 0.016) and hepatitis B surface antigen (HBsAg) (at baseline: r s  = -0.49, p = 0.028; at 6 months: r s -0.71, p < 0.001). At logistic regression analysis, both miR-155-5p (at baseline: OR = 4.52, p = 0.022; at 6 months: OR = 5.30, p = 0.029) and HDV RNA (at baseline: OR = 0.19, p = 0.022; at 6 months: OR = 0.38, p = 0.018) resulted significantly associated to virologic response. Considering that Peg-IFNα still has a relevant role in the treatment of patients with chronic hepatitis D infection, the assessment of EV miR-155-5p may represent an additional valuable tool for the management of HDV patients undergoing Peg-IFNα treatment., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Inflammatory bowel disease (IBD) includes patients affected by Crohn's disease or ulcerative colitis. IBD is thought to be a chronic immune-mediated disease, but its origin remains elusive, and this limits new therapeutic approaches. Human endogenous retroviruses (HERVs) originate from ancestral infections and represent 8% of the human genome. HERVs are no longer infectious, but some retroviral sequences can be activated, and their aberrant expressions have been implicated in inflammatory and autoimmune disorders. HERV transcription is regulated by TRIM28 and SETDB1, which are also directly involved in epigenetic processes and modulation of the immune response. Using a PCR real-time Taqman amplification assay, we assessed, for the first time, the transcription levels of pol genes of HERV-H, -K, and -W families of env genes of syncytin 1 (SYN1), SYN2, and HERV-W, as well as of TRIM28 and SETDB1 in the whole blood of 48 patients with Crohn's disease (CD), 20 with ulcerative colitis (UC), and in healthy controls (HC) of comparable age. The transcriptional levels of HERV-H-pol ( p = 0.0003) and HERV-K-pol ( p = 0.001) were significantly higher in IBD patients compared with HC, with no differences between patients with CD and UC. No significant differences were found for the remaining HERVs between IBD patients and HC. The transcript levels of TRIM28 were significantly downregulated in IBD patients ( p < 0.001), without differences between CD and UC, while the SETDB1 levels were preserved. The enhanced transcription of HERV-H-pol and HERV-K-pol, as well as the impaired activation of TRIM28, were not influenced by clinical disease activity and type of treatment. The overexpression of HERVs and impaired transcription of TRIM28 in patients affected by CD or UC suggest that they might be the main actors in the pathophysiology of IBD, opening the way to innovative targeted interventions.

The relationship between serum 25-hydroxyvitamin D (25(OH)D) levels, genomic response to vitamin D (Vit.D), and positivity to SARS-CoV-2 remains understudied. In this pilot study, during the follow-up of patients with Inflammatory Bowel Disease (IBD) and COVID-19, we investigated this issue by analyzing the molecular contents of serum extracellular vesicles (EVs) from six groups of IBD patients (n = 32), classified according to anti-SARS-CoV-2 status, 25(OH)D level, and Vit.D supplementation, by small RNA-seq. This analysis revealed differentially expressed miRNAs, PIWI-RNA, transfer RNA, small nucleolar RNAs, and protein-coding RNAs in the EVs obtained from these cohorts of IBD patients. Experimental validation evidenced a statistically significant increase in miR30d-5p, miR150-5p, Let-7f-5p, and Let-7a-5p in the anti-SARS-CoV-2-positive and low 25(OH)D and Vit.D supplemented groups with respect to the non-Vit.D supplemented group, indicating their responsiveness to Vit.D treatment. Bioinformatics analysis highlighted the regulation of these validated miRNAs by oxidative stress and inflammation, hallmarks of IBD and COVID-19. Our study reports an unprecedented panel of circulating EV-enclosed inflammation- and oxidative stress-related miRNAs, the potentiality of which, as biomarkers for Vit.D responsivity in IBD patients, needs to be explored in future studies on larger cohorts in order to allow clinicians to optimize current treatment strategies upon viral infection.

Plant-based diets (PBDs) are gaining attention as a sustainable and health-conscious alternative for managing various chronic conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD). In the absence of pharmacological treatments, exploring the potential of lifestyle modifications to improve biochemical and pathological outcomes becomes crucial. The adoption of PBDs has demonstrated beneficial effects such as weight control, increased metabolic health and improved coexisting diseases. Nonetheless, challenges persist, including adherence difficulties, ensuring nutritional adequacy, and addressing potential deficiencies. The aim of this review is to provide a comprehensive overview of the impact of PBDs on MASLD, emphasizing the need for tailored dietary interventions with professional support to optimize their effectiveness in preventing and treating metabolic diseases.

Over the years, vedolizumab (VDZ) has emerged as a more effective target therapy for inflammatory bowel disease. The aim of this work was to analyze a cohort of inflammatory bowel disease patients, evaluating the association between VDZ serum concentrations at 6 months from starting therapy and their clinical and biochemical indexes within one year of treatment, correlating drug levels with response and clinical remission. Forty patients treated with VDZ were enrolled. Drug concentrations were quantified through ELISA methods. VDZ levels correlated with hemoglobin levels at twelve months of therapy ( p = 0.03) and with clinical remission at twelve months of therapy ( p = 0.03); patients who reached clinical remission showed higher VDZ concentrations. A VDZ cut-off value of 43.1 μg/mL was suggested, predicting clinical remission at twelve months of therapy. A statistically significant association between VDZ levels at T6 and calprotectin <250 μg/g at T12 was found ( p = 0.04). Furthermore, the optimal threshold value of VDZ levels at T6 associated with calprotectin <250 μg/g at T12 was identified: through levels higher than 45.2 µg/mL, we were able to predict remission one year after therapy. In the final regression multivariate model, no factor was retained as a predictor of clinical remission at one year of treatment. In conclusion, this is the first pilot study reporting a possible VDZ serum cut-off value able to predict not only the clinical remission at twelve months of therapy but also the calprotectin level, which is very important, as it is a surrogate marker of mucosal healing.

Objective: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death., Design: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate., Results: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65)., Conclusions: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD., Competing Interests: Competing interests: LM is supported by Investigator Driven Grants: Gilead, Intercept, Siemens Healthineers. Advisor/Consultancy: Alfa-Sigma, Boehringer-Ingelheim, BMS, Echosens, Galmed, Gilead Sciences, IBSA, Intercept, MEDA, MyGenomics, Merck Sharp & Dohme, Novartis, Pfizer, ProLon, Promethera, Resalis, Rottapharm-Madaus, Siemens Healthineers, Synageva. HH’s institutions have received research funding from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer. He has served as consultant or on advisory boards for Astra Zeneca, Bristol Myers-Squibb, MSD and Novo Nordisk and has been part of hepatic events adjudication committees for Boehringer Ingelheim, KOWA and GW Pharma., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Mounting evidence indicates that periodontitis-related oral bacteria may contribute to gut microbial dysbiosis. This clinical study aimed to explore the oral-gut microbial signatures associated with periodontitis and to longitudinally evaluate the effect of periodontal treatment on the oral and gut microbial composition. Stool and saliva samples from generalized stage III/IV periodontitis patients ( n = 47) were collected and analyzed by 16S ribosomal RNA gene amplicon sequencing, before and 3 mo after steps I to II of periodontal therapy. Periodontally healthy matched subjects ( n = 47) were used as controls. Principal component analysis was carried out to identify oral-gut microbial profiles between periodontitis patients at baseline and healthy subjects; periodontitis samples were longitudinally compared before and after treatment. β-Diversity of gut microbial profiles of periodontitis patients before treatment significantly differed from healthy controls ( P < 0.001). Periodontal therapy was associated with a significant change in gut microbiota ( P < 0.001), with post-treatment microbial profiles similar to healthy volunteers. A higher abundance of Bacteroides , Faecalibacterium , Fusobacterium , and Lachnospiraceae was noted in fecal samples of periodontitis patients at baseline compared to healthy controls. In contrast, Lactobacillus was the only genus more abundant in the latter. Additionally, periodontal therapy led to a parallel reduction in the salivary carriage of periodontal pathobionts, as well as gut Bacteroides , Lachnoclostridium , Lachnospiraceae , Oscillospiraceae , and Ruminococcaceae , to levels similar to healthy controls. Collectively, discriminating oral-gut microbial signatures of periodontitis were found. Periodontal treatment both mitigated oral dysbiosis and altered gut microbial composition, signifying potential broader implications for gastrointestinal health and disease., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Helicobacter pylori ( H. pylori ) infection is a prominent entity within human infectious diseases which cause chronic gastritis, peptic ulcers, gastric malignancies, and extragastric disorders. Its persistent colonization can lead to a systemic inflammatory cascade, potentially instigating autoimmune responses and contributing to the pathogenesis of autoimmune diseases. While the specific etiopathogenesis of inflammatory bowel diseases (IBDs) is still unknown, it is widely recognized that immunological, genetic, and environmental factors are implicated. Various bacterial and viral pathogens have been implicated in the pathogenesis of IBDs. Numerous studies suggest a correlation between H. pylori infection and IBDs. While subject to debate, this link suggests that the bacterium's presence somehow impacts the progression of IBDs by modifying the diversity of the gut microbiota, consequently altering local chemical profiles and disrupting the pattern of gut immune response. However, epidemiological evidence indicates a protective role of H. pylori infection against the onset of autoimmune diseases. Additionally, laboratory findings demonstrate H. pylori 's capacity to promote immune tolerance and restrict inflammatory reactions. The aim of this review is to elucidate the proposed mechanisms and confounding factors that underlie the potential association between H. pylori infection and IBDs.

Although the role of vitamin D (VD) in the pathogenesis and progression of Crohn's disease (CD) is known, the association between single-nucleotide polymorphisms (SNPs) of genes linked to vitamin D pathway and CD risk is still under study. Furthermore, no significant association has been previously found between these SNPs and perianal CD (pCD), a severe phenotypic manifestation of CD that may present as perianal fistula, abscess, and recto-vaginal fistula. Among the mechanisms involved in its pathogenesis, local inflammation and intestinal microbiota alteration are recognized. VD seems to act on these elements. The aim of this study was to evaluate the presence of an association between SNPs of genes coding for enzymes, transporters, and receptors involved in the VD pathway and the occurrence of pCD. Blood samples of 206 patients with CD, including 34 with pCD, were analyzed for VDR , CYP27B1 , CYP24A1 , and GC genetic variants. VDR Apal Aa genotype and VDR BsmI Bb genotype resulted in an association with pCD ( p = 0.01 and p = 0.02, respectively). Our study demonstrates for the first time the impact of the polymorphisms of genes associated with the VD pathway on the onset of pCD. Future multicenter studies are needed to confirm these data.

Background & Aims: Nephrotoxicity of intravenous iodinated contrast media (ICM) in cirrhosis is still a debated issue, due to scarce, low-quality and conflicting evidence. This study aims to evaluate the incidence and predisposing factors of acute kidney injury (AKI) in patients with cirrhosis undergoing contrast-enhanced computed tomography (CECT)., Methods: We performed a prospective, multicenter, cohort study including 444 inpatients, 148 with cirrhosis (cohort 1) and 163 without cirrhosis (cohort 3) undergoing CECT and 133 with cirrhosis (cohort 2) unexposed to ICM. Kidney function parameters were assessed at T0, 48-72 h (T1), 5 and 7 days after CECT/enrollment. Urinary neutrophil gelatinase-associated lipocalin (U-NGAL) was measured in 50 consecutive patients from cohort 1 and 50 from cohort 2 as an early biomarker of tubular damage., Results: AKI incidence was not significantly increased in patients with cirrhosis undergoing CECT (4.8%, 1.5%, 2.5% in cohorts 1, 2, 3 respectively, p = n.s.). Most AKI cases were mild and transient. The presence of concomitant infections was the only independent predictive factor of contrast-induced AKI (odds ratio 22.18; 95% CI 2.87-171.22; p = 0.003). No significant modifications of U-NGAL between T0 and T1 were detected, neither in cohort 1 nor in cohort 2 (median ΔU-NGAL: +0.2 [-7.6 to +5.5] ng/ml, +0.0 [-6.8 to +9.5] ng/ml, respectively [p = 0.682])., Conclusions: AKI risk after CECT in cirrhosis is low and not significantly different from that of the general population or of the cirrhotic population unexposed to ICM. It mostly consists of mild and rapidly resolving episodes of renal dysfunction and it is not associated with tubular kidney injury. Patients with ongoing infections appear to be the only ones at higher risk of AKI., Impact and Implications: Nephrotoxicity due to intravenous iodinated contrast media (ICM) in patients with cirrhosis is still a debated issue, as the available evidence is limited and based on very heterogeneous studies, often conducted on small and retrospective cohorts. In this prospective three-cohort study we found that intravenous administration of ICM was associated with a low risk of AKI, similar to that of the general population and to that of patients with cirrhosis unexposed to ICM. Patients with ongoing infections were the only ones to have a significantly increased risk of contrast-induced AKI. Therefore, the actual recommendations of performing contrast imaging studies cautiously in cirrhosis do not seem to be reasonable anymore, with the exception of infected patients, who have a significantly higher risk of contrast-induced AKI., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The administration of biological drugs in inflammatory bowel diseases (IBD) is increasingly moving from intravenous to subcutaneous formulations., Aims: To evaluate the efficacy and safety of vedolizumab subcutaneous administration after switching from intravenous administration in ulcerative colitis (UC) patients in corticosteroid-free clinical remission., Methods: An observational, multicentre, prospective study was conducted by the Italian Group for the study of IBD (IG-IBD). UC patients in clinical remission (pMAYO < 2) not receiving steroids for > 8 months before the switch, and with at least 6 months of follow-up were included. Switch from intravenous to subcutaneous vedolizumab was defined as successful in patients not experiencing a disease flare (pMAYO ≥ 2) or needing oral steroids or stopping subcutaneous vedolizumab during the 6 months of follow-up after the switch., Results: Overall, 168 patients were included. The switch was a success in 134 patients (79.8%). Vedolizumab retention rate was 88.7% at month six. C-reactive protein and faecal calprotectin values did not change after the switch (p = 0.07 and p = 0.28, respectively). Ten of the 19 patients who stopped subcutaneous formulation switched back to intravenous formulation recapturing clinical remission in 80%. Side effects were observed in 22 patients (13.1%)., Conclusion: Effectiveness of switching from intravenous to subcutaneous vedolizumab formulation in UC patients in steroid-free clinical remission is confirmed in a real-world setting., Competing Interests: Conflicts of Interest and source of funding Davide Giuseppe Ribaldone Lecture fees and Advisory Board per Janssen-Cilag, Takeda, Galapagos, Biogen. Laura Parisio Nothing to declare. Angela Variola Lecture fees and Advisory Board per Janssen-Cilag, Takeda, Pfizer, Ferring, MSD, Zambon, Abbvie, Celltrion. Fabrizio Bossa Lecture fees and Advisory Board per Janssen-Cilag, Takeda, Galapagos, Biogen, Abbvie, MSD, Celltrion, Mundipharma. Fabiana Castiglione Consultant for Abbvie, Fresenius, Sandoz, Galapagos, Pfizer, Takeda, Janssen, Biogen, Celltrion. Manuela Marzo Nothing to declare. Nicole Piazza Nothing to declare. Annalisa Aratari Advisory Board for Galapagos. Consultant for Abbvie, Galapagos, Pfizer, Takeda, Janssen. Edoardo Vincenzo Savarino Speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, Mayoly Biohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, Unifarco. Consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, Unifarco. He received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici. Giorgia Bodini Nothing to declare. Mauro Mastronardi Lecture fees and Advisory Board per Takeda, Galapagos, Biogen, AuroraPharma Abbvie. Silvia Mazzuoli Lecture fees and Advisory Board per Janssen, Galapagos, Takeda, Abbvie, MSD, Pfizer. Federica Micheli Nothing to declare. Silvia Mazzuoli Nothing to declare. Marta Ascolani Nothing to declare. Chiara Viganò Lecture fees and Advisory Board for Janssen-Cilag, Takeda, Galapagos, Pfizer, Celltrion, Alfasigma. Maria Cappello Lecture fees and Advisory Board for Takeda, Janssen-Cilag, Biogen, Galapagos, Pfizer. Cristina Bezzio Lecture fees and Consultant for Ferring, Takeda, Janssen, Abbvie, Galapagos, Pfizer. Nothing to declare. Rachele Ciccocioppo Advisory Board for Galapagos, Takeda; scientific consultant for Revalma, and lecture fee from Fresenius-Kabi and Takeda. Giulia Scardino Nothing to declare. Ennio Sarli Nothing to declare. Daniela Pugliese Lecture fees and Advisory Board per Janssen-Cilag, Takeda, Galapagos, Biogen, MSD, Pfizer. Franco Scaldaferri Lecture fees and Advisory Board per Janssen-Cilag, Takeda, Galapagos, Ferring, Sandoz, MSD, Pfizer, Celltrion. Daniele Napolitano Nothing to declare. Alessia Todeschini. Andrea Geccherle Nothing to declare. Nicoletta Colaci Nothing to declare. Maria Guerra. Nothing to declare. Monica Annese Nothing to declare. Anna Testa Lecture fees and Consultant for Takeda, Janssen, Abbvie, Galapagos, Pfizer. Anna Caiazzo Nothing to declare. Francesco Simone Conforti Nothing to declare. Stefano Festa Advisory Board for Janssen-Cilag. Consultancy fees for Takeda, Pfizer. Greta Lorenzon Nothing to declare. Antonella Marra Nothing to declare. Ambra Magiotta Nothing to declare. Flavia Baccini Nothing to declare. Arnaldo Amato Nothing to declare. Anxhela Poshnjari Nothing to declare. Marta Vernero Nothing to declare. Flavio Caprioli Consultant to Abbvie, MSD, Takeda, Janssen, Roche, Celgene, Bristol-Meyers Squibb, Galapagos, Gilead, Pfizer, Mundipharma, Galapagos, Biogen, Ferring, Eli-Lilly, Nestlè. Lecture fees from Abbvie, Ferring, Takeda, Allergy Therapeutics, Janssen, Pfizer, Biogen, Sandoz, Tillotts Pharma. Unrestricted research grants from Giuliani, Sofar, MSD, Takeda, Abbvie, Celltrion, Pfizer. Gian Paolo Caviglia Nothing to declare., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

(1) Background: when the pathologist faces histologic slides from colonoscopies in daily practice, given the large number of entities and etiologies under inflammatory bowel conditions, in-depth definition of the histological spectrum and the recommendations of current guidelines are often not enough to conclusively define a diagnostic framework. Histological patterns should be organized hierarchically in flowcharts that consider the correlation with clinical data. We conducted an online survey asking a group of gastroenteropathologists to apply a pattern classification based on the most significant lesions in colitis differential diagnosis: crypt distortion and activity. (2) Methods: digital slides from 20 endoscopy samples were analyzed by twenty pathologists and classified according to the occurrence of crypt distortion (nondestructive-destructive colitis) and subsequently to the evidence of activity (ND1-2-3, D1-2). (3) Results: in 8 out of 20 (40%) cases, the participants reached a full agreement regarding the evaluation of crypt distortion (5 cases: nondestructive colitis; 3 cases: destructive colitis). The calculated agreement was k = 0.432. In the second-level quiz (ND1-2-3 and D1-2), full agreement between participants was achieved for 7 of the 28 (25%) possible classifications, with k = 0.229. (4) Conclusions: The findings from this survey are indicative of an unexpectedly low consensus, even among dedicated pathologists, about the recognition of histological changes that are commonly considered critical lesions in the histologic identification of bowel non-neoplastic diseases. In our opinion, these divergences imply a significant risk of misdiagnosis of bowel inflammatory conditions, hampering the usefulness of histological assessment.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a complex disease, resulting from the interplay between environmental determinants and genetic variations. Single nucleotide polymorphism rs738409 C>G in the PNPLA3 gene is associated with hepatic fibrosis and with higher risk of developing hepatocellular carcinoma. Here, we analyzed a longitudinal cohort of biopsy-proven NAFLD subjects with the aim to identify individuals in whom genetics may have a stronger impact on disease progression., Methods: We retrospectively analyzed 756 consecutive, prospectively enrolled biopsy-proven NAFLD subjects from Italy, United Kingdom, and Spain who were followed for a median of 84 months (interquartile range, 65-109 months). We stratified the study cohort according to sex, body mass index (BMI) 2 ) and age (

Background & Aims: The Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 single nucleotide polymorphism (SNP) is one of the major genetic determinant of non-alcoholic fatty liver disease (NAFLD) and is strongly regulated by changes in energy balance and dietary factors. We aimed to investigate the association between the PNPLA3 rs738409 SNP, nutrient intake and NAFLD severity., Method: PNPLA3-rs738409 SNP was genotyped in 181 patients with NAFLD who completed the EPIC Food Frequency Questionnaire. Liver steatosis was evaluated by Controlled Attenuation Parameter (CAP) (Fibroscan®530, Echosens). According to the established cut-off, a CAP value ≥ 300 dB/m was used to identify severe steatosis (S3). An independent group of 46 biopsy-proven NAFLD subjects was used as validation cohort., Results: Overall, median age was 53 years (range 44; 62) and 60.2% of patients were male. Most subjects (56.3%) had S3 and showed increased liver stiffness (p < 0.001), AST (p = 0.003) and ALT levels (p < 0.001) compared to those with CAP<300 dB/m. At logistic regression analyses we found that the interaction between carbohydrates intake and the carriers of the PNPLA3 G risk allele was significantly associated with S3 (p = 0.001). The same result was confirmed in the validation cohort, were the interaction between high carbohydrate intake (48%) and PNPLA3 SNP was significantly associated with steatosis ≥33% (p = 0.038)., Conclusion: The intake of greater than or equal to 48% carbohydrate in NAFLD patients carriers of the CG/GG allele of PNPLA3 rs738409 may increase the risk of significant steatosis., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Inflammatory bowel disease (IBD) is a term used to represent a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are the two major clinical forms. The global incidence and prevalence of IBD have increased over the last 2-4 decades. Despite the specific etiopathogenesis of IBD still being unknown, it is widely recognized that immunological, genetic, and environmental factors are implicated. A greater understanding of the multiple signaling pathways involved has led to the development of biologic therapies in the last two decades. Although these treatments have dramatically transformed the course of IBD, there is not a definitive cure and available therapies may cause adverse events (AEs), limiting their use, or have an inadequate effect in some patients. In this context, emerging therapies addressing new specific pathogenetic mechanisms have shown promising efficacy and safety data in early clinical trials. The purpose of this review is to highlight the available clinical trial data for these new drugs, such as more preferential JAK inhibitors, anti-IL-23 antibodies, sphingosine-1-phosphate receptor modulators, anti-integrin therapies, and other small molecules that are currently under research. We will emphasize the potential significance of these agents in shaping future treatment options.

Late chronotype, the individual's aptitude to perform daily activities late in the day, has been associated with low adherence to the Mediterranean diet (MedDiet) and metabolic syndrome. The aim of this work was to investigate the potential association of chronotype and adherence to the MedDiet with the liver fibrosis risk in patients with non-alcoholic fatty liver disease (NAFLD). Liver stiffness was assessed in 126 patients by FibroScan ® 530. Significant (F ≥ 2) and advanced (F ≥ 3) hepatic fibrosis were defined according to liver stiffness values ≥7.1 kPa and ≥8.8 kPa, respectively. Chronotype (MSFsc) was defined by the Munich Chronotype Questionnaire, and adherence to the MedDiet was defined by the Mediterranean diet score (MDS). Overall, the median age was 55 (46-63) years, and 57.9% of participants were male. The principal comorbidities were type-2 diabetes mellitus (T2DM) (26.1%), arterial hypertension (53.1%), dyslipidaemia (63.4%), obstructive sleep apnoea (5.5%) and depression (5.5%). Most subjects (65.0%) had intermediate + late chronotype and showed higher mid-sleep on workdays ( p < 0.001) and on work-free days ( p < 0.001) compared to those with early chronotype. In the logistic regression model, intermediate + late chronotype ( p = 0.024), MDS ( p = 0.019) and T2DM ( p = 0.004) were found to be significantly and independently associated with the risk of both F ≥ 2 And F ≥ 3. We observed that the intermediate + late chronotype and low adherence to the MedDiet were associated with both significant and advanced liver fibrosis in patients with NAFLD.

Patients with non-alcoholic fatty liver disease (NAFLD) display impaired health-related quality of life (HRQoL) that is often linked to an unhealthy dietary pattern. The aim of this work was to investigate the impact of HRQoL and adherence to the Mediterranean diet on the risk of liver fibrosis (LF) in patients with NAFLD. LF was assessed in 244 patients through transient elastography (FibroScan ® 530. Echosens, Paris, France). Significant LF was defined according to liver stiffness measurements (LSM) values ≥ 7.1 kPa. The Mediterranean diet score and the Short Form-36 questionnaires were also completed. The median age was 54 (44-62) years and 57% of participants were male. A total of 42 (17.2%) participants had LSM ≥ 7.1 kPa and showed increased GGT ( p = 0.001), glucose ( p < 0.001), and triglycerides levels ( p = 0.015) compared to those with LSM ≤7.0 kPa. Moreover, patients with significant LF had significantly lower scores related to Physical Functioning ( p < 0.001) and Role Physical ( p < 0.001). In the logistic regression analysis, lower role physical and lower adherence to the MedDiet ( p = 0.001 and p = 0.009, respectively), after adjusting for age, diabetes, and obstructive sleep apnea, were associated with an increased risk of significant LF. Low adherence to MedDiet and low role physical may influence the risk of significant liver fibrosis in patients with NAFLD.

The study of intestinal permeability is gaining growing interest due to its relevance in the onset and progression of several gastrointestinal and non-gastrointestinal diseases. Though the involvement of impaired intestinal permeability in the pathophysiology of such diseases is recognized, there is currently a need to identify non-invasive biomarkers or tools that are able to accurately detect alterations in intestinal barrier integrity. On the one hand, promising results have been reported for novel in vivo methods based on paracellular probes, i.e., methods that can directly assess paracellular permeability and, on the other hand, on fecal and circulating biomarkers able to indirectly assess epithelial barrier integrity and functionality. In this review, we aimed to summarize the current knowledge on the intestinal barrier and epithelial transport pathways and to provide an overview of the methods already available or currently under investigation for the measurement of intestinal permeability.

Aims: Patients with inflammatory bowel disease (IBD) are known to be at increased risk for venous thrombosis, while their risk for arterial ischemic events is debated. The purpose of this study was to conduct a systematic review of the published literature on the risk of myocardial infarction (MI) in IBD patients and to identify any potential risk factors., Methods: The present study was performed according to PRISMA, with a systematic search on PubMed, Cochrane, and Google Scholar. Risk of MI was the primary end point, while all causes of death and stroke were secondary endpoints. Both univariate and multivariate pooled analysis were performed., Results: An overall population of 515,455 controls and 77,140 persons with IBD (26,852, 34.8% Crohn's disease, CD and 50,288, 65.2% ulcerative colitis, UC) was included. Mean age was similar across controls and IBD. Persons with CD and UC had lower rates of hypertension (14.5% vs. 14.6% vs. 25%), diabetes (2.9% vs. 5.2% vs. 9.2%) and dyslipidaemia (3.3% vs. 6.5% vs. 16.1%) compared to controls. Smoking did not significantly differ (17% vs. 17.5% vs. 10.6%). Pooled results of multivariate adjustment showed that, after a 5 years-follow-up, both CD and UC were at increased risk of MI (respectively HR 1.36 [1.12-1.64] and HR 1.24 [1.05-1.46]), of death (HR 1.55 [1.27-1.90] and HR 1.29 [1.01-1.64]), and of other CV disease as stroke (HR 1.22 [1.01-1.49] and HR 1.09 [1.03-1.15], all 95% CI)., Conclusions: Persons with IBD are at increased risk of MI, despite a lower prevalence of the classic risk factors for MI (hypertension, diabetes, dyslipidemia)., Competing Interests: Declaration of Competing Interest Conflict of interest: none declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Non-alcoholic steatohepatitis (NASH) is a high-prevalence, rapidly growing form of non-alcoholic fatty liver disease (NAFLD), which is closely linked to obesity and metabolic disorders. Gut microbiota has been increasingly recognized as a key factor in the onset of NAFLD in recent years. The liver can be strongly influenced by changes in the gut microbiota through the portal vein, giving the gut-liver axis a very important role in understanding the pathophysiology of liver diseases. A healthy intestinal barrier is characterized by selective permeability to nutrients, metabolites, water and bacterial products and its impairment may be a predisposing or aggravating condition for the progression of NAFLD. In most cases, NAFLD patients follow a Western diet pattern, which is closely linked to obesity and associated metabolic diseases, promoting inflammation, structural and behavioral changes in the gut microbiota. In fact, factors such as age, gender, genetic or environmental factors may induce a dysbiotic microbiota that promotes epithelial barrier dysfunction and increased intestinal permeability, favoring the progression of NAFLD. In this context, new dietary approaches, such as prebiotics, are emerging to prevent disease and maintain health. In this review, we reported the role of the gut-liver axis in the pathogenesis of NAFLD and investigated the potential therapeutic effect of prebiotics on the enhancement of intestinal barrier dysfunction, hepatic steatosis and, consequently, the progression of NAFLD.

Hepatocellular carcinoma (HCC) represents a relevant disease burden in cirrhotic patients with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the prognostic value of simple non-invasive tests (NITs) (AAR, APRI, BARD, FIB-4) for the stratification of HCC risk development in a cohort of 122 consecutive cirrhotic individuals with NAFLD. Over a median follow up of 5.9 (3.2-9.3) years, 13 (10.7%) developed HCC. Only FIB-4 was associated with HCC risk (HR = 1.27, 95% CI 1.03-1.58, p = 0.027). After evaluating different established FIB-4 cut-offs, the lowest cut-off of 1.45 allowed the ruling out of a greater number of patients with a minimal risk of HCC than the 1.3 cut-off (23 vs. 18 patients). Conversely, the cumulative incidence of HCC using the highest cut-off of 3.25 (rule in) was distinctly higher than the 2.67 cut-off (19.4% vs. 13.3%). After multivariate Cox regression analysis, these cut-offs were independently associated with HCC after adjusting for sex, BMI and T2DM (HR = 6.40, 95% CI 1.71-24.00, p = 0.006). In conclusion, FIB-4 values of <1.3 and >3.25 could allow for the optimal stratification of long-term HCC risk in cirrhotic individuals with NAFLD.

Background: Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyl transferase (NAPRT) are key intracellular enzymes that participate in the biosynthesis on NAD but have also been shown to be released as proinflammatory cytokines. A number of reports have shown that circulating NAMPT is increased in serum of patients with inflammatory disorders, including inflammatory bowel diseases (IBD), while nothing is known regarding circulating NAPRT and the presence of both cytokines in IBD patient stools. In the present study, we evaluated eNAMPT and eNAPRT levels in a large cohort of IBD patients not on biological therapy and in a subset that then was prescribed biologics., Methods: We conducted a retro-perspective study on 180 patients, of which 111 underwent subsequent biological treatment (adalimumab, vedolizumab, and ustekinumab). We analyzed eNAMPT and eNAPRT concentrations in serum and faces of IBD patients, correlating them with response to biologics., Results: We now report that eNAMPT and eNAPRT are significantly increased in both serum and stools of IBD patients. NAMPT and NAPRT levels correlate with disease severity, with C reactive protein and with serum IL-6 levels. Importantly, levels of NAMPT in patients starting treatment with adalimumab correlate with response failure at three months: patients with levels above 4 ng/ml were significantly less likely to obtain benefit. Serum NAMPT as a biomarker of response yields a sensitivity of 91% and a specificity of 100%., Conclusion: The present work strongly suggests that a prospective trial evaluating eNAMPT and eNAPRT levels in relation to response to biologicals in IBD should be initiated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Colombo, Caviglia, Ravera, Tribocco, Frara, Rosso, Travelli, Genazzani and Ribaldone.)

Background and aims: Non-invasive tests (NITs) are needed in clinical practice to replace histology for the identification of liver fibrosis and prognostication in Non-Alcoholic Fatty Liver Disease (NAFLD). Novel collagen-derived fibrogenesis markers including N-terminal type III collagen pro-peptide (PRO-C3) are among the most promising tools in this field. The aim of this study was to assess the diagnostic accuracy of PRO-C3, the derivative ADAPT score, and other NITs for the identification of advanced fibrosis (stages 3-4) and changes over 12 months of follow-up. Methods: In this longitudinal study, 96 patients with biopsy-proven NAFLD were evaluated at baseline, of which 50 underwent a follow-up visit after 12 months. Clinical-biochemical parameters, liver stiffness (LS) by transient elastography, PRO-C3, and other NITs (ADAPT, FIB-4, NFS, APRI) were collected at baseline and follow-up. Results: LS showed the best accuracy for the identification of advanced fibrosis, with Area under the Receiving Operator Curve (AUROC) 0.82 (0.73-0.89) for a cut-off value of 9.4 kPa. Among the other NITs, the ADAPT score showed the best accuracy, with AUROC 0.80 (0.71-0.88) for a cut-off of 5.02 (Se 62%, Sp 89%, PPV 74%, NPV 83%). The comparison between the AUROC of LS with that of ADAPT was not statistically different (DeLong test p value 0.348). At follow-up, LS was slightly reduced, whilst PRO-C3 displayed a significant increase from baseline median 11.2 ng/mL to 13.9 ng/mL at follow-up ( p = 0.017). Accordingly, ADAPT score increased from median 5.3 to 6.1 ( p = 0.019). The other NITs did not significantly change over 12 months. Conclusions: The ADAPT score shows the best performance among non-invasive scores for the identification of advanced fibrosis, not different from LS. Collagen-derived biomarker PRO-C3 and the derivative score ADAPT display significant changes over time, and may be useful tools for monitoring the progression of liver disease or assessing responses to treatments.

The burden of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is increasing worldwide. The aim of the present study was to investigate the clinical characteristics and the changing in epidemiology of IBD in the Healthcare District Bra, an area of North-West Italy accounting for 57,615 inhabitants as of 31 December 2021. Clinical and demographic data were retrieved from administrative databases and the medical records of general practitioners ( n = 39) at Verduno Hospital. Prevalence and incidence rates were calculated for the time span 2016-2021 and compared to the 2001-2006 period. IBD prevalence was 321.2 per 100,000 population in 2021 and, compared with 2006 (200 per 100,000 population), the prevalence has increased at a rate of +46%. Similarly, the average incidence has increased from the period 2001-2006 (6.7 per 100,000 population/year) to the period 2016-2021 (18.0 per 100,000 population/year) at a rate of +169%; such an increase was greater for CD than UC. In the 2016-2021 period, the mean age at diagnosis was 42.0 ± 17.4 years and 30.9% required at least one hospitalization, while 10.9% of patients underwent at least one surgery. In conclusion, the prevalence and incidence of IBD distinctly increased over a two decade period in the Healthcare District Bra paralleling the results of previous surveys from other Italian regions. These data warrant specific interventions to improve patients' management and resources' allocation.

Background and aims: The identification of patients with Hepatitis C Virus (HCV)-positive advanced chronic liver disease (aCLD) successfully treated by Direct Acting Antiviral Agents (DAAs) who really benefit from Hepatocellular Carcinoma (HCC) surveillance programs is still a matter of debate. We performed a long-term prospective cohort study on F3-F4 HCV-positive patients achieving Sustained Virologic Response (SVR) after DAAs treatment in order to identify patients who can safely suspend surveillance. Methods: 1000 patients with HCV-positive aCLD obtaining SVR by DAAs from January 2015 to December 2017 were divided into four groups according to baseline elastographic, ultrasonographic, clinical and biochemical features: (1) Group 1: 324 patients with Liver Stiffness Measurement (LSM) ≥ 9.5 ≤ 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (2) Group 2: 133 patients with LSM ≥ 9.5 ≤ 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5 (3) Group 3: 158 patients with LSM > 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (4) Group 4: 385 patients with LSM > 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5. FIB-4 and APRI scores were calculated at baseline and at SVR achievement. Each patient was surveiled twice-yearly by ultrasound for a median follow-up of 48 months. Results: among Group 1 patients, 1/324 (0.3%) developed HCC (0.09/100 patients/year [PY]), compared to 6/133 (4.5%) Group 2 patients (1.22/100 PY, p = 0.0009), 10/158 (6.3%) Group 3 patients (1.68/100 PY, p = 0.0001), 54/385 (14.0%) Group 4 patients (4.01/100 PY, p < 0.0001). HCC incidence was significantly lower in Group 2 compared to Group 3 (p = 0.004) and in Group 3 compared to Group 4 (p = 0.009). HCC risk fell in patients showing a decrease of FIB-4/APRI scores. Conclusions: the risk of HCC occurrence is negligible in about 90% of HCV-positive patients with baseline LSM ≥ 9.5 ≤ 14.5 kPa plus FIB-4 < 3.25 and APRI < 1.5 achieving SVR. Among this particular subset of patients, FIB-4/APRI scores may represent an accurate and inexpensive tool to distinguish patients not needing long-term HCC surveillance.

Patients with cirrhosis are at risk of hepatocellular carcinoma (HCC) development and, according to current guidelines, should undergo surveillance by ultrasound at six month intervals. Due to the known limitations of surveillance strategies based on ultrasonography, the use of tumor biomarkers, although debated, is common practice in many centers. The aim of the study was to identify the best cut-off value for one of such biomarkers, protein induced by vitamin K absence, or antagonist-II (PIVKA-II). We retrospectively enrolled 1187 patients with liver cirrhosis: 205 with a diagnosis of HCC (median age 67 years, 81.0% males) and 982 without tumor (median age 64 years, 56.2% males). During a median follow-up (FU) of 34.6 (11.4−43.7) months, 118 out of 982 (12.0%) patients developed HCC. Serum PIVKA-II was assessed by chemiluminescence immunoassay on the Lumipulse® G600 II platform (Fujirebio, Tokyo, Japan). In the overall cohort (n = 1187), PIVKA-II showed an area under the curve (AUC) of 0.802 for HCC detection. The best cut-off value that maximized sensitivity was 50 mAU/mL (sensitivity = 80%, specificity = 64%). In the 982 patients without HCC at baseline, PIVKA-II > 50 mAU/mL was associated with an increased risk of HCC development during the FU (HR = 1.74, 95% CI 1.21−2.51; p = 0.003)). In conclusion, the evaluation of serum PIVKA-II showed a good performance for HCC detection; a cut-off value > 50 mAU/mL could be suitable for the surveillance of patients who are at risk of developing HCC.

Intrahepatic oxidative stress is a key driver of inflammation and fibrogenesis in non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the role of extracellular Nicotinamide phosphoribosyltransferase (eNAMPT) and extracellular nicotinic acid phosphoribosyltransferase (eNAPRT) for the detection of advanced fibrosis. eNAMPT and eNAPRT were tested in 180 consecutive biopsy-proven NAFLD patients and compared with liver stiffness (LS) and the FIB-4 score. eNAMPT was similarly distributed across fibrosis stages, whereas eNAPRT was increased in patients with advanced fibrosis ( p = 0.036) and was associated with advanced fibrosis (OR 1.08, p = 0.016). A multiple stepwise logistic regression model containing significant variables for advanced fibrosis (eNAPRT, type 2 diabetes, age, male sex, ALT) had an area under the curve (AUC) of 0.82 (Se 89.6%, Sp 67.3%, PPV 46.7%, NPV 93.8%) when compared to that of LS (0.79; Se 63.5%, Sp 86.2%, PPV 66.0%, NPV 84.8%) and to that of the FIB-4 score (0.73; Se 80.0%, Sp 56.8%, PPV 44.9%, NPV 86.6%). The use of eNAPRT in clinical practice might allow for the better characterization of NAFLD patients at higher risk of disease progression.

Current treatment for celiac disease (CD) is adhering to a gluten-free diet (GFD), although its long-term molecular effects are still undescribed. New molecular features detectable in stool may improve and facilitate noninvasive clinical management of CD. For this purpose, fecal small non-coding RNAs (sncRNAs) and gut microbiome profiles were concomitantly explored in CD subjects in relation to strict (or not) GFD adherence over time. In this observational study, we performed small RNA and shotgun metagenomic sequencing in stool from 63 treated CD (tCD) and 3 untreated subjects as well as 66 sex- and age-matched healthy controls. tCD included 51 individuals on strict GFD and with negative transglutaminase (TG) serology (tCD-TG-) and 12 symptomatic with not strict/short-time of GFD adherence and positive TG serology (tCD-TG+). Samples from additional 40 healthy adult individuals and a cohort of 19 untreated pediatric CD subjects and 19 sex/age matched controls were analyzed to further test the outcomes. Several miRNA and microbial profiles were altered in tCD subjects (adj. p < .05). Findings were validated in the external group of adult controls. In tCD-TG-, GFD duration correlated with five miRNA levels (p < .05): for miR-4533-3p and miR-2681-3p, the longer the diet adherence, the less the expression differed from controls. tCD-TG+ and untreated pediatric CD patients showed a similar miRNA dysregulation. Immune-response, trans-membrane transport and cell death pathways were enriched in targets of identified miRNAs. Bifidobacterium longum, Ruminococcus bicirculans , and Haemophilus parainfluenzae abundances shifted (adj. p < .05) with a progressive reduction of denitrification pathways with GFD length. Integrative analysis highlighted 121 miRNA-bacterial relationships (adj. p < .05). Specific molecular patterns in stool characterize CD subjects, reflecting either the long-term GFD effects or the gut inflammatory status, in case of a not strict/short-time adherence. Our findings suggest novel host-microbial interplays and could help the discovery of biomarkers for GFD monitoring over time.

The coronavirus disease (COVID-19) pandemic represents a global health challenge, particularly considering concomitant diseases. Patients with inflammatory bowel diseases (IBD) can be considered a population at risk. On the other hand, the risk of developing IBD and COVID-19 have both been described as modulated by vitamin D (VD) levels. In this work, a cohort of 106 adult patients affected by IBD was prospectively enrolled, during the second wave of the pandemic in Italy. In these patients, VD plasma levels, demographic, and clinical characteristics were tested for a correlation/an association with the risk of infection with SARS-CoV-2 in the study period (anti-spike IgG positivity) and the severity of COVID-19 symptoms. By multivariate logistic regression analysis, VD supplementation (Odds Ratio; OR 0.116, p = 0.002), therapy with monoclonal antibodies (OR 0.227, p = 0.007), and the use of mesalazine (OR 2.968, p = 0.046) were found to be independent predictors of SARS-CoV-2 positivity. Moreover, hypertension was associated with severe disease ( p = 0.019), while a VD level higher than 30 ng/mL ( p = 0.031, OR 0.078) was associated with asymptomatic infection. No interplay between IBD activity and COVID-19 risk of infection or symptoms was observed. These results confirm the importance of VD levels in defining the risk of COVID-19 and give encouraging data about the safety of maintaining immunomodulatory treatments for IBD during the COVID-19 pandemic.

Background: Glypican-3 (GPC-3) is a heparan sulfate proteoglycan overexpressed by hepatocellular carcinoma (HCC) cells. Several studies highlighted the diagnostic and prognostic value of GPC-3 expression in liver tissue, while data on the reliability of serum GPC-3 are limited and conflicting. We aimed to evaluate the prognostic value of serum GPC-3 in patients with HCC., Methods: A total of 449 patients (91 F and 358 M; median age 65 [38-86] years) with a new diagnosis of HCC and available serum samples collected at tumor diagnosis were retrospectively analyzed. All patients had cirrhosis and the main underlying etiology was viral (N.=323, 72%). Barcelona Clinic Liver Cancer (BCLC) staging system was adopted for patients' classification (BCLC 0/A, N.=293, 65% vs. B/C/D, N.=156, 35%) and treatment allocation. Response to therapy was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST)., Results: Median overall survival (OS) after HCC diagnosis was 30 months (95% confidence interval [CI]: 27-34). Patients with serum GPC-3>150 pg/mL showed lower overall survival (16; 95%CI: 13-24 months) compared to those with GPC-3≤150 pg/mL (36; 95%CI: 30-56 months) (Log-rank test, P<0.001). At multivariate Cox proportional-hazard regression analysis, presence of ascites (adjusted Hazard Ratio [aHR]=1.84; 95%CI: 1.23-2.74, P=0.003), BCLC stage (aHR=1.65; 95%CI: 1.39-1.97, P<0.001), mRECIST (aHR=0.33; 95%CI: 0.21-0.51, P<0.001) and GPC-3>150 pg/mL (aHR=2.02; 95%CI: 1.47-2.78, P<0.001) resulted significantly associated to overall survival., Conclusions: Serum GPC-3 resulted an independent prognostic factor for patients with HCC irrespectively from tumor stage and response to therapy.

Several features of the modern lifestyle, such as weekly schedules or irregular daily eating patterns, have become major drivers of global health problems, including non-alcoholic fatty liver disease (NAFLD). Sleep is an essential component of human well-being, and it has been observed that when circadian rhythms are disrupted, or when sleep quality decreases, an individual's overall health may worsen. In addition, the discrepancy between the circadian and social clock, due to weekly work/study schedules, is called social jetlag and has also been associated with adverse metabolic profiles. Current management of NAFLD is based on dietary intake and physical activity, with circadian preferences and other environmental factors also needing to be taken into account. In this regard, dietary approaches based on chrononutrition, such as intermittent fasting or time-restricted feeding, have proven to be useful in realigning lifestyle behaviors with circadian biological rhythms. However, more studies are needed to apply these dietary strategies in the treatment of these patients. In this review, we focus on the impact of circadian rhythms and the role of sleep patterns on the pathogenesis and development of NAFLD, as well as the consideration of chrononutrition for the precision nutrition management of patients with NAFLD.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous disorder, but the factors that determine this heterogeneity remain poorly understood. Adipose tissue dysfunction is causally linked to NAFLD since it causes intrahepatic triglyceride (IHTG) accumulation through increased hepatic lipid flow, due to insulin resistance and pro-inflammatory adipokines release. While many studies in NAFLD have looked at total adiposity (i.e. mainly subcutaneous fat, SC-AT), it is still unclear the possible impact of visceral fat (VF). Thus, we investigated how VF versus SC-AT was related to NAFLD severity in lean, overweight and obese individuals versus lean controls., Methods: Thirty-two non-diabetic NAFLD with liver biopsy (BMI 21.4-34.7 kg/m 2 ) and eight lean individuals (BMI 19.6-22.8 kg/m 2 ) were characterized for fat distribution (VF, SC-AT and IHTG by magnetic resonance imaging), lipolysis and insulin resistance by tracer infusion, free fatty acids (FFAs) and triglyceride (TAG) concentration and composition (by mass spectrometry)., Results: Intrahepatic triglyceride was positively associated with lipolysis, adipose tissue insulin resistance (Adipo-IR), TAG concentrations, and increased saturated/unsaturated FFA ratio. Compared to controls VF was higher in NAFLD (including lean individuals), increased with fibrosis stage and associated with insulin resistance in liver, muscle and adipose tissue, increased lipolysis and decreased adiponectin levels. Collectively, our results suggest that VF accumulation, given its location close to the liver, is one of the major risk factors for NAFLD., Conclusions: These findings propose VF as an early indicator of NAFLD progression independently of BMI, which may allow for evidence-based prevention and intervention strategies., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Chronic hepatitis (CH) of dysmetabolic or viral etiology has been associated with poor prognosis in patients who experienced the severe acute respiratory coronavirus virus-2 (SARS-Cov-2) infection. We aimed to explore the impact of SARS-Cov-2 infection on disease severity in a group of patients with CH. Forty-two patients with CH of different etiology were enrolled (median age, 56 years; male gender, 59%). ACE2 and TMPRSS2 were measured in plasma samples of all patients by ELISA and in the liver tissue of a subgroup of 15 patients by Western blot. Overall, 13 patients (31%) experienced SARS-Cov-2 infection: 2/15 (15%) had CHB, 5/12 (39%) had CHC, and 6/15 (46%) had non-alcoholic fatty liver disease (NAFLD). Compared to viral CH patients, NAFLD subjects showed higher circulating ACE2 levels ( p = 0.0019). Similarly, hepatic expression of ACE2 was higher in subjects who underwent SARS-Cov-2 infection compared to the counterpart, (3.24 ± 1.49 vs. 1.49 ± 1.32, p = 0.032). Conversely, hepatic TMPRSS2 was significantly lower in patients who experienced symptomatic COVID-19 disease compared to asymptomatic patients ( p = 0.0038). Further studies are necessary to understand the impact of COVID-19 in patients with pre-existing liver diseases.

Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of refractory forms of epilepsy and depression. The brain-gut axis is increasingly being studied as a possible etiological factor of chronic inflammatory diseases, including inflammatory bowel diseases (IBD). A significant percentage of IBD patients lose response to treatments or experience side effects. In this perspective, VNS has shown the first efficacy data. The aim of this narrative review is to underline the biological plausibility of the use of VNS in patients affected by IBD, collect all clinical data in the literature, and hypothesize a target IBD population on which to focus the next clinical study.

Despite the availability of an effective vaccination, chronic hepatitis B virus (HBV) infection is still a major health concern worldwide. Chronic HBV infection can lead to fibrosis accumulation and overtime to cirrhosis, the principal risk factor for liver failure and hepatocellular carcinoma development. Liver biopsy is still considered the gold standard for fibrosis assessment, even though it is invasive and not exempt of complications. Overtime, several non-invasive methods for the detection of liver fibrosis have been developed and gradually introduced into clinical practice. However, their main limitation is the poor performance for the detection of intermediate stages of fibrosis. Finally, novel serological biomarkers, polygenic risk scores and imaging methods have been proposed in last years as novel promising tools to correctly identify the degree of liver fibrosis and to monitor liver disease progression. In this narrative review, we provide an overview on the novel non-invasive approaches for the evaluation of liver fibrosis and risk stratification of patients with chronic hepatitis B.

In patients with Crohn’s disease (CD) that underwent surgery, predictive factors of surgical recurrence have been only partially identified. The aim of our study was to identify potential factors associated with an increased risk of surgical recurrence. A monocentric retrospective observational study was conducted including patients diagnosed with CD, according to ECCO criteria who received their first ileocolic resection. Overall, 162 patients were enrolled in our study; 54 of them were excluded due to a lack of sufficient data. The median follow-up was 136.5 months, IQR 91.5−176.5, and the surgical recurrence rate after the median follow-up was 21.3%. In the multivariate analysis, an age ≤ 28 years at the first surgical resection (aHR = 16.44, p < 0.001), current smoking (aHR = 15.84, p < 0.001), female sex (aHR = 7.58, p < 0.001), presence of granulomas at local lymph nodes (aHR = 12.19, p < 0.001), and treatment with systemic corticosteroids after the first surgical resection (aHR = 7.52, p = 0.002) were factors significantly associated with a risk of surgical recurrence, while cryptitis resulted in a protective factor (aHR = 0.02, p < 0.001). In conclusion, the heterogeneous spectrum of factors associated to the risk of surgical recurrence in patients with CD that underwent ileocolic resection supports the need of a personalized follow-up taking into account different clinical, surgical, and histologic features.

Hepatitis D is the most severe viral hepatitis. Hepatitis D virus (HDV) has a very small RNA genome with unique biological properties. It requires for infection the presence of hepatitis B virus (HBV) and is transmitted parenterally, mainly by superinfection of HBsAg carriers who then develop chronic hepatitis D. HDV has been brought under control in high-income countries by the implementation of HBV vaccination, and the clinical pattern has changed to a chronic hepatitis D seen in ageing patients with advanced fibrotic disease; the disease remains a major health concern in developing countries of Africa and Asia. Every HBsAg-positive subject should be tested for HDV serum markers by reflex testing, independently of clinical status. Vaccination against HBV provides the best prophylaxis against hepatitis D. The only therapy available so far has been the poorly performing Interferon alfa; however, several new and promising therapeutic approaches are under study.

The advent of direct antiviral agents (DAAs) has radically changed the natural history of hepatitis C virus (HCV) chronic liver disease. Even patients with cirrhosis may display improvements in liver function or features of portal hypertension following viral eradication. The aim of this study was to assess whether a HCV cure would lead to improvements in cirrhotic patients using simple, readily available tools in clinical practice, together with liver stiffness (LS) measurement. This is a retrospective study of cirrhotic patients with cured HCV infection, with or without previous decompensation. Clinical and biochemical parameters as well as LS measurements were collected before antiviral treatment with DAAs and after 6 months following sustained virological response. Hepatic synthesis was assessed by serum albumin levels. Portal hypertension was indirectly assessed by platelet count. Liver function was determined by the CHILD score. A total of 373 cirrhotic patients with successful HCV eradication were retrospectively included. After 6 months of follow-up, a significantly higher proportion of patients showed improved liver function, shifting from the CHILD B/C to CHILD A group, (71.4%, p < 0.001). Similarly, LS improved from a median of 19.3 kPa (14.7−27) at the baseline vs. a median of 11.6 (7.7−16.8 kPa) at follow-up (p < 0.001). The proportion of patients who showed improved hepatic synthesis was 66.0%, which was statistically different when compared to that of patients who had a worsened condition (0.3%) (p < 0.001). Moreover, when classifying the cohort according to the RESIST-HCV score, we found that a significant proportion of patients shifted into the “low risk” group following DAA treatment (52% baseline vs. 45.6% at follow-up, p = 0.004). Even in the decompensated patients, LS improved from 1.6 to 2-fold from the baseline. Antiviral treatment is effective in improving indirect signs of hepatic synthesis and portal hypertension. Similarly, the LS values displayed significant improvements, even in decompensated patients.

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., Competing Interests: Conflicts of interest None declared., (Copyright © 2021. Published by Elsevier Ltd.)

Reliable non-invasive biomarkers for the surveillance of patients at risk of hepatocellular carcinoma (HCC) development represent an unmet medical need. Recently, the liver-cancer-specific isoform of serine protease inhibitor Kazal (LC-SPIK) has been proposed as a valuable biomarker for the detection of HCC in patients with chronic liver disease of viral etiology. In the present study, we assessed the diagnostic accuracy of LC-SPIK, alone or in combination with standard serologic biomarkers (i.e., alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II, PIVKA-II), for the detection of HCC among patients with dysmetabolic liver disease. A total of 120 patients with non-alcoholic fatty liver disease (NAFLD), including 62 patients with a diagnosis of HCC and 58 with cirrhosis but without tumor, were retrospectively analyzed. The serum levels of LC-SPIK were measured by enzyme-linked immunosorbent assay (ImCare Biotech, Doylestown, PA). The serum LC-SPIK values were significantly different between patients with HCC (24.3, 17.6−39.8 ng/mL) and those with cirrhosis but without tumor (11.7, 8.7−18.2 ng/mL) (p < 0.001). By receiver operating characteristic curve analysis, we observed an area under the curve (AUC) of 0.841 for the detection of HCC; the combination with PIVKA-II further increased the accuracy to AUC = 0.926 (cross-validation). The promising results observed in the present pilot study foster additional research to investigate the usefulness of LC-SPIK for the stratification of the risk of HCC development in patients with NAFLD and advanced liver disease.