Intestinal barrier dysfunction as a key driver of severe COVID-19

The intestinal lumen harbors a diverse consortium of microorganisms that participate in reciprocal crosstalk with intestinal immune cells and with epithelial and endothelial cells,forming a multi-layered barrier that enables the efficient absorption of nutrients without an excessive influx of pathogens.Despite being a lung-centered disease,severe coronavirus disease 2019(COVID-19)affects multiple systems,including the gastrointestinal tract and the pertinent gut barrier function.Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)can inflict either direct cytopathic injury to intestinal epithelial and endothelial cells or indirect immune-mediated damage.Alternatively,SARS-CoV-2 undermines the structural integrity of the barrier by modifying the expression of tight junction proteins.In addition,SARS-CoV-2 induces profound alterations to the intestinal microflora at phylogenetic and metabolomic levels(dysbiosis)that are accompanied by disruption of local immune responses.The ensuing dysregu-lation of the gut-lung axis impairs the ability of the respiratory immune system to elicit robust and timely responses to restrict viral infection.The intestinal vasculature is vulnerable to SARS-CoV-2-induced endothelial injury,which simultaneously triggers the activation of the innate immune and coagulation systems,a condition referred to as“immunothrombosis”that drives severe thrombotic complications.Finally,increased intestinal permeability allows an aberrant dissemination of bacteria,fungi,and endotoxin into the systemic circulation and contributes,to a certain degree,to the over-exuberant immune responses and hyper-inflammation that dictate the severe form of COVID-19.In this review,we aim to elucidate SARS-CoV-2-mediated effects on gut barrier homeostasis and their implications on the progression of the disease.

Role of NLRP3 inflammasome in inflammatory bowel diseases

Inflammasomes are multiprotein intracellular complexes which are responsible for the activation of inflammatory responses. Among various subtypes of inflammasomes, NLRP3 has been a subject of intensive investigation. NLRP3 is considered to be a sensor of microbial and other danger signals and plays a crucial role in mucosal immune responses, promoting the maturation of proinflammatory cytokines interleukin 1β(IL-1β) and IL-18. NLRP3 inflammasome has been associated with a variety of inflammatory and autoimmune conditions, including inflammatory bowel diseases(IBD). The role of NLRP3 in IBD is not yet fully elucidated as it seems to demonstrate both pathogenic and protective effects. Studies have shown a relationship between genetic variants and mutations in NLRP3 gene with IBD pathogenesis. A complex interaction between the NLRP3 inflammasome and the mucosal immune response has been reported. Activation of the inflammasome is a key function mediated by the innate immune response and in parallel the signaling through IL-1β and IL-18 is implicated in adaptive immunity. Further research is needed to delineate the precise mechanisms of NLRP3 function in regulating immune responses. Targeting NLRP3 inflammasome and its downstream signaling will provide new insights into the development of future therapeutic strategies.

Recurrence of choledocholithiasis following endoscopic bile duct clearance: Long term results and factors associated with recurrent bile duct stones

AIM To evaluate the rate of recurrence of symptomatic chol-edocholithiasis and identify factors associated with the recurrence of bile duct stones in patients who underwent endoscopic retrograde cholangiopancreatography(ERCP) and endoscopic sphincterotomy(EST) for bile duct stone disease.METHODS All patients who underwent ERCP and EST for bile duct stone disease and had their bile duct cleared from 1/1/2005 until 31/12/2008 was enrolled. All symptomatic recurrences during the study period(until 31/12/2015) were recorded. Clinical and laboratory data potentially associated with common bile duct(CBD) stone recurrence were retrospectively retrieved from patients' files.RESULTS A total of 495 patients were included. Sixty seven(67) out of 495 patients(13.5%) presented with recurrent symptomatic choledocholithiasis after 35.28 ± 16.9 mo while twenty two(22) of these patients(32.8%) experienced a second recurrence after 35.19 ± 23.2 mo. Factors associated with recurrence were size(diameter) of the largest CBD stone found at first presentation(10.2 ± 6.9 mm vs 7.2 ± 4.1 mm, P = 0.024), diameter of the CBD at the first examination(15.5 ± 6.3 mm vs 12.0 ± 4.6 mm, P = 0.005), use of mechanical lithotripsy(ML)(P = 0.04) and presence of difficult lithiasis(P = 0.04). Periampullary diverticula showed a trend towards significance(P = 0.066). On the contrary, number of stones, angulation of the CBD, number of ERCP sessions required to clear the CBD at first presentation, more than one ERCP session needed to clear the bile duct initially and a gallbladder in situ did not influence recurrence. CONCLUSION Bile duct stone recurrence is a possible late complication following endoscopic stone extraction and CBD clearance. It appears to be associated with anatomical parameters(CBD diameter) and stone characteristics(stone size, use of ML, difficult lithiasis) at first presentation.

Role of band ligation for secondary prophylaxis of variceal bleeding

AIM To summarize and critically examine the role of band ligation in secondary prophylaxis of variceal bleeding in patients with cirrhosis. METHODS A literature review was performed using the MEDLINE and PubM ed databases. The search terms consisted of the words "endoscopic band ligation" OR "variceal band ligation" OR "ligation" AND "secondary prophylaxis" OR "secondary prevention" AND "variceal bleeding" OR "variceal hemorrhage" AND "liver cirrhosis". The data collected from relevant meta-analyses and from the most recent randomized studies that were not included in these meta-analyses were used to evaluate the role of endoscopic band ligation in an effort to demonstrate the most recent advances in the treatment of esophageal varices. RESULTS This study included 11 meta-analyses published from 2002 to 2017 and 10 randomized trials published from 2010 to 2017 that evaluated the efficacy of band ligation in the secondary prophylaxis of variceal bleeding. Overall, the results proved that band ligation was superior to endoscopic sclerotherapy. Moreover, the use of β-blockers in combination with band ligation increased the treatment effectiveness, supporting the current recommendations for secondary prophylaxis of variceal bleeding. The use of transjugular intrahepatic portosystemic shunt was superior to combination therapy regarding rebleeding prophylaxis, with no difference in the survival rates; however, the results concerning the hepatic encephalopathy incidence were conflicting. Recent advances in the management of secondary prophylaxis of variceal bleeding have targeted a decrease in portal pressure based on the pathophysiological mechanisms of portal hypertension.CONCLUSION This review suggests that future research should be conducted to enhance current interventions and/or to develop innovative treatment options with improved clinical endpoints.

Risk of hepatitis B reactivation in patients treated with direct-acting antivirals for hepatitis C

The recent introduction of direct-acting antiviral drugs(DAAs) for treatment of the hepatitis C virus(HCV) has greatly improved the management of HCV for infected patients. These viral protein inhibitors act rapidly, allowing HCV clearance and increasing the sustained virological response rates. However, hepatitis B virus(HBV) reactivation has been reported in HCV/HBV co-infected patients. Hepatitis B reactivation refers to an abrupt increase in the HBV and is welldocumented in patients with previously undetected HBV DNA due to inactive or resolved HBV infection. Reactivation can occur spontaneously, but in most cases, it is triggered by various factors. Reactivation can be transient, without clinical symptoms; however, it usually causes a hepatitis flare. HBV reactivation may occur regardless of HCV genotype and type of DAA regimen. HBV screening is strongly recommended for co-infected HCV/HBV patients before initiation and during DAA therapy regardless of HBV status, HCV genotype and class of DAAs used. HBV reactivation can be prevented with pretreatment screening and prophylactic treatment when necessary. Additional data are required to evaluate the underlying mechanisms of HBV reactivation in this setting.

Impact of muscle wasting on survival in patients with liver cirrhosis

Muscle wasting is defined as the progressive and generalized loss of muscle mass. Muscle depletion is a common feature of chronic liver disease foundin approximately 40% of patients with cirrhosis. Its etiology is multifactorial subsequent to liver failure and its prevalence increases along with disease severity. Cross-sectional analytic morphometry using computed tomography(CT) scan or magnetic resonance imaging are considered by consensus the gold standards to assess muscle size in cirrhosis for research purposes because they are not biased by fluid accumulation. Several studies have assessed the impact of muscle wasting on overall survival of patients in the waiting list for liver transplantation and there is a general agreement that decreased muscle size assessed by CT scan is an independent predictor for mortality in cirrhosis. It has been proposed that the addition of cross-sectional muscle area into the Model for End-stage Liver Disease can increase its prognostic performance. Nevertheless, the use of CT scan in assessing muscle size is inappropriate for routine clinical practice and an alternative cost-effective, easy to use and accurate tool should be developed. In conclusion, muscle wasting has a detrimental impact on survival of patients with cirrhosis and, thus, it remains to be elucidated if nutritional interventions and exercise could improve muscle wasting and, subsequently, survival in this setting.

Interleukin 12/interleukin 23 pathway: Biological basis and therapeutic effect in patients with Crohn's disease

Considering that both innate and adaptive immune responses are involved in the pathogenesis of Crohn's disease(CD), novel therapeutic options have significantly been developed. Biological agents represent an important addition to the conventional treatments for immuno-inflammatory conditions, acting as antagonists of adhesion molecules or various inflammatory cytokines. The interleukin 12(IL-12)/IL-23 common pathway has been found to play a determinant role in the induction of inflammation in adaptive immune responses. In particular, IL-23 promotes the differentiation of na?ve T helper cells into Th17 phenotype with the concomitant secretion of several inflammatory cytokines such as IL-17 and IL-22, whereas IL-12 induces the Th1 polarization and production of critical cytokines such as interferon-γ and tumor necrosis factor. Nowadays, there is increased interest regarding the role of IL-23 as a therapeutic target of CD through the blockage of IL-23 mediated pathways. In this editorial, we focus on the role of IL-12/IL-23 pathway in the regulation of mucosal immunity and in the induction and maintenance of chronic inflammation. In parallel, we critically discuss the available data regarding the therapeutic effect of the IL-12/IL-23 inhibitors and especially of ustekinumab, a human monoclonal antibody which has been recently approved by the United States Food and Drug Administration for the management of moderateto-severe CD and its potential to be used as first-line therapy in everyday clinical practice.

Epidemiology of hepatitis C in Greece

Hepatitis C is a global health issue and constitutes a major cause of chronic liver disease worldwide. In this article, a comprehensive literature search was conducted for the prevalence of hepatitis C virus(HCV) infection in Greece, since data on the HCV prevalence, viremia and genotypes are important for developing strategies to manage or eliminate HCV infection. In addition, the pattern of HCV infection was analyzed according to the geographic region and the risk factors. These differences reflect not only distinct epidemiological characteristics among populations, but also differences on the strategy of data acquisition and quantification. Although there are not enough data, the estimation of the current prevalence of Hepatitis C in Greece ranges from 0.5% to 2%. The most important risk factors for HCV infection include blood product transfusion, intravenous drug use, chronic hemodialysis, organ transplantation, occupational exposure, sexual transmission, and vertical transmission. Because of lack of vaccine or effective post-exposure prophylaxis for HCV, the main focus of prevention is to recognize and control these risk factors. HCV infection in Greece is closely associated with the development of chronic liver disease, cirrhosis, and primary hepatocellular carcinoma. As far as the genotype distribution is concerned genotype 1 estimated to be 45%-47% and it constitutes the prevalent genotype in Greece, followed by genotype 3.