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Introduction: Liver fibrosis has been extensively studied at the cellular and molecular level, but very few data exist on the final enzymatic stages of collagen synthesis (prolyl hydroxylase, PH) and degradation (matrix metalloproteinases, MMPs), particularly in primary biliary cholangitis (PBC). Aim: We studied enzyme activities in liver tissue from patients with chronic liver diseases and compared them to normal livers. Patients: Eighteen patients with PBC of early and late stages (Ludwig’s classification) and seven on treatment with ursodeoxycholate (UDCA) were studied and compared to 34 patients with alcoholic liver disease (ALD), 25 patients with chronic viral liver disease and five normal biopsies. Sera were available from a total of 140 patients. Methods: The tritiated water released from the tritiated proline was measured in PH assessment. 14C intact and heat-denatured collagen substrates were used to measure collagenase and gelatinases, respectively. 3H Elastin was the substrate for elastase. In serum, ELISAs were used for MMP-1, TIMP-1, and TIMP-2 measurements while MMP-2 and MMP-9 were estimated by zymography. Results: PH was significantly increased in early and late PBC. Collagenase was reduced only in the late stages (p < 0.01), where the ratio PH/collagenase was increased. UDCA treatment restored values to almost normal. Gelatinases were reduced in late stages (p < 0.05). In contrast to PBC and ALD fibrosis, collagen synthesis is not increased in viral fibrosis. The balance shifted towards collagen deposition due to reduced degradation. Interestingly, gelatinolytic activity is not impaired in ALD. Elastase was similar to controls in all diseases studied. TIMP-1 was reduced in early PBC and viral and alcoholic hepatitis and cirrhosis (p < 0.001). Conclusions: (1) There is evidence that collagen synthesis increases in the early stages of PBC, but the collagenolytic mechanism may compensate for the increased synthesis. (2) In viral disease, fibrosis may be due to decreased degradation rather than increased synthesis. (3) The final biochemical stages of liver fibrosis may be quantitatively different according to underlying etiology.

The current coronavirus disease 2019 (COVID-19) pandemic has caused a global health emergency crisis, since its outbreak at the end of 2019. Although it mainly affects the respiratory system, it is documented that several important extrapulmonary manifestations exist in the context of the COVID-19 infection. Amongst the major pathophysiological mechanisms, the generation of a prothrombotic environment is increasingly recognized and is related to thromboembolic events. We conducted a review of the literature and summarized the coagulation disorders in the liver in patients with COVID-19., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Clinical and Experimental Hepatology.)

Background: Bacterial infections are associated with the risk of variceal bleeding through complex pathophysiologic pathways., Objectives: The primary objective of the present case-control study was to investigate the role of bacterial translocation and intestinal barrier dysfunction in the pathogenesis of variceal bleeding. A secondary objective was to determine independent predictors of key outcomes in variceal bleeding, including bleeding-related mortality., Methods: Eighty-four ( n = 84) consecutive patients participated in the study, 41 patients with acute variceal bleeding and 43 patients with stable cirrhosis, and were followed up for 6 weeks. Peripheral blood samples were collected at patient admission and before any therapeutic intervention., Results: Child-Pugh (CP) score (OR: 1.868; p = 0.044), IgM anti-endotoxin antibody levels (OR: 0.954; p = 0.016) and TGF-β levels (OR: 0.377; p = 0.026) were found to be significant predictors of variceal bleeding. Regression analysis revealed that albumin (OR: 0.0311; p = 0.023), CRP (OR: 3.234; p = 0.034) and FABP2 levels (OR:1.000, p = 0.040), CP score (OR: 2.504; p = 0.016), CP creatinine score (OR: 2.366; p = 0.008), end-stage liver disease model (MELD), Na (OR: 1.283; p = 0.033), portal vein thrombosis (OR: 0.075; p = 0.008), hepatocellular carcinoma (OR: 0.060; p = 0.003) and encephalopathy (OR: 0.179; p = 0.045) were significantly associated with 6-week mortality., Conclusions: Bacterial translocation and gut barrier impairment are directly related to the risk of variceal bleeding. Microbiota-modulating interventions and anti-endotoxin agents may be promising strategies to prevent variceal bleeding., 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 © 2022 Triantos, Kalafateli, Assimakopoulos, Karaivazoglou, Mantaka, Aggeletopoulou, Spantidea, Tsiaoussis, Rodi, Kranidioti, Goukos, Manolakopoulos, Gogos, Samonakis, Daikos, Mouzaki and Thomopoulos.)

Background: Spontaneous bacterial peritonitis (SBP) is an ominous complication of decompensated cirrhosis. This study aimed to assess several epidemiological, clinical, microbiological and outcome characteristics in Greek patients with SBP, as no solid representative nationwide data of this type was available., Methods: During a 3-year period, 77 consecutive patients with SBP (61 male; median age: 67 years; model for end-stage liver disease [MELD] score: 20), diagnosed and followed in 5 tertiary liver units, were prospectively recruited and studied. Various prognostic factors for disease outcome were studied., Results: Thirty-eight patients had alcohol-related cirrhosis, 17 viral hepatitis, 6 non-alcoholic steatohepatitis, 6 autoimmune liver diseases, and 10 cryptogenic cirrhosis. Hepatocellular carcinoma (HCC) was present in 23 (29.9%), whereas 10 (13%) had portal vein thrombosis. The first SBP episode at baseline was community-acquired in 53 (68.8%), while in 24 (31.1%) was hospital-acquired, with predominant symptoms abdominal pain and encephalopathy. A positive ascitic culture was documented in 36% of patients in the initial episode, with almost equal gram (+) and gram (-) pathogens, including 3 multidrug-resistant pathogens. Significant factors for 6-month survival were: higher MELD score, previous b-blocker use, lower serum albumin, higher lactate on admission and need for vasopressors, while factors for 12-month survival were MELD score and lactate. For overall survival, higher MELD score and lactate along with HCC presence were negative predictive factors., Conclusions: MELD score, lactate, albumin, HCC and treatment with vasopressors were predictive of survival in SBP patients. In hospital-acquired SBP the prevalence of difficult-to-treat pathogens was higher., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation., Competing Interests: Conflict-of-interest statement: The authors declare that there are no conflicts of interest relevant to this article and no financial support., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: No evidence is available on the natural history of grade 1 ascites and its progression to grade 2/3 in patients with liver cirrhosis. The aim of the current study was to address this issue, to assess the development of main comorbid disorders closely related to ascites progression, and to identify the predictive factors for survival in this setting., Methods: Consecutive Caucasian cirrhotic patients with grade 1 ascites were retrospectively analyzed. None of patients was under treatment with diuretics at diagnosis. Control groups consisted of 145 cirrhotics with grade 2/3 ascites and 175 cirrhotics without ascites., Results: Diuretics were initiated in 58 patients with grade 1 ascites at baseline by the attending physician. At the last follow up, 29 patients had no ascites, 33 patients had grade 1 and 38 patients had grade 2/3 ascites. No variable was found to be an independent predictor of grade 2/3 ascites. Seven patients developed spontaneous bacterial peritonitis while under treatment with diuretics; at that time only 1 patient had grade 1 ascites. The mortality rate was similar among all examined groups., Conclusions: This study suggests that the presence of grade 1 ascites does not constitute a precursor of grade 2/3 ascites in patients with cirrhosis. Thus, patients with grade 1 ascites do not require specific treatment with diuretics., Competing Interests: Conflict of Interest: None, (Copyright: © 2021 Hellenic Society of Gastroenterology.)

Objectives: To examine the impact of endoscopy setting (hospital-based vs. office-based) on sedation/analgesia administration and to provide nationwide data on monitoring practices among Greek gastroenterologists in real-world settings. Material and Methods . A web-based survey regarding sedation/analgesia rates and monitoring practices during endoscopy either in a hospital-based or in an office-based setting was disseminated to the members of the Hellenic Society of Gastroenterology and Professional Association of Gastroenterologists. Participants were asked to complete a questionnaire, which consisted of 35 items, stratified into 4 sections: demographics, preprocedure (informed consent, initial patient evaluation), intraprocedure (monitoring practices, sedative agents' administration rate), and postprocedure practices (recovery)., Results: 211 individuals responded (response rate: 40.3%). Propofol use was significantly higher in the private hospital compared to the public hospital and the office-based setting for esophagogastroduodenoscopy (EGD) (85.8% vs. 19.5% vs. 10.5%, p < 0.0001) and colonoscopy (88.2% vs. 20.1% vs. 9.4%, p < 0.0001). This effect was not detected for midazolam, pethidine, and fentanyl use. Endoscopists themselves administered the medications in most cases. However, a significant contribution of anesthesiology sedation/analgesia provision was detected in private hospitals (14.7% vs. 2.8% vs. 2.4%, p < 0.001) compared to the other settings. Only 35.2% of the private offices have a separate recovery room, compared to 80.4% and 58.7% of the private hospital- and public hospital-based facilities, respectively, while the nursing personnel monitored patients' recovery in most of the cases. Participants were familiar with airway management techniques (83.9% with bag valve mask and 23.2% with endotracheal intubation), while 49.7% and 21.8% had received Basic Life Support (BLS) and Advanced Life Support (ALS) training, respectively., Conclusion: The private hospital-based setting is associated with higher propofol sedation administration both for EGD and for colonoscopy. Greek endoscopists are adequately trained in airway management techniques., Competing Interests: The authors declare no competing interests., (Copyright © 2020 Georgios Tziatzios et al.)

Portal vein thrombosis (PVT) is a frequent complication in cirrhosis and its prevalence increases with disease severity. Several factors are involved in the development and progression of PVT. The challenge for the management of PVT is the precise evaluation of the bleeding risk as opposed to life-threatening extension of thrombosis. Nevertheless, the impact on the progression and outcome of liver disease is unclear. A critical evaluation of the available data discloses that treating PVT in cirrhotics is safe and effective. However, there are open issues, such as which anticoagulant could represent a safer therapeutic option, and when and for how long this treatment should be administered to cirrhotic patients with PVT., Competing Interests: Conflict of Interest: None

Many patients with hepatocellular carcinoma (HCC) are diagnosed in an advanced stage, so they cannot be offered the option of curative treatments. The results of systemic chemotherapy are unsatisfactory and this has led to molecular targeted approaches. HCC develops in chronically damaged tissue due to cirrhosis in most patients. Several different cell types and molecules constitute a unique microenvironment in the liver, which has significant implications in tumor development and invasion. This, together with genome instability, contributes to a significant heterogeneity which is further enhanced by the molecular differences of the underlying causes. New classifications based on genetic characteristics of the tissue microenvironment have been proposed and key carcinogenic signaling pathways have been described. Tumor and adjacent tissue profiling seem biologically promising, but have not yet been translated into clinical settings. The encouraging first results with molecular - genetic signatures should be validated and clinically applicable. A more personalized approach to modern management of HCC is urgently needed., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest in relation to this paper.

Aim: To study these characteristics and prognostic patterns in a Greek patient population., Methods: We analyzed a large cohort of cirrhotic patients referred to the department of Gastroenterology and Hepatology and the outpatient clinics of this tertiary hospital, between 1991 and 2008. We included patients with established cirrhosis, either compensated or decompensated, and further decompensation episodes were registered. A data base was maintained and updated prospectively throughout the study period. We analyzed differences in cirrhosis aetiology, time to and mode of decompensation, hepatocellular carcinoma (HCC) occurrence and ultimately patient survival., Results: Five hundreds and twenty-two patients with median age 67 (range, 29-91) years and average follow up 9 years-10 mo (range, 1-206 mo) were studied. Commonest aetiology was hepatitis C virus (HCV, 41%) followed by alcohol (31%). The median survival time in compensated cirrhotics was 115 mo (95%CI: 95-133), whereas in decompensated patients was 55 mo (95%CI: 36-75). HCV patients survived longer while HBV patients had over twice the risk of death of HCV patients. The median time to decompensation was 65 mo (95%CI: 51-79), with alcoholics having the highest risk (RR = 2.1 vs HCV patients). Hepatitis B virus (HBV) patients had the highest risk of HCC, alcoholics the lowest. Leading causes of death: liver failure, hepatorenal syndrome, sepsis and HCC progression., Conclusion: Cirrhosis aetiology and decompensation at presentation were predictors of survival. Alcoholics had the highest decompensation risk, HBV cirrhotics the highest risk of HCC and HCV cirrhotics the highest decompensation-free time.

Progression of fibrosis following recurrent hepatitis C virus (HCV) infection is frequent after liver transplantation (LT). Histology remains the gold standard to assess fibrosis, but the value of hepatic venous pressure gradient (HVPG) is being explored. We evaluated patients with recurrent HCV infection after LT to assess whether HVPG correlates with liver histology, particularly fibrosis. A total of 90 consecutive patients underwent 170 HVPG measurements concomitant with transjugular liver biopsy (TJB), with 31.5 (range, 6-156) months of follow up. Median biopsy length was 22 mm and total portal tract count was 12 (complete 6, partial 6). Median HVPG was 4 mmHg: 38% of patients > or =6 mmHg (portal hypertension, PHT), 13% > or =10 mmHg. HVPG correlated with Ishak stage (r = 0.73, P < 0.001) for mild (0-3) and severe fibrosis (4-6), and grade score (r = 0.47, P < 0.001), but neither correlated with interval from LT nor biopsy length. HVPG was > or =10 mmHg in 15 patients: 12 had stage 5 or 6, and 3 severe portal expansion. HVPG was repeated in 49, between 7 and 60 months with weak correlation to fibrosis score (r = 0.30, P = 0.045). A total of 12 patients with HVPG > or =6 mmHg had fibrosis score < or =3, while 8 patients had normal HVPG but fibrosis stage > or =4. These discrepancies were mostly associated with specific histological features such as perisinusoidal fibrosis rather than errors in measuring HVPG. In 29 with HVPG <6 mmHg at 1 yr, none decompensated compared to 4 of 13 (31%) with PHT. In conclusion, HVPG correlates with fibrosis and its progression, due to recurrent HCV infection, assessed in TJB., (Copyright 2007 AASLD.)

Recurrence of Hepatitis C (HCV) post-liver transplantation (LT) is universal and its course is more aggressive than in immunocompetent individuals. Human cytomegalovirus (CMV) infection is a common post-LT infection and has immunomodulatory effects that could adversely affect the outcome of HCV. To date, the effect of HCV replication on the dynamics of CMV have not been investigated. From 2000 to 2004, a cohort of 69 HCV-infected liver transplant recipients and 188 HCV-negative liver transplant recipients (NON-HCV cohort) were monitored for CMV infection twice weekly by CMV polymerase chain reaction (PCR) with preemptive therapy initiated after 2 consecutive positive results. None of the patients received CMV prophylaxis. A subset of 18 HCV-infected patients had their HCV viral load monitored regularly post-LT by quantitative PCR. CMV DNAemia (>200 genomes/mL blood) did not influence the level of HCV replication within 150 days posttransplantation or the stage of liver fibrosis in liver biopsies at 1 yr post-LT. There were no differences in the incidence of CMV DNAemia or replication dynamics in the HCV cohort compared to the NON-HCV cohort. In conclusion, short term CMV viremia does not enhance the replication of HCV after LT, while HCV replication does not alter the replication dynamics of CMV., ((c) 2006 AASLD.)

In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13-73) and median follow-up of 38 months (1-155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short-term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage > or = 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76-4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23-0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage.

Treatment of portal hypertension is evolving based on randomised controlled trials. In acute variceal bleeding, prophylactic antibiotics are mandatory, reducing mortality as well as preventing infections. Terlipressin or somatostatin combined with endoscopic ligation or sclerotherapy is the best strategy for control of bleeding but there is no added effect of vasoactive drugs on mortality. Non-selective beta-blockers are the first choice therapy for both secondary and primary prevention; if contraindications or intolerance to beta-blockers are present then band ligation should be used. Novel therapies target the increased intrahepatic resistance caused by microcirculatory intrahepatic deficiency of nitric oxide and contraction of activated intrahepatic stellate cells.