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Federico Costante,1,* Leonardo Stella,1,* Francesco Santopaolo,1,2 Antonio Gasbarrini,1,2 Maurizio Pompili,1,2 Tarik Asselah,3,* Francesca Romana Ponziani1,2 1Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy; 2Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy; 3Service d’Hépatologie, Hôpital Beaujon UMR 1149 Inserm - Université de Paris, Clichy, France*These authors contributed equally to this workCorrespondence: Francesca Romana Ponziani; Federico Costante, Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito 1, Rome, 00168, Italy, Tel +390630156264, Email francesca.ponziani@gmail.com; federico.costante93@gmail.comAbstract: Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.Keywords: hepatitis B virus, hepatitis delta virus, chronic hepatitis B, CHB, chronic delta hepatitis, CDH, dual infection, HCC

This article, published in the journal Endoscopy, presents a case report of a 78-year-old male with oxaliplatin-associated portal sinusoidal vascular disease (PSVD) who experienced variceal bleeding. The patient underwent endoscopic band ligation for treatment, but subsequent gastroscopy revealed recurrent high-risk gastro-esophageal varices (GOV) and a nearby mucosal lesion with high-grade dysplasia. Due to the high risk of bleeding associated with endoscopic submucosal dissection (ESD), a transjugular intrahepatic portosystemic shunt (TIPS) was placed to reduce portal pressure. The TIPS procedure was successful, and two months later, the patient underwent ESD to remove the sub-cardial lesion without complications. [Extracted from the article]

In Italy, HDV-prevalence and its fluctuations over time are controversial while an extensive characterization of HDV-infected patients is missing. To assess HDV-seroprevalence in a large cohort of HBsAg-positive subjects, followed in Central Italy over time, and the epidemiological/virological characteristics of HDV-infected patients. 1,579 consecutive and well-characterized HBsAg-positive patients, firstly referred to Tor Vergata-University-Hospital from 2005-2022, were included. HDV-RNA was quantified by a commercial assay (LLOQ:100copies/ml) and HDV sub-genotypes were defined by phylogenetic-analysis. Among 1,579 HBsAg-positive patients, 45.3% (715/1579) received HDV-screening with an increasing temporal-trend: 17.1% (2005-2010), 43.2% (2011-2015), 56.5% (2016-2019), 75.8% (2020-2022). The lack of HDV-screening significantly correlated with normal ALT (OR[95%CI]:1.69[1.28-2.22], P<0.001) and being Italian (OR[95%CI]:1.4[1.12-184], P=0.005), while no factors were identified in 2020-2022. Overall, this suggests a higher awareness towards HDV-screening in all HBsAg+ in recent years. 13.4% (96/715) of HDV-screened patients resulted anti-HDV+ with a stable temporal trend: 10.7% (2005-2010), 15.6% (2011-2015), 10.8% (2016-2019), 10% (2020-2022). Among them, 80.5% had detectable HDV-RNA (median[IQR]log:4.6[3.6-5.6]copies/ml) with altered ALT in 89.3% (median[IQR]:92[62-177]U/L). Anti-HDV positivity was higher in patients from Eastern Europe than from Italy (23.6% versus 12.9%, P=0.002). Notably, anti-HDV+ patients from Eastern Europe were younger (44[37-54] versus 53[47-62]years, P<0.001) with higher HDV-RNA (4.8[3.6-5.8] versus 3.9[1.4-4.9]copies/ml, P=0.016) and HBsAg (9,461[4,159-24,532] versus 4,447[737-13,336]IU/ml), P=0.032), indicating more pronounced HDV-replication. Phylogenetic-analysis revealed the circulation of HDV sub-genotype 1a (25.9%), 1b (33.4%), 1c (25.9) and 1d (14.8%). Notably, sub-genotype 1a and 1c correlated with 3xULN ALT compared to 1b and 1d (75%% versus 27.3%, P=0.039). The awareness to request HDV-screening is increasing over time even if some gaps remain to achieve HDV-screening in all HBsAg-positive patients. Immigration from Eastern Europe contributes to the circulation of HDV-strains with enhanced replication. The detection of different sub-genotypes, triggering variable inflammatory stimuli, supports the need to expand HDV molecular characterization. [ABSTRACT FROM AUTHOR]

PSVD includes a group of vascular diseases featuring lesions encompassing portal venules and sinusoids, irrespective of the presence of portal hypertension (PH). Liver biopsy (LB) is fundamental for diagnosis. A recent monocenter study showed high rates of PSVD in patients with isolated and unexplained GGT elevation who underwent a LB; due to the small sample, the study could not identify factors associated with PSVD. Aim of this study was to validate in a multicenter cohort the rate of PSVD in patients with isolated GGT elevation and identify clinical factors associated with PSVD. We retrospectively included all patients who underwent a LB for unexplained isolated and persistent GGT elevation in five Italian Hepatology Units from March, 2015 to December, 2021. All LB specimens were reviewed by hepatopathologists. 144 patients met the inclusion criteria and were enrolled in the study. Most patients were males (76/144, 53%) with the mean age being 52 years (range 19-74). 11 patients (7.6%) presented liver stiffness (LS) suggestive of advanced liver disease (>10 kPa) but none showed clinical features of PH. The histological findings were compatible with PSVD in 96 out of 144 patients (67%). In 13 patients (9%) histology was compatible with NASH, in 3 patients (2%) with hepatic sarcoidosis and in 3 patients with congenital hepatic fibrosis (CHF). Histology showed healthy liver in 29 (20%) patients. At univariate analyses male sex, LS <10 kPa and GGT <214 UI/L were associated with PSVD (p<0.05). The same factors were confirmed by logistic regression: LS <10 kPa (OR 7.5 (95%, CI 1.7-32.3), GGT <214 UI/L (OR 2.8 (95%, CI 1.29-6.28) and male gender (OR 2.5 (95%, CI 1.19-5.58). PSVD is common in patients with elevated GGT and no signs of PH. Male gender, LS and GGT levels can be used to identify these patients a priori. [ABSTRACT FROM AUTHOR]

Recent studies analyzed the prognostic role of coagulation parameters such as factor VIII (FVIII) /protein C (PC) ratio on advanced chronic liver disease (ACLD) decompensation or liver-related outcomes [1]. We recently demonstrated that a disintegrin and metalloprotease with thrombospondin 1 repeats number 13 (ADAMTS-13)/von Willebrand factor (VWF) ratio is useful to predict the development of portal vein thrombosis (PVT) [2], but little is known about its role as marker of decompensated ACLD (dACLD). To investigate the prognostic role of ADAMTS13/VWF ratio on the development of dACLD and compare it with FIII/VWF ratio. We assessed 86 patients with ACLD (median age 66 years; 65.47% male; etiology viral/nonviral 50%/50%; Child Pugh A/B/C 80.2%/15.1%/4.7% and median model for end-stage liver disease [MELD] 8). 20 patients (23.25%) developed decompensated ACLD after a median of 48.8 months and presented a significantly a lower ADAMTS-13/VWF ratio and a higher FVIII/PC ratio compared to their counterparts maintaining compensated ACLD (ADAMTS-13/VWF 0.26 [0.22-0.41] vs 0.52 [0.16-0.62], p<0.0001; FVIII/PC 2.62 [1.87-3.81] vs 1.44 [1.13-1.77], p<0.0001 Figure 1A-B). Both these indices correlated with Child Pugh and MELD score, although FVIII/PC ratio showed the strongest correlation with clinical and coagulation parameters (Figure 1C). Moreover, ADAMTS-13/VWF ratio or FVIII/PC ratio showed a good prognostic ability on dACLD-free survival and liver-related death (p<0.0001, Figure 1D-E), although ADAMTS-13/VWF ratio showed a limitation in identifying clinically relevant early events. Finally, the four patients who developed portal vein thrombosis (PVT) had a lower ADAMTS-13/VWF or a higher FVIII/PC compared to their counterparts. Coagulation parameters, historically used only for assessing bleeding risk in patients with ACLD, are instead harbingers of important prognostic information. Indeed, ADAMTS13/VWF ratio and FVIII/PC ratio correlate with liver disease severity and can predict liver-related death or decompensation in patients with ACLD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In the last decades, liver biopsy was the reference procedure for the diagnosis and follow-up of liver disease. Aim of present retrospective analysis was to assess the prevalence of complications and risk factors after Percutaneous Liver Biopsy (PLB) performed for diagnosis and staging in patients with chronic liver disease and for monitoring the graft in liver transplanted patients PATIENTS AND METHODS: Data were collected from a total of 1.011 PLB performed with the Menghini technique between January 2004 and December 2014 at the Hepatology and Transplant Units of the University of Rome Tor Vergata. The indications for biopsy were: follow-up of liver transplantation, chronic Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV), with or without Human Immunodeficiency Virus (HIV) and alcohol-related liver disease. Our patients were divided into two groups according to the biopsy indication: follow-up of liver transplantation (Group A) and chronic liver disease (Group B). All the procedures were performed in Day Hospital regimen. After the biopsy, patients remained in bed for about 4-6 hours. In the absence of complications, they were then discharged on the same day. RESULTS: The most frequent complication after biopsy was pain (Group A n. 57, 8.8%; Group B n. 105, 29.0%), hypotension as a result of a vasovagal reaction resolved spontaneously (Group A n. 7, 1.1%; Group B n. 6, 1.7%), and intrahepatic bleeding resolved with conservative therapy (Group A n. 1, 0.2%; Group B n. 6, 1.7%). Two cases of pneumothorax in the Group A (0.3%) were treated with a chest tube. Other complications did not have a significant impact. Also, we did not observe statistically significant differences in patients who underwent PLB without and with ultrasound guidance. CONCLUSIONS: Liver biopsy is not a replaceable tool in diagnosis and follow-up of several European Review for Medical and Pharmacological Sciences A retrospective analysis of 1.011 percutaneous liver biopsies performed in patients with liver transplantation or liver disease: ultrasonography can reduce complications? V. FILINGERI, S. FRANCIOSO1, D. SFORZA, F. SANTOPAOLO1, F.M. ODDI, G. TISONE Department of Experimental Medicine and Surgery, Transplant Unit, and 1Department of Internal Medicine, Hepatology Unit, University of Rome "Tor Vergata", Rome, Italy percutaneous trans costal approach, might be preferred because less traumatic and related with a low occurrence of minor and major complications. According to our case load and comparing our findings with the previous published data, we speculate that ultrasound guidance is not crucial in the prevention of major complications. [ABSTRACT FROM AUTHOR]

Hepatobiliary malignancies, which include hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are the sixth most common cancers and the third leading cause of cancer-related death worldwide. Hepatic carcinogenesis is highly stimulated by chronic inflammation, defined as fibrosis deposition, and an aberrant imbalance between liver necrosis and nodular regeneration. In this context, the gut-liver axis and gut microbiota have demonstrated a critical role in the pathogenesis of HCC, as dysbiosis and altered intestinal permeability promote bacterial translocation, leading to chronic liver inflammation and tumorigenesis through several pathways. A few data exist on the role of the gut microbiota or bacteria resident in the biliary tract in the pathogenesis of CCA, and some microbial metabolites, such as choline and bile acids, seem to show an association. In this review, we analyze the impact of the gut microbiota and its metabolites on HCC and CCA development and the role of gut dysbiosis as a biomarker of hepatobiliary cancer risk and of response during anti-tumor therapy. We also discuss the future application of gut microbiota in hepatobiliary cancer management.

Background & Aims: Porto-sinusoidal vascular disorder (PSVD) is a group of vascular disorders characterized by lesions involving portal venules and sinusoids, irrespective of the presence of portal hypertension. Liver biopsy is essential for diagnosis. In a single-center study, we demonstrated high rates of PSVD in patients with persistently elevated gamma-glutamyltransferase (GGT). This multicenter study aims to establish PSVD prevalence in a larger dataset of individuals with persistent and unexplained GGT elevation, and to identify associated risk factors., Methods: The study included all patients who underwent liver biopsy for persistent and unexplained GGT elevation in five Italian hepatology units between March 2015 and December 2021., Results: A total of 144 patients met the inclusion criteria. The majority were males (76/144, 52.8%) and mean age was 51.9 years (range 19-74). Only 12 (8.3%) had liver stiffness measurements (LSM) >10 kPa, while 7 (4.8%) had ultrasound evidence of portal hypertension. Histological findings were consistent with PSVD in 96 patients (67%). Alternative diagnoses were steatohepatitis in 13 (9%), sarcoidosis in 3 (2%) and congenital hepatic fibrosis in 3 (2%) patients. Histological findings were non-specific in 29 (20%) patients. PSVD was associated with male sex (odds ratio [OR] 2.60, 95% CI 1.13-5.99), LSM <10 kPa (OR 11.05, 95% CI 2.16-56.66) and GGT <200 U/L (OR 2.69, 95% CI 1.22-5.98)., Conclusions: PSVD was the main cause of persistent and unexplained elevation of GGT3. Male sex, LSM <10 kPa and GGT <200 U/L were associated with PSVD. These findings highlight the role of liver biopsy in elucidating the underlying pathology and aiding in the diagnosis of patients with persistent and unexplained GGT elevation., Impact and Implications: In outpatient settings, it is common to encounter individuals with persistent and unexplained gamma-glutamyltransferase elevations. This study reveals, for the first time, a non-negligible prevalence of porto-sinusoidal vascular disorder among these individuals when they undergo liver biopsy. Male sex, liver stiffness measurement <10 kPa, and gamma-glutamyltransferase <200 IU/L predict this histological finding. These results may raise awareness of clinically relevant conditions that may be present in patients with persistent liver enzyme changes, even in the absence of signs of advanced chronic liver disease or portal hypertension. Additionally, the data may encourage further studies in the field of porto-sinusoidal vascular disorder, particularly to define its clinical evolution in patients without signs of portal hypertension at diagnosis., (© 2024 The Author(s).)

Porto-sinusoidal vascular disorder (PSVD) encompasses a group of vascular disorders characterized by lesions involving the portal venules and sinusoids, independent of the presence of portal hypertension (PH), and for which liver biopsy is essential for diagnosis. PSVD has been shown to be common in patients with immune-mediated diseases, including inflammatory bowel disease (IBD). The association between PSVD and the use of thiopurines and thioguanine in patients with IBD has been well established. In addition, research suggests an association between PSVD and IBD, even in cases where patients haven't been exposed to specific medications, probably related to changes in intestinal permeability. The identification and management of patients with known IBD and PSVD is a challenge for gastroenterologists. This narrative review aims to summarize the currently available data on the association between IBD and PSVD and provide practical suggestions for the management of this group of patients., Competing Interests: Conflicts of interest All authors of the paper ``Exploring the link: porto-sinusoidal vascular disorder and inflammatory bowel disease – A comprehensive narrative review'' declare that they have no conflicts of interest with the subject discussed., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted., Competing Interests: The authors declare no conflicts of interest.

Objectives: Here we investigate Hepatitis D virus (HDV)-prevalence in Italy and its fluctuations over time and we provide an extensive characterization of HDV-infected patients., Methods: The rate of HDV seroprevalence and HDV chronicity was assessed in 1579 hepatitis B surface antigen (HBsAg)+ patients collected from 2005 to 2022 in Central Italy., Results: In total, 45.3% of HBsAg+ patients received HDV screening with an increasing temporal trend: 15.6% (2005-2010), 45.0% (2011-2014), 49.4% (2015-2018), 71.8% (2019-2022). By multivariable model, factors correlated with the lack of HDV screening were alanine-aminotransferase (ALT) less than two times of upper limit of normality (<2ULN) and previous time windows (P <0.002). Furthermore, 13.4% of HDV-screened patients resulted anti-HDV+ with a stable temporal trend. Among them, 80.8% had detectable HDV-ribonucleic acid (RNA) (median [IQR]:4.6 [3.6-5.6] log copies/ml) with altered ALT in 89.3% (median [IQR]:92 [62-177] U/L). Anti-HDV+ patients from Eastern/South-eastern Europe were younger than Italians (44 [37-54] vs 53 [47-62] years, P <0.0001), less frequently nucleos(t)ide analogs (NUC)-treated (58.5% vs 80%, P = 0.026) with higher HDV-RNA (4.8 [3.6-5.8] vs 3.9 [1.4-4.9] log copies/ml, P = 0.016) and HBsAg (9461 [4159-24,532] vs 4447 [737-13,336] IU/ml, P = 0.032). Phylogenetic analysis revealed the circulation of HDV subgenotype 1e (47.4%) and -1c (52.6%). Notably, subgenotype 1e correlated with higher ALT than 1c (168 [89-190] vs 58 [54-88] U/l, P = 0.015) despite comparable HDV-RNA., Conclusions: HDV-screening awareness is increasing over time even if some gaps persist to achieve HDV screening in all HBsAg+ patients. HDV prevalence in tertiary care centers tend to scarcely decline in native/non-native patients. Detection of subgenotypes, triggering variable inflammatory stimuli, supports the need to expand HDV molecular characterization., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Direct acting antivirals(DAAs) are effective in reducing inflammatory ant fibrotic markers in patients with chronic hepatitis C virus(HCV) infection and to prevent liver-related complications. Two-dimensional shear wave elastography(2D-SWE) is an effective technique for the assessment of liver fibrosis., Aim: To evaluate changes in liver stiffness(LS) in HCV cirrhotic patients undergoing DAA therapy and to identify non-invasive parameters that predict the occurrence of liver-related events., Methods: We enrolled 229 patients who received DAAs between January 2015 and October 2018. Ultrasound parameters and laboratory data were assessed before treatment and 24(T1) and 48(T2) weeks after end of treatment. Patients were followed up every 6 months to evaluate the development of HCC and other liver related complications. Multiple Cox regression analysis was used to determine parameters associated with the development of complications., Results: Model for End-stage Liver Disease(MELD) score(HR 1.16; CI 95% 1.01-1.33; p = 0.026) and a change in LS at T2(1-year Delta LS) < 20%(HR 2.98; CI 95% 1.01-8.1; p = 0.03) were independently associated with HCC risk. One-year Delta-LS <20% was independently associated with the development of ascites(HR 5.08; CI 95% 1.03 - 25.14; p = 0.04)., Conclusions: Dynamic changes of 2D-SWE-measured LS after DAA therapy may be a useful tool to identify patients who are at higher risk of liver related complications., Competing Interests: Conflict of interest All authors confirm that there are no known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome., (Copyright © 2023. Published by Elsevier Ltd.)

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.

Vascular liver disorders (VLDs) comprise a wide spectrum of clinical-pathological entities that primarily affect the hepatic vascular system of both cirrhotic and non-cirrhotic patients. VLDs more frequently involve the portal and the hepatic veins, as well as liver sinusoids, resulting in an imbalance of liver homeostasis with serious consequences, such as the development of portal hypertension and liver fibrosis. Surprisingly, many VLDs are characterized by a prothrombotic phenotype. The molecular mechanisms that cause thrombosis in VLD are only partially explained by the alteration in the Virchow's triad (hypercoagulability, blood stasis, and endothelial damage) and nowadays their pathogenesis is incompletely described and understood. Studies about this topic have been hampered by the low incidence of VLDs in the general population and by the absence of suitable animal models. Recently, the role of coagulation imbalance in liver disease has been postulated as one of the main mechanisms linked to fibrogenesis, so a novel interest in vascular alterations of the liver has been renewed. This review provides a detailed analysis of the current knowledge of molecular mechanisms of VLD. We also focus on the promising role of anticoagulation as a strategy to prevent liver complications and to improve the outcome of these patients.

Fibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized by alterations in primary and secondary hemostasis but unlike previously thought, these changes are not associated with an increased risk of bleeding complications. In recent years, the role of coagulation imbalance has been postulated as one of the main mechanisms promoting hepatic fibrogenesis. In this review, we aim to investigate the function of microvascular thrombosis in the progression of liver disease and highlight the molecular and cellular networks linking hemostasis to fibrosis in this context. We analyze the predictive and prognostic role of coagulation products as biomarkers of liver decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy) and liver-related mortality. Finally, we evaluate the current evidence on the application of antiplatelet and anticoagulant therapies for prophylaxis of hepatic decompensation or prevention of the progression of liver fibrosis.

Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut-liver-brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting.

Type 2 diabetes mellitus is a widespread disease worldwide, and is one of the cornerstones of metabolic syndrome. The existence of a strong relationship between diabetes and the progression of liver fibrosis has been demonstrated by several studies, using invasive and noninvasive techniques. Patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) show faster progression of fibrosis than patients without diabetes. Many confounding factors make it difficult to determine the exact mechanisms involved. What we know so far is that both liver fibrosis and T2DM are expressions of metabolic dysfunction, and we recognize similar risk factors. Interestingly, both are promoted by metabolic endotoxemia, a low-grade inflammatory condition caused by increased endotoxin levels and linked to intestinal dysbiosis and increased intestinal permeability. There is broad evidence on the role of the gut microbiota in the progression of liver disease, through both metabolic and inflammatory mechanisms. Therefore, dysbiosis that is associated with diabetes can act as a modifier of the natural evolution of NAFLD. In addition to diet, hypoglycemic drugs play an important role in this scenario, and their benefit is also the result of effects exerted in the gut. Here, we provide an overview of the mechanisms that explain why diabetic patients show a more rapid progression of liver disease up to hepatocellular carcinoma (HCC), focusing especially on those involving the gut-liver axis.

A correct differentiation between hepatocellular carcinoma (HCC) and intracellular cholangiocarcinoma (ICC) is essential for clinical management and prognostic prediction. However, non-invasive differential diagnosis between HCC and ICC remains highly challenging. Dynamic contrast-enhanced ultrasound (D-CEUS) with standardized software is a valuable tool in the diagnostic approach to focal liver lesions and could improve accuracy in the evaluation of tumor perfusion. Moreover, the measurement of tissue stiffness could add more information concerning tumoral environment. To explore the diagnostic performance of multiparametric ultrasound (MP-US) in differentiating ICC from HCC. Our secondary aim was to develop an US score for distinguishing ICC and HCC. Between January 2021 and September 2022 consecutive patients with histologically confirmed HCC and ICC were enrolled in this prospective monocentric study. A complete US evaluation including B mode, D-CEUS and shear wave elastography (SWE) was performed in all patients and the corresponding features were compared between the tumor entities. For better inter-individual comparability, the blood volume-related D-CEUS parameters were analyzed as a ratio between lesions and surrounding liver parenchyma. Univariate and multivariate regression analysis was performed to select the most useful independent variables for the differential diagnosis between HCC and ICC and to establish an US score for non-invasive diagnosis. Finally, the diagnostic performance of the score was evaluated by receiver operating characteristic (ROC) curve analysis. A total of 82 patients (mean age ± SD, 68 ± 11 years, 55 men) were enrolled, including 44 ICC and 38 HCC. No statistically significant differences in basal US features were found between HCC and ICC. Concerning D-CEUS, blood volume parameters (peak intensity, PE; area under the curve, AUC; and wash-in rate, WiR) showed significantly higher values in the HCC group, but PE was the only independent feature associated with HCC diagnosis at multivariate analysis ( p = 0.02). The other two independent predictors of histological diagnosis were liver cirrhosis ( p < 0.01) and SWE ( p = 0.01). A score based on those variables was highly accurate for the differential diagnosis of primary liver tumors, with an area under the ROC curve of 0.836 and the optimal cut-off values of 0.81 and 0.20 to rule in or rule out ICC respectively. MP-US seems to be a useful tool for non-invasive discrimination between ICC and HCC and could prevent the need for liver biopsy at least in a subgroup of patients.

Over the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue regeneration, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine., (Copyright © 2022. Published by Elsevier Ltd.)

Liver cirrhosis is a chronic disease that can be complicated by episodes of decompensation such as variceal bleeding, hepatic encephalopathy, ascites, and jaundice, with subsequent increased mortality. Infections are also among the most common complications in cirrhotic patients, mostly due to a defect in immunosurveillance. Among them, one of the most frequent is spontaneous bacterial peritonitis (SBP), defined as the primary infection of ascitic fluid without other abdominal foci. SBP is mainly induced by Gram-negative bacteria living in the intestinal tract, and translocating through the intestinal barrier, which in cirrhotic patients is defective and more permeable. Moreover, in cirrhotic patients, the intestinal microbiota shows an altered composition, poor in beneficial elements and enriched in potentially pathogenic ones. This condition further promotes the development of leaky gut and increases the risk of SBP. The first-line treatment of SBP is antibiotic therapy; however, the antibiotics used have a broad spectrum of action and may adversely affect the composition of the gut microbiota, worsening dysbiosis. For this reason, the future goal is to use new therapeutic agents that act primarily on the gut microbiota, selectively modulating it, or on the intestinal barrier, reducing its permeability. In this review, we aim to describe the reciprocal relationship between gut microbiota and SBP, focusing on pathogenetic aspects but also on new future therapies.

The gut microbiota plays a critical role in the modulation of host metabolism and immune response, and its impairment has been implicated in many gastrointestinal and extraintestinal diseases. Current evidence shows the well-documented role of A. muciniphila in maintaining the integrity of the intestinal barrier, modulating the host immune response, and improving several metabolic pathways, making it a key element in the pathogenesis of several human diseases. In this scenario, A. muciniphila is the most promising next-generation probiotic and one of the first microbial species suitable for specific clinical use when compared with traditional probiotics. Further studies are needed to provide more accurate insight into its mechanisms of action and to better elucidate its properties in several major areas, paving the way for a more integrated and personalized therapeutic approach that finally makes the most of our knowledge of the gut microbiota.

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with metabolic disorders, being highly prevalent in obese and diabetic patients. Many concomitant factors that promote systemic and liver inflammation are involved in NAFLD pathogenesis, with a growing body of evidence highlighting the key role of the gut microbiota. Indeed, the gut-liver axis has a strong impact in the promotion of NAFLD and in the progression of the wide spectrum of its manifestations, claiming efforts to find effective strategies for gut microbiota modulation. Diet is among the most powerful tools; Western diet negatively affects intestinal permeability and the gut microbiota composition and function, selecting pathobionts, whereas Mediterranean diet fosters health-promoting bacteria, with a favorable impact on lipid and glucose metabolism and liver inflammation. Antibiotics and probiotics have been used to improve NAFLD features, with mixed results. More interestingly, medications used to treat NAFLD-associated comorbidities may also modulate the gut microbiota. Drugs for the treatment of type 2 diabetes mellitus (T2DM), such as metformin, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose cotransporter (SGLT) inhibitors, are not only effective in the regulation of glucose homeostasis, but also in the reduction of liver fat content and inflammation, and they are associated with a shift in the gut microbiota composition towards a healthy phenotype. Even bariatric surgery significantly changes the gut microbiota, mostly due to the modification of the gastrointestinal anatomy, with a parallel improvement in histological features of NAFLD. Other options with promising effects in reprogramming the gut-liver axis, such as fecal microbial transplantation (FMT) and next-generation probiotics deserve further investigation for future inclusion in the therapeutic armamentarium of NAFLD., 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 Maestri, Santopaolo, Pompili, Gasbarrini and Ponziani.)

Lipopolysaccharide (LPS), also known as endotoxin, is a component of the membrane of gram-negative bacteria and a well-recognized marker of sepsis. In case of disruption of the intestinal barrier, as occurs with unhealthy diets, alcohol consumption, or during chronic diseases, the microbiota residing in the gastrointestinal tract becomes a crucial factor in amplifying the systemic inflammatory response. Indeed, the translocation of LPS into the bloodstream and its interaction with toll-like receptors (TLRs) triggers molecular pathways involved in cytokine release and immune dysregulation. This is a critical step in the exacerbation of many diseases, including metabolic disorders and cancer. Indeed, the role of LPS in cancer development is widely recognized, and examples include gastric tumor related to Helicobacter pylori infection and hepatocellular carcinoma, both of which are preceded by a prolonged inflammatory injury; in addition, the risk of recurrence and development of metastasis appears to be associated with endotoxemia. Here, we review the mechanisms that link the promotion and progression of tumorigenesis with endotoxemia, and the possible therapeutic interventions that can be deployed to counteract these events.

The intestinal barrier, with its multiple layers, is the first line of defense between the outside world and the intestine. Its disruption, resulting in increased intestinal permeability, is a recognized pathogenic factor of intestinal and extra-intestinal diseases. The identification of a gut-vascular barrier (GVB), consisting of a structured endothelium below the epithelial layer, has led to new evidence on the etiology and management of diseases of the gut-liver axis and the gut-brain axis, with recent implications in oncology as well. The gut-brain axis is involved in several neuroinflammatory processes. In particular, the recent description of a choroid plexus vascular barrier regulating brain permeability under conditions of gut inflammation identifies the endothelium as a key regulator in maintaining tissue homeostasis and health.

Benign liver lesions are increasingly diagnosed in daily clinical practice due to the growing use of imaging techniques for the study of the abdomen in patients who have non-specific symptoms and do not have an increased risk of hepatic malignancy. They include simple or parasitic hepatic cysts and solid benign tumors which differ widely in terms of prevalence, clinical relevance, symptoms and natural history and often lead to significant clinical problems relating to diagnosis and clinical management. Following the need to have updated guidelines on the management of benign focal liver lesions, the Scientific Societies mainly involved in their management have promoted the drafting of a new dedicated document. This document was drawn up according to the present Italian rules and methodologies necessary to produce clinical, diagnostic, and therapeutic guidelines based on evidence. Here we present the second part of the guideline, concerning the diagnosis and clinical management of hemangioma, focal nodular hyperplasia, and hepatocellular adenoma., Competing Interests: Declaration of Competing Interest The Authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Background and Aims: In cirrhosis, decreased portal flow velocity, thrombophilia factors, and portal hypertension are considered risk factors for portal vein thrombosis (PVT). In cirrhosis, the transformation of the stellate cells causes a progressive decrease of ADAMTS-13, while VWF multimers secretion by endothelial cells is strongly enhanced. This imbalance leads to an accumulation of ultra-large VWF multimers that in sinusoidal circulation could favor PVT both in intra- and extra-hepatic branches, mostly in decompensated cirrhosis. This prospective study was aimed at identifying possible clinical, biochemical, and hemostatic factors predictive for non-tumoral PVT in a cohort of patients with compensated cirrhosis., Methods: Seventynine compensated cirrhosis patients were prospectively followed for 48 months, receiving a periodic Doppler-ultrasound liver examination associated with an extensive evaluation of clinical, biochemical, and hemostatic profile., Results: Five patients developed PVT (cumulative prevalence = 6.3%), occurring 4-36 months after enrollment. In logistic regression analysis, the ADAMTS-13/VWF:GpIbR ratio < 0.4 was the only independent variable significantly associated with PVT (OR 14.6, 95% C.I.:1.36-157.2, p = 0.027). A Cox-regression-analysis confirmed this finding (HR = 7.7, p = 0.027)., Conclusions: The ADAMTS-13/VWF ratio < 0.4 measured in compensated cirrhosis could be a reliable predictive biomarker for PVT development, paving the way to novel therapeutic strategies to prevent and treat PVT in this clinical setting., Competing Interests: Conflict of Interest Authors declare that they have no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Selective internal radiation therapy represents an endovascular treatment option for patients with primary liver malignancies, in different clinical stages. Potential applications of this treatment are in early-stage hepatocellular carcinoma, as a curative option, or in combination with systemic treatments in intermediate and advanced-stages. This review, based on existing literature and ongoing trials, will focus on the future of this treatment in patients with hepatocellular carcinoma, in combination with systemic treatments, or with the use of new devices and technological developments; it will also describe new potential future indications and structural and organizational perspectives., (© 2022. The Author(s).)

Benign liver lesions are increasingly diagnosed in daily clinical practice due to the growing use of imaging techniques for the study of the abdomen in patients who have non-specific symptoms and do not have an increased risk of hepatic malignancy. They include simple or parasitic cysts and solid benign tumors which differ widely in terms of prevalence, clinical relevance, symptoms and natural history and often lead to significant clinical problems relating to diagnosis and clinical management. Following the need to have updated guidelines on the management of benign focal liver lesions, the Scientific Societies mainly involved in their management have promoted the drafting of a new dedicated document. This document was drawn up according to the present Italian rules and methodologies necessary to produce clinical, diagnostic, and therapeutic guidelines based on evidence. Here we present the first part of the guideline, concerning the characterization of focal hepatic lesions detected by ultrasound, and the diagnosis and clinical management of simple and parasitic hepatic cysts, and of polycystic liver disease., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

The treatment perspectives of advanced hepatocellular carcinoma (HCC) have deeply changed after the introduction of immunotherapy. The results in responders show improved survival compared with Sorafenib, but only one-third of patients achieve a significant benefit from treatment. As the tumor microenvironment exerts a central role in shaping the response to immunotherapy, the future goal of HCC treatment should be to identify a proxy of the hepatic tissue condition that is easy to use in clinical practice. Therefore, the search for biomarkers that are accurate in predicting prognosis will be the hot topic in the therapeutic management of HCC in the near future. Understanding the mechanisms of resistance to immunotherapy may expand the patient population that will benefit from it, and help researchers to find new combination regimens to improve patients' outcomes. In this review, we describe the current knowledge on the prognostic non-invasive biomarkers related to treatment with immune checkpoint inhibitors, focusing on serological markers and gut microbiota.

About one-fourth of adults globally suffer from nonalcoholic fatty liver disease (NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma (HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment (TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors (ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to declare., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Portal vein thrombosis (PVT) and venous thromboembolism (VTE) are fearsome complications of liver cirrhosis., Objectives: To assess the prevalence and the main risk factors for venous thrombotic complications in hospitalized cirrhotic patients., Patients/methods: We retrospectively reviewed electronic administrative discharge data of 19461 cirrhotic patients hospitalized over a 35-year period; univariate and multivariate logistic regression was used to asses risk factors for PVT or VTE and their impact on hospital stay and mortality., Results: 382 out of 7445 patients (5.1%) were diagnosed with PVT and 95 (1.3%) with VTE. Liver cirrhosis complications were observed in 45% of patients. Hepatic encephalopathy (HE) (OR 13.88 [10.76-17.98] p < 0.0001), endoscopic signs of portal hypertension (OR 1.33 [1.02-1.75] p = 0.02), hepatocellular carcinoma (HCC) (OR 4.59 [3.6-5.84] p < 0.0001), diabetes (OR 1.68 [1.27-2.22] p = 0.0001), abdominal surgery/invasive procedures (OR 2.03 [1.56-2.64] p < 0.0001) emerged as independent predictors of PVT. Higher risk of VTE was observed in patients with HE (OR 3.21 [1.78-5.79] p < 0.0001), HCC (OR 1.98 [1.23-3.19] p = 0.002) or other tumors (OR 2.48 [1.42-4.32] p = 0.001), acute illnesses (infections OR 3.01 [1.84-5.05] p = 0.0001; cardiac/respiratory insufficiency OR 2.4 [1.27-4.53] p = 0.003; acute myocardial infarction/stroke OR 7.86 [1.76-35.12] p = 0.003). VTE was the only independent predictor of in-hospital mortality (OR 4.45 [1.05-18.81] p = 0.042)., Conclusions: Liver disease complications related to portal hypertension, HCC or other tumors, diabetes, acute illnesses (i.e. infections, cardiac/pulmonary insufficiency, acute myocardial infarction/stroke) and abdominal interventions are associated with increased risk of PVT or VTE in hospitalized cirrhotic patients, and should be considered to define personalized preemptive approaches., (© 2022. The Author(s).)

Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Programmed death 1 (PD1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte associated protein 4 (CTLA-4) are proteins involved in the modulation of immune response, which are upregulated in hepatocellular carcinoma (HCC) tumor microenvironment (TME). Immune checkpoint inhibitors (ICIs) are a new class of drugs that counteract immunological tolerance to cancer cells. Despite the aggressiveness of HCC and its poor prognosis, only a few tyrosine kinase inhibitors (TKIs) and ICIs have been approved for patients with advanced disease., Areas Covered: We analyze the current knowledge on Durvalumab, a human antibody against PD-L1 its pharmacodynamics, and pharmacokinetics. We provide a description of its application in HCC, illustrating clinical trials that have demonstrated the safety and efficacy in this setting, either as monotherapy or in combination with other ICIs or TKIs, or as adjuvant treatment., Expert Opinion: Durvalumab is a promising drug that could extend the landscape of approved treatments for HCC. The clinical safety profile of Durvalumab was well manageable and comparable to other ICIs, with a low incidence of severe immune-related adverse events (irAEs). The importance of personalized therapy according to tumor characteristics is emerging, but very little is known about factors that could influence the efficacy of ICIs.