A story of liver and gut microbes: How does the intestinal flora affect liver disease? A review of the literature

Each individual is endowed with a unique gut microbiota (GM) footprint that mediates numerous host-related physiological functions, such as nutrient metabolism, maintenance of the structural integrity of the gut mucosal barrier, immunomodulation, and protection against microbial pathogens. Because of increased scientific interest in the GM, its central role in the pathophysiology of many intestinal and extraintestinal conditions has been recognized. Given the close relationship between the gastrointestinal tract and the liver, many pathological processes have been investigated in the light of a microbial-centered hypothesis of hepatic damage. In this review we introduce to neophytes the vast world of gut microbes, including prevalent bacterial distribution in healthy individuals, how the microbiota is commonly analyzed, and the current knowledge of the role of GM in liver disease pathophysiology. Also, we highlight the potentials and downsides of GM-based therapy

MicroRNAs as Regulators of Neo-Angiogenesis in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a highly vascularized neoplasm. In the tumor niche, abundant angiogenesis is fundamental in providing nutrients for tumor growth and represents the first escape route for metastatic cells. Active angiogenesis, together with metastasis, are responsible for the reduction of recurrence-free survival of HCC. MicroRNAs (miRNAs) are small non-coding RNAs that have recently drawn attention in molecular targeted therapy or as diagnostic and prognostic biomarkers. MiRNA expression in HCC has been widely studied in the last decade. Some miRNAs have been found to be up- or down-regulated, besides association with apoptosis, metastasis progression and drug resistance have been found. This review article aims to summarize the angiogenetic process in tumor diseases and to update on what has been found in the vast world of HCC-related-miRNAs and, eventually, to report the latest finding on several miRNAs involved in HCC angiogenesis. We searched the state of the arts for the 12 miRNAs found to be involved with angiogenesis in HCC (miR-29b, miR-126-3p, miR-144-3p, miR-146a, miR-195, miR-199a-3p, miR-210-3p, miR-338- 3p, mir-491, mir-497, mir-638, mir-1301) and reported their main molecular targets and their overall effect in the sprouting of new vessels

The Role of Liver and Spleen Elastography in the Screening of Esophageal Varices in Patients with Liver Cirrhosis: Do We Really Need Endoscopy?

Background: recently, the Baveno VI guidelines have suggested that esophagogastroduodenoscopy (EGD) to stage esophageal varices can be avoided in patients with advanced liver disease who have a liver stiffness (LS) 150x103/\u3bcL. Our study aims to analyze spleen stiffness (SS) as a non\u2010invasive method of diagnosis for clinically significant portal hypertension in order to avoid EGD in low\u2010risk patients for esophageal varices. We also want to compare the SS to other non\u2010invasive techniques and analyze their reproducibility and inter\u2010observer concordance. Patients and Methods: in this prospective study, we detected the SS and LS in 150 patients diagnosed with liver cirrhosis to be submitted for endoscopic screening for esophageal varices. In addition, we enrolled 70 healthy control individuals, who for other reasons, had undergone an endoscopic examination of the upper digestive tracts and who were negative for hepatic and lymphoproliferative disease. The discriminatory capacity for the presence of esophageal varices of the SS has been compared with that deriving from other non\u2010invasive procedures (LS, splenic diameter, splenic surface, platelet count, and combined scores deriving from these parameters). Optimal SS cut\u2010offs were sought to exclude the presence of varices. Particular emphasis was placed on the search for possible correlations of the with ultrasound parameters of portal hypertension and platelet count. Finally, we studied in a double\u2010blind fashion inter\u2010operator concordance with 50 measurements for LS, and 25 for SS. Results: cirrhotic patients have significantly higher SS and LS values than controls. The SS values were higher in cirrhotic patients with varices (n = 62) compared to patients without esophageal varices (n = 88) and to healthy controls (p <0.001). SS showed an AUROC of 0.93 (95% C.I., 0.89\u20100.97), statistically different from the other predictors (p <0.001). The cut\u2010off, chosen according to Youden\u2019s Index and equal to 38.55 kPa, showed sensitivity of 87%, specificity of 89%, NPV of 91%, and PPV of 84%. Instead, the cut\u2010off of 30.79 kPa has 100% sensitivity and 100% NPV. The cut\u2010off of 69.73 kPa demonstrated specificity and PPV of 100%. The SS demonstrated weak linear correlation with the splenic dimensions (bipolar diameter and surface measured at the organ\u2019s hilum). Moreover, it has a linear correlation with the platelet count, which was greater than that present with LS (r = 0.5 vs r = 0.32). The test revealed an excellent intraclass correlation coefficient (ICC) equal to 0.96 for SS and 0.97 for LS. Conclusion: the results of this study show how the SS can play an important role in the daily clinical management of cirrhotic patients. The SS (alone or combined with other indicators) may play an important role as a non\u2010invasive screening test for predicting the risk of varices

A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs

The role of elastography in alcoholic liver disease: fibrosis staging and confounding factors, a review of the current literature

INTRODUCTION: Alcohol-related liver disease (ALD) was estimated to have a prevalence of 2% among the USA population. Since severe fibrosis in compensated patients is the main predictor of long-term survival, it is of utmost importance to early detect patients with severe fibrosis before decompensation occurs. Liver elastography has been used to stage liver fibrosis. However, there is a widespread lack in guidelines for the correct use of liver stiffness (LS) in ALD. EVIDENCE ACQUISITION: A structured search was carried out on MEDLINE/PubMed database. From the original 225 research articles identified, only 12 studies met the inclusion criteria, with 10 studies being eventually included. EVIDENCE SYNTHESIS: According to reported data, patients with aspartate aminotransferase (AST)>100 IU/L and 50 IU/L showed significantly higher values of LS if compared to patients with the same fibrosis stage. Also, excessive alcohol consumption greatly influences elastography, leading to false fibrosis staging. When LS values >5-6 kPa are detected, several aspects should be taken into account. First of all, the patient should be asked about the current alcohol consumption (i.e. active vs. abstinence, determination of abstinence period, and quantification of alcohol intake), and if the patient is an active drinker, liver elastography can be repeated after a complete abstinence period of at least two weeks. and if the patient is an active drinker, liver elastography can be repeated after a complete abstinence period of at least two weeks. Secondly, clinicians should check liver transaminases level, and if AST are above 100 IU/L, they should be aware of a possible overestimation of fibrosis. However, whether transaminases-adapted cut-off values should be used for ad-hoc decisions in patients with no time or option to withdraw from alcohol consumption is still a matter of debate. CONCLUSIONS: We hope that our review article may serve as a reference point in the prospect of futures guidelines