Residual burden of liver disease after HCV clearance in hemophilia: a word of caution in the era of gene therapy.

Ruling out advanced fibrosis/cirrhosis is mandatory for persons with hemophilia (PWH) who are candidates for gene therapy. However, clinical evaluation and noninvasive tests (NITs) may be inaccurate after hepatitis C virus (HCV) clearance. We conducted a prospective hepatological screening to detect advanced fibrosis/cirrhosis in PWH after HCV clearance. Any risk factor of chronic liver damage was registered by using biochemical data, liver stiffness measurement (LSM), and ultrasound (US). A pre/post-HCV clearance analysis was conducted prospectively in a subgroup of patients who underwent LSM, US, and NITs for fibrosis. We evaluated 119 patients (median age, 53 years; range, 36-87 years) with a previous HCV infection (hemophilia A, n = 108; hemophilia B, n = 11). Ninety-six (81%) presented at least 1 potential risk factor of chronic liver damage. Metabolic risk factors were the most prevalent, with 51 patients (44%) having US steatosis. In 21 patients (18%), clinical, biochemical, liver morphology, and/or LSM were suggestive of advanced fibrosis/cirrhosis. Furthermore, 10 patients (8%) had esophageal varices and 3 (3%) had hepatocellular carcinoma. In 57 patients included in the prospective analysis, LSM and NITs were reduced after HCV clearance (P < .05), but US signs specific of cirrhosis remained unchanged. Overall, 23 of 80 patients (29%) with LSM <10 KPa had at least 1 US sign suggestive of advanced fibrosis/cirrhosis. A similar proportion (18%) was observed for LSM <8 KPa. Overall, risk factors of chronic liver damage are frequent after HCV clearance, but changes in LSM and NITs after clearance may be inaccurate to rule out advanced fibrosis/cirrhosis. A specific diagnostic workup is warranted to evaluate liver health in PWH in the era of gene therapy.

Improving Management of Portal Hypertension: The Potential Benefit of Non-Etiological Therapies in Cirrhosis.

Portal hypertension is the consequence of cirrhosis and results from increased sinusoidal vascular resistance and hepatic blood inflow. Etiological therapies represent the first intervention to prevent a significant increase in portal pressure due to chronic liver damage. However, other superimposed pathophysiological drivers may worsen liver disease, including inflammation, bacterial translocation, endothelial dysfunction, and hyperactivation of hemostasis. These mechanisms can be targeted by a specific class of drugs already used in clinical practice. Albumin, rifaximin, statins, aspirin, and anticoagulants have been tested in cirrhosis and were a topic of discussion in the last Baveno consensus as non-etiological therapies. Based on the pathogenesis of portal hypertension in cirrhosis, our review summarizes the main mechanisms targeted by these drugs as well as the clinical evidence that considers them a valid complementary option to manage patients with cirrhosis and portal hypertension.

High prevalence of lower limb atherosclerosis is linked with the gut-liver axis in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: Hypercholesterolemia is frequent in people with primary biliary cholangitis (PBC); however, it does not seem to confer an increased risk of cardiovascular disease. We aimed to evaluate the prevalence of peripheral arterial disease in PBC women and its association with the gut-liver axis and systemic inflammation. METHODS: Thirty patients affected by PBC and hypercholesterolemia were enrolled, with equal-sized groups of women with non-alcoholic fatty liver disease (NAFLD) and healthy controls (CTRL). All patients underwent Doppler ultrasound examination of peripheral arteries, assessment of flow-mediated dilation, quantification of circulating cytokines and vasoactive mediators and characterization of the gut microbiota. RESULTS: PBC patients had a higher prevalence of lower extremity arterial disease (LEAD) defined as atherosclerotic plaques in any of femoral, popliteal and/or tibial arteries compared with both NAFLD and CTRL women (83.3% vs. 53.3% and 50%, respectively; p = .01). Factors associated with LEAD at univariate analysis were VCAM-1 (p = .002), ICAM-1 (p = .003), and TNF-alpha (p = .04) serum levels, but only VCAM-1 (OR 1.1, 95% CI 1.0-1.1; p = .04) and TNF-alpha (OR 1.12, 95% CI 0.99-1.26; p = .04) were confirmed as independent predictors in the multivariate model. Gut microbiota analysis revealed that Acidaminococcus (FDR = 0.0008), Bifidobacterium (FDR = 0.001) and Oscillospira (FDR = 0.03) were differentially expressed among groups. Acidaminococcus, which was increased in PBC, was positively correlated with TNF-alpha serum levels. Down-regulation of metabolic pathways linked to fatty acid and butyrate metabolism, glyoxylate metabolism and branched-chain amino acids degradation was found in the functional gut metagenome of PBC women. CONCLUSIONS: LEAD is common in patients affected by PBC and is associated with inflammatory markers and alterations in the gut-liver axis.