Ezetimibe: Its Novel Effects on the Prevention and the Treatment of Cholesterol Gallstones and Nonalcoholic Fatty Liver Disease

The cholesterol absorption inhibitor ezetimibe can significantly reduce plasma cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter that can actively facilitate the uptake of cholesterol for intestinal absorption. Unexpectedly, ezetimibe treatment also induces a complete resistance to cholesterol gallstone formation and nonalcoholic fatty liver disease (NAFLD) in addition to preventing hypercholesterolemia in mice on a Western diet. Because chylomicrons are the vehicles with which the enterocytes transport cholesterol and fatty acids into the body, ezetimibe could prevent these two most prevalent hepatobiliary diseases possibly through the regulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver. It is highly likely that there is an intestinal and hepatic cross-talk through the chylomicron pathway. Therefore, understanding the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine could offer an efficacious novel approach to the prevention and the treatment of cholesterol gallstones and NAFLD

New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile

Cholesterol gallstone formation represents a failure of biliary cholesterol homeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed. Lithogenic bile is mainly caused by persistent hepatic hypersecretion of biliary cholesterol and sustained cholesterol-supersaturated bile is an essential prerequisite for the precipitation of solid cholesterol monohydrate crystals and the formation of cholesterol gallstones. The metabolic determinants of the supply of hepatic cholesterol molecules that are recruited for biliary secretion are dependent upon the input-output balance of cholesterol and its catabolism in the liver. The sources of cholesterol for hepatic secretion into bile have been extensively investigated; however, to what extent each cholesterol source contributes to hepatic secretion is still unclear both under normal physiological conditions and in the lithogenic state. Although it has been long known that biliary lithogenicity is initiated by hepatic cholesterol hypersecretion, the genetic mechanisms that cause supersaturated bile have not been defined yet. Identification of the Lith genes that determine hepatic cholesterol hypersecretion should provide novel insights into the primary genetic and pathophysiological defects for gallstone formation. In this review article, we focus mainly on the pathogenesis of the formation of supersaturated bile and gallstones from the viewpoint of genetics and pathophysiology. A better understanding of the molecular genetics and pathophysiology of the formation of cholesterol-supersaturated bile will undoubtedly facilitate the development of novel, effective, and noninvasive therapies for patients with gallstones, which would reduce the morbidity, mortality, and costs of health care associated with gallstones, a very prevalent liver disease worldwide. Keywords: Bile flow, Bile acid, Biliary secretion, Lith gene, Micelle, Vesicl

Automated CT and MRI Liver Segmentation and Biometry Using a Generalized Convolutional Neural Network.

PurposeTo assess feasibility of training a convolutional neural network (CNN) to automate liver segmentation across different imaging modalities and techniques used in clinical practice and apply this to enable automation of liver biometry.MethodsWe trained a 2D U-Net CNN for liver segmentation in two stages using 330 abdominal MRI and CT exams acquired at our institution. First, we trained the neural network with non-contrast multi-echo spoiled-gradient-echo (SGPR)images with 300 MRI exams to provide multiple signal-weightings. Then, we used transfer learning to generalize the CNN with additional images from 30 contrast-enhanced MRI and CT exams.We assessed the performance of the CNN using a distinct multi-institutional data set curated from multiple sources (n = 498 subjects). Segmentation accuracy was evaluated by computing Dice scores. Utilizing these segmentations, we computed liver volume from CT and T1-weighted (T1w) MRI exams, and estimated hepatic proton- density-fat-fraction (PDFF) from multi-echo T2*w MRI exams. We compared quantitative volumetry and PDFF estimates between automated and manual segmentation using Pearson correlation and Bland-Altman statistics.ResultsDice scores were 0.94 ± 0.06 for CT (n = 230), 0.95 ± 0.03 (n = 100) for T1w MR, and 0.92 ± 0.05 for T2*w MR (n = 169). Liver volume measured by manual and automated segmentation agreed closely for CT (95% limit-of-agreement (LoA) = [-298 mL, 180 mL]) and T1w MR (LoA = [-358 mL, 180 mL]). Hepatic PDFF measured by the two segmentations also agreed closely (LoA = [-0.62%, 0.80%]).ConclusionsUtilizing a transfer-learning strategy, we have demonstrated the feasibility of a CNN to be generalized to perform liver segmentations across different imaging techniques and modalities. With further refinement and validation, CNNs may have broad applicability for multimodal liver volumetry and hepatic tissue characterization

Portal Hypertensive Gastropathy in Chronic Hepatitis C Patients with Bridging Fibrosis and Compensated Cirrhosis: Results from the HALT-C Trial

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72863/1/j.1572-0241.2006.00461.x.pd

Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-assigned Steatosis Grades of Liver Biopsies from Adults with Nonalcoholic Steatohepatitis

Background & Aims We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. Methods We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed. Results At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0–1 vs 2–3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91–0.98), and grade 0–2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93–0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2–3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71–0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63–0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity. Conclusions Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference

Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis

Background Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. Methods We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Results Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P Conclusions Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.

Current considerations for clinical management and care of non-alcoholic fatty liver disease: Insights from the 1st International Workshop of the Canadian NASH Network (CanNASH).

Non-alcoholic fatty liver disease (NAFLD) affects approximately 8 million Canadians. NAFLD refers to a disease spectrum ranging from bland steatosis to non-alcoholic steatohepatitis (NASH). Nearly 25% of patients with NAFLD develop NASH, which can progress to liver cirrhosis and related end-stage complications. Type 2 diabetes and obesity represent the main risk factors for the disease. The Canadian NASH Network is a national collaborative organization of health care professionals and researchers with a primary interest in enhancing understanding, care, education, and research around NAFLD, with a vision of best practices for this disease state. At the 1st International Workshop of the CanNASH network in April 2021, a joint event with the single topic conference of the Canadian Association for the Study of the Liver (CASL), clinicians, epidemiologists, basic scientists, and community members came together to share their work under the theme of NASH. This symposium also marked the initiation of collaborations between Canadian and other key opinion leaders in the field representative of international liver associations. The main objective is to develop a policy framework that outlines specific targets, suggested activities, and evidence-based best practices to guide provincial, territorial, and federal organizations in developing multidisciplinary models of care and strategies to address this epidemic