Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.

The copy of record is available from the publisher at https://doi.org/10.1002/hep4.1116. Copyright © 2017 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract: The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14‐16 weeks) and old (\u3e1.5 years) wild‐type (WT) littermates and global Opn knockout (Opn−/−) mice for HPSC mobilization to the liver. In addition, WT and Opn−/− mice were chronically fed the Lieber–DeCarli diet for 7 weeks. Bone marrow (BM), blood, spleen, and liver were analyzed by flow cytometry for HPSC progenitors and polymorphonuclear neutrophils (PMNs). Chemokines, growth factors, and cytokines were measured in serum and liver. Prussian blue staining for iron deposits and naphthol AS‐D chloroacetate esterase staining for PMNs were performed on liver sections. Hematopoietic progenitors were lower in liver and BM of young compared to old Opn−/− mice. Granulocyte colony‐stimulating factor and macrophage colony‐stimulating factor were increased in Opn−/− mice, suggesting potential migration of HPSCs from the BM to the liver. Furthermore, ethanol‐fed Opn−/− mice showed significant hepatic PMN infiltration and hemosiderin compared to WT mice. As a result, ethanol feeding caused greater liver injury in Opn−/− compared to WT mice. Conclusion: Opn deletion promotes HPSC mobilization, PMN infiltration, and iron deposits in the liver and thereby enhances the severity of ALD. The age‐associated contribution of OPN to HPSC mobilization to the liver, the prevalence of PMNs, and accumulation of hepatic iron, which potentiates oxidant stress, reveal novel signaling mechanisms that could be targeted for therapeutic benefit in patients with ALD

Consensus report from the 9th International Forum for Liver Magnetic Resonance Imaging: applications of gadoxetic acid-enhanced imaging

Objectives The 9th International Forum for Liver Magnetic Resonance Imaging (MRI) was held in Singapore in September 2019, bringing together radiologists and allied specialists to discuss the latest developments in and formulate consensus statements for liver MRI, including the applications of gadoxetic acid-enhanced imaging. Methods As at previous Liver Forums, the meeting was held over 2 days. Presentations by the faculty on days 1 and 2 and breakout group discussions on day 1 were followed by delegate voting on consensus statements presented on day 2. Presentations and discussions centered on two main meeting themes relating to the use of gadoxetic acid-enhanced MRI in primary liver cancer and metastatic liver disease. Results and conclusions Gadoxetic acid-enhanced MRI offers the ability to monitor response to systemic therapy and to assist in pre-surgical/pre-interventional planning in liver metastases. In hepatocellular carcinoma, gadoxetic acid-enhanced MRI provides precise staging information for accurate treatment decision-making and follow-up post therapy. Gadoxetic acid-enhanced MRI also has potential, currently investigational, indications for the functional assessment of the liver and the biliary system. Additional voting sessions at the Liver Forum debated the role of multidisciplinary care in the management of patients with liver disease, evidence to support the use of abbreviated imaging protocols, and the importance of standardizing nomenclature in international guidelines in order to increase the sharing of scientific data and improve the communication between centers

Banff 2022 liver group meeting report: monitoring long term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participantsincluded hepatologists, surgeons, pathologists, immunologists and histocompatibility specialists.Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimisation and long-term structural changes.Potential revision of the rejection classification scheme to better accommodate and communicate lateT cell-mediated rejection patterns and related structural changes, such as nodular regenerativehyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression tomatch the heterogeneity of patient settings will be central to improving long-term patient survival.Such personalised therapeutics are in turn contingent on better understanding and monitoring ofallograft status within a rational decision-making approach, likely to be facilitated in implementationwith emerging decision support tools. Proposed revisions to rejection classification emerging fromthe meeting include incorporation of interface hepatitis and fibrosis staging. These will be opened toonline testing, modified accordingly and subject to consensus discussion leading up to the next Banffconference

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Increasing hepatic arteriole wall thickness and decreased luminal diameter occur with increasing age in normal livers

Background & Aims: There is no data to suggest that the size of bile ducts, portal venules, and hepatic arterioles varies according to age in the normal human liver. We sought to examine whether hepatic arteriolar size, wall thickness, and luminal diameter change with increasing age

Acute cellular rejection resulting in sinusoidal obstruction syndrome and ascites postliver transplantation.

BACKGROUND.: The cause of ascites formation postliver transplantation (LT) is multifactorial. Sinusoidal obstruction syndrome (SOS) is a rare cause of ascites post-LT and has been reported to occur as a sequela of acute cellular rejection (ACR). We sought to examine the histologic features of patients developing ascites in the setting of ACR. METHODS.: By using the pathology database, we identified five patients with ACR who had ascites and 10 control patients with severe ACR without ascites. Features of SOS such as congestion, central venulitis, and hepatocyte necrosis were scored (zero absent, one mild, two moderate, and three severe) and perivenular fibrosis (zero absent, one mild, two fibrous septa present, three bridging fibrous septa, and four numerous septa with architectural distortion). Rejection activity index (Banff criteria) was determined. Clinical, biochemical and outcome information were obtained from chart review. RESULTS.: All five ascites patient had histologic evidence of SOS. Statistical significance was noted between the ascites and control groups for perivenular fibrosis score (3.6 vs. 0.8, P=0.0004), congestion (3 vs. 1.2, P=0.000005), and central venulitis (3 vs. 1.7, P=0.002). All patients in the ascites group required re-LT or died whereas all control patients remain alive. No significant statistical difference was noted with donor age despite the mean being older in the ascites group (52.8 vs. 35.8 years). CONCLUSIONS.: ACR resulting in SOS and associated with significant perivenular fibrosis, central venulitis and congestion may be the cause of ascites post-LT and may portend a poor prognosis for recovery