No abstract

Patients with advanced cirrhosis experience frequent infections leading to sepsis, which carries high mortality. While innate immune dysfunction underlies this vulnerability, the precise cause remains elusive. We found prostaglandin (PGE 2 ) elevated in acutely decompensated (AD) patients at immunosuppressive levels. Plasma from AD and end-stage liver disease (ESLD) patients suppressed macrophage cytokine secretion and bacteria killing in a PGE 2 receptor-dependent manner, effects not seen in stable cirrhosis. Mouse models (bile duct ligation and CCL4-liver injury) also demonstrated elevated PGE 2 , which when inhibited completely restored immune competence and survival following infection. Importantly, albumin binds/inactivates PGE 2 resulting in greater PGE 2 bioavailability. This results in enhanced immunosuppressive effects of AD plasma in patients with low albumin levels. Administering albumin to AD patients reversed immunosuppressive properties of their plasma; protective effects recapitulated in rodent survival studies. Thus, elevated PGE 2 combined with hypoalbuminemia mediates immunosuppression in AD and ESLD patients, which can be reversed with albumin. Cyclooxygenase (COX)-derived lipid mediators have broad immunosuppressive effects12-15 that could explain the aetiology of infection susceptibility in cirrhosis patients. Thus, we used a number of in vitro and in vivo assays using plasma from patients with AD and ESLD derived from clinical trials to investigate the role of bioactive lipid mediators in immunosuppression as well as animal models of liver injury for survival analyses. ResultsProstaglandin E 2 (PGE 2 ) is elevated in patients with acute decompensation at levels that are immunosuppressive via its effect on the EP2/3 receptor ESI/LC-MS/MS analysis of acutely decompensated patient plasma (day 1-2 of hospital admission) demonstrated significantly elevated PGE 2 , PGF 2 α, 5-and 15-HETE compared to HV ( Figure 1A and supplementary Figure 1E-G). However, only PGE 2 dampened TNFα release from LPS-stimulated human monocyte-derived macrophages when pre-treated with the mean concentrations observed in AD patients (0.1ng/ml) ( Figure 1B).Human monocyte-derived macrophages were incubated with culture media supplemented with 25% (vol./vol.) plasma from AD patients (see Table 1 for clinical characteristics).Compared to macrophages treated with media supplemented with HV plasma, AD plasma caused a significant decrease in LPS-stimulated TNFα that was reversed by pre-incubating Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts macrophages with the E-prostanoid (EP) 1-3/D-prostanoid (DP) 1 receptor antagonist, AH6809 ( Figure 1C). Additionally, macrophages were incubated with E. coli in the presence/absence of HV or AD plasma. Compared to macrophages treated with HV plasma, those with AD plasma exhibited reduced bacterial killing, an effect reversed by pretreatment with AH6809 (50μM) ( Figure 1D). AH6809 had no direct bactericidal effect while cell viability was unaffected b...

ObjectiveTo estimate the risk of acute myocardial infarction (AMI) or stroke in adults with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).DesignMatched cohort study.SettingPopulation based, electronic primary healthcare databases before 31 December 2015 from four European countries: Italy (n=1 542 672), Netherlands (n=2 225 925), Spain (n=5 488 397), and UK (n=12 695 046).Participants120 795 adults with a recorded diagnosis of NAFLD or NASH and no other liver diseases, matched at time of NAFLD diagnosis (index date) by age, sex, practice site, and visit, recorded at six months before or after the date of diagnosis, with up to 100 patients without NAFLD or NASH in the same database.Main outcome measuresPrimary outcome was incident fatal or non-fatal AMI and ischaemic or unspecified stroke. Hazard ratios were estimated using Cox models and pooled across databases by random effect meta-analyses.Results120 795 patients with recorded NAFLD or NASH diagnoses were identified with mean follow-up 2.1-5.5 years. After adjustment for age and smoking the pooled hazard ratio for AMI was 1.17 (95% confidence interval 1.05 to 1.30; 1035 events in participants with NAFLD or NASH, 67 823 in matched controls). In a group with more complete data on risk factors (86 098 NAFLD and 4 664 988 matched controls), the hazard ratio for AMI after adjustment for systolic blood pressure, type 2 diabetes, total cholesterol level, statin use, and hypertension was 1.01 (0.91 to 1.12; 747 events in participants with NAFLD or NASH, 37 462 in matched controls). After adjustment for age and smoking status the pooled hazard ratio for stroke was 1.18 (1.11 to 1.24; 2187 events in participants with NAFLD or NASH, 134 001 in matched controls). In the group with more complete data on risk factors, the hazard ratio for stroke was 1.04 (0.99 to 1.09; 1666 events in participants with NAFLD, 83 882 in matched controls) after further adjustment for type 2 diabetes, systolic blood pressure, total cholesterol level, statin use, and hypertension.ConclusionsThe diagnosis of NAFLD in current routine care of 17.7 million patient appears not to be associated with AMI or stroke risk after adjustment for established cardiovascular risk factors. Cardiovascular risk assessment in adults with a diagnosis of NAFLD is important but should be done in the same way as for the general population.

Background Non-alcoholic fatty liver disease (NAFLD) is a common condition that progresses in some patients to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Here we used healthcare records of 18 million adults to estimate risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls. Methods Data were extracted from four European primary care databases representing the UK, Netherlands, Italy and Spain. Patients with a recorded diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up for incident cirrhosis and HCC diagnoses. Each coded NAFLD/NASH patient was matched to up to 100 “non-NAFLD” patients by practice site, gender, age ± 5 years and visit recorded within ± 6 months. Hazard ratios (HR) were estimated using Cox models adjusted for age and smoking status and pooled across databases by random effects meta-analyses. Results Out of 18,782,281 adults, we identified 136,703 patients with coded NAFLD/NASH. Coded NAFLD/NASH patients were more likely to have diabetes, hypertension and obesity than matched controls. HR for cirrhosis in patients compared to controls was 4.73 (95% CI 2.43–9.19) and for HCC, 3.51 (95% CI 1.72–7.16). HR for either outcome was higher in patients with NASH and those with high-risk Fib-4 scores. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes. Conclusions Real-world population data show that recorded diagnosis of NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk. Electronic supplementary material The online version of this article (10.1186/s12916-019-1321-x) contains supplementary material, which is available to authorized users.

Local immune responses to surgery lead to systemic pro-inflammatory and immunosuppressive phases that are temporally related and proportionate in magnitude. Improved understanding of these mechanisms has implications for clinical study design and has led to the emergence of novel biomarkers such as Toll-like receptor expression. These can be used to stratify patient care pathways to maximize the benefit from current therapies or to select the right target at the right phase of illness for future drug development.