Dataset Information

Molecular Profiling of Decompensated Cirrhosis by a Novel MicroRNA Signature.

ABSTRACT: Noninvasive staging of decompensated cirrhosis is an unmet clinical need. The aims of this study were to characterize and validate a novel microRNA (miRNA) signature to stage decompensated cirrhosis and predict the portal pressure and systolic cardiac response to nonselective beta-blockers (NSBBs). Serum samples from patients with decompensated cirrhosis (n = 36) and healthy controls (n = 36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p) identified in the secretome of primary human hepatocytes and for three miRNAs (miR-192-5p, miR-34a-5p, and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, which was refractory in 18 (50%), and were placed on NSBBs for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient, and an echocardiogram study were performed before and 1 month after NSBBs. Patients with cirrhosis had lower serum levels of miR-429, miR-885-5p, miR-181b-5p, miR-122-5p, miR-192-5p, and miR-29a-5p (P < 0.05). Baseline serum miR-452-5p and miR-429 levels were lower in NSBB responders (P = 0.006). miR-181b-5p levels were greater in refractory ascites than in diuretic-sensitive ascites (P = 0.008) and correlated with serum creatinine. miR-452-5p and miR-885-5p were inversely correlated with baseline systemic vascular resistance (? = -0.46, P = 0.007; and ? = -0.41, P = 0.01, respectively) and with diminished systolic contractility (? = -0.55, P = 0.02; and ? = -0.55, P = 0.02, respectively) in patients with refractory ascites after NSBBs. Conclusion: Analysis of a miRNA signature in serum discriminates between patients with decompensated cirrhosis who show more severe systemic circulatory dysfunction and compromised systolic function after beta-blockade and those more likely to benefit from NSBBs.

SUBMITTER: Garcia Garcia de Paredes A

PROVIDER: S-EPMC7850302 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Molecular Profiling of Decompensated Cirrhosis by a Novel MicroRNA Signature.

Garcia Garcia de Paredes Ana A Manicardi Nicolo N Tellez Luis L Ibañez Luis L Royo Felix F Bermejo Javier J Blanco Carolina C Fondevila Constantino C Fernandez Lanza Val V Garcia-Bermejo Laura L Falcon-Perez Juan Manuel JM Bañares Rafael R Bañares Rafael R Gracia-Sancho Jordi J Albillos Agustin A

Hepatology communications 20201202 2

Noninvasive staging of decompensated cirrhosis is an unmet clinical need. The aims of this study were to characterize and validate a novel microRNA (miRNA) signature to stage decompensated cirrhosis and predict the portal pressure and systolic cardiac response to nonselective beta-blockers (NSBBs). Serum samples from patients with decompensated cirrhosis (n = 36) and healthy controls (n = 36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR- ...[more]

PMID: 33553977

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Project description:INTRODUCTION:Malnutrition is a leading cause of morbidity and mortality in cirrhosis. Although multiple noninvasive measures of nutritional status have been studied, no consensus exists for early identification of malnutrition in cirrhosis. Serum metabolomics offers a novel approach for identifying biomarkers in multiple disease states. To characterize alterations in metabolic pathways associated with malnutrition in hospitalized cirrhotic patients and to identify biomarkers for disease prognosis. METHODS:In this cross-sectional, observational cohort study, 51 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on low mid-arm muscle circumference and dominant handgrip strength. Anthropometric measurements and computed tomography body composition analysis were performed. Serum was collected after overnight fasting for unbiased metabolomics analysis. RESULTS:Malnourished cirrhotic patients exhibited mild reductions in skeletal muscle index, with more marked reductions in visceral fat index. Seventy-one biochemicals were significantly altered in malnourished subjects. The serum metabolite profile was significantly different between nourished and malnourished cirrhotic patients. Pathway analysis demonstrated that only sphingolipid metabolic pathways were significantly enriched in altered metabolites. Hierarchical clustering revealed that sphingolipid metabolites clustered into nourished and malnourished cohorts. Spearman analysis demonstrated multiple statistically significant correlations between sphingolipid species and Model for End-Stage Liver Disease-Sodium. Using logistic regression, we identified 8 sphingolipids that were significantly associated with malnutrition after controlling for Model for End-Stage Liver Disease-Sodium, age, and gender. CONCLUSIONS:Malnutrition in hospitalized cirrhotic patients is characterized by reductions in multiple sphingolipid species. Dysregulated sphingolipid metabolism may be involved in the pathophysiology of malnutrition in cirrhosis and potentially serve as a biomarker of nutritional status in this population.

Project description:Background & aimsBacterial infections in cirrhosis are associated with increased bleeding risk. To assess the factors responsible for bleeding tendency in patients with bacterial infections, we conducted a prospective study comparing all 3 aspects of hemostasis (platelets, coagulation, and fibrinolysis) in hospitalized patients with decompensated cirrhosis with vs. without bacterial infections.MethodsPrimary hemostasis assessment included whole blood platelet aggregation and von Willebrand factor (VWF). Coagulation assessment included procoagulant factors (fibrinogen, factor II, V, VII, VIII, IX, X, XI, XII, XIII), natural anticoagulants (protein C, protein S, antithrombin) and thrombomodulin-modified thrombin generation test. Fibrinolysis assessment included fibrinolytic factors (plasminogen, t-PA, PAI-1, α2-AP, TAFIa/ai) and plasmin-antiplasmin complex (PAP).ResultsEighty patients with decompensated cirrhosis were included (40 with and 40 without bacterial infections). Severity of cirrhosis and platelet count were comparable between groups. At baseline, patients with cirrhosis and bacterial infections had significantly lower whole blood platelet aggregation, without significant differences in VWF. Regarding coagulation, bacterial infections were associated with reduced procoagulant factors VII and XII, and a significant reduction of all natural anticoagulants. However, thrombomodulin-modified thrombin generation was comparable between the study groups. Finally, although mixed potentially hypo-fibrinolytic (lower plasminogen) and hyper-fibrinolytic (higher t-PA) changes were present in bacterial infections, a comparable level of PAP was detected in both groups. Upon resolution of infection (n = 29/40), platelet aggregation further deteriorated whereas coagulation and fibrinolysis factors returned to levels observed in patients without bacterial infections.ConclusionIn hospitalized patients with decompensated cirrhosis, bacterial infections are associated with reduced whole blood platelet aggregation and a significant decrease of all natural anticoagulants, which may unbalance hemostasis and potentially increase the risk of both bleeding and thrombosis.Lay summaryBacterial infections are a common issue in hospitalized patients with decompensated cirrhosis (i.e. patients hospitalized due to severe complications of advanced chronic liver disease). Patients with decompensated cirrhosis who acquire infections may be at increased risk of bleeding complications following invasive procedures (that is a procedure in which the body is penetrated or entered, for instance by a needle or a tube). As bleeding complications in decompensated cirrhosis are associated with a high risk of further decompensation and death, there is an urgent need to understand the factors responsible for such increased bleeding tendency. Herein, we investigated the alterations of hemostasis (that is the physiological process responsible for clot formation and stability) in patients with decompensated cirrhosis and bacterial infections. We found that development of bacterial infections in these patients is associated with alterations of hemostasis (particularly of platelets and clotting cascade) that may increase the risk of both bleeding and thrombotic complications.

Project description:Background & aimsGut dysbiosis and inflammation perpetuate loss of gut barrier integrity (GBI) and pathological bacterial translocation (BT) in cirrhosis, contributing to infection risk. Little is known about gut inflammation in cirrhosis and how this differs in acute decompensation (AD). We developed a novel approach to characterise intestinal immunopathology by quantifying faecal cytokines (FCs) and GBI markers.MethodsFaeces and plasma were obtained from patients with stable cirrhosis (SC; n = 16), AD (n = 47), and healthy controls (HCs; n = 31). A panel of 15 cytokines and GBI markers, including intestinal fatty-acid-binding protein-2 (FABP2), d-lactate, and faecal calprotectin (FCAL), were quantified by electrochemiluminescence/ELISA. Correlations between analytes and clinical metadata with univariate and multivariate analyses were performed.ResultsFaecal (F) IL-1β, interferon gamma, tumour necrosis factor alpha, IL-21, IL-17A/F, and IL-22 were significantly elevated in AD vs. SC (q <0.01). F-IL-23 was significantly elevated in AD vs. HC (p = 0.0007). FABP2/d-lactate were significantly increased in faeces in AD vs. SC and AD vs. HC (p <0.0001) and in plasma (p = 0.0004; p = 0.011). F-FABP2 correlated most strongly with disease severity (Spearman's rho: Child-Pugh 0.466; p <0.0001; model for end-stage liver disease 0.488; p <0.0001). FCAL correlated with plasma IL-21, IL-1β, and IL-17F only and none of the faecal analytes. F-cytokines and F-GBI markers were more accurate than plasma in discriminating AD from SC.ConclusionsFC profiling represents an innovative approach to investigating the localised intestinal cytokine micro-environment in cirrhosis. These data reveal that AD is associated with a highly inflamed and permeable gut barrier. FC profiles are very different from the classical innate-like features of systemic inflammation. There is non-specific upregulation of TH1/TH17 effector cytokines and those known to mediate intestinal barrier damage. This prevents mucosal healing in AD and further propagates BT and systemic inflammation.Lay summaryThe gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.

Dataset Information

Molecular Profiling of Decompensated Cirrhosis by a Novel MicroRNA Signature.

Publications

Molecular Profiling of Decompensated Cirrhosis by a Novel MicroRNA Signature.

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