New concepts and perspectives in decompensated cirrhosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Jalan R
PROVIDER: S-EPMC9272485 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.
| S-EPMC7282556 | biostudies-literature
Project description:Decompensated cirrhosis is a common reason for admission to the acute medical unit, and such patients typically have complex medical needs and are at high risk of in-hospital death. It is therefore vital that these patients receive appropriate investigations and management as early as possible in their patient journey. Typical presenting clinical features include jaundice, ascites, hepatic encephalopathy, hepato-renal syndrome or variceal haemorrhage. A careful history, examination and investigations can help identify the precipitating cause (infections, gastrointestinal bleeding, high alcohol intake / alcohol-related hepatitis or drug-induced liver injury), so appropriate treatment can be given. A 'care bundle' that has been endorsed by the British Society of Gastroenterology is available to help guide the management of patients with decompensated cirrhosis for the first 24 hours and ensure all aspects are addressed. Specific management of complications, such as infections, gastrointestinal bleeding, hepatic encephalopathy and hepatorenal syndrome, are discussed.
| S-EPMC6334027 | biostudies-literature
Project description:Peritoneal macrophages (PM) are thought to regulate peritoneal inflammation and control bacterial infections in decompensated liver cirrhosis. The aim of this study was to characterize human PM heterogeneity. Employing CD206 surface expression, we identified subsets of human large (LPM) and small (SPM) PM, which differed in granularity and maturation states. FACS-sorted LPM from patients with decompensated cirrhosis revealed discrete transcriptome clusters, comprising more than 4000 differentially regulated genes involved in cell cycle, metabolism, and immune signaling.
2020-03-24 | GSE124878 | GEO
Project description:In patients with decompensated cirrhosis, sarcopenia and frailty are prevalent. Although several definitions exist for these terms, in the field of hepatology, sarcopenia has commonly been defined as loss of muscle mass, and frailty has been broadly defined as the phenotypic manifestation of the loss of muscle function. Prompt recognition and accurate assessment of these conditions are critical as they are both strongly associated with morbidity, mortality, poor quality of life and worse post-liver transplant outcomes in patients with cirrhosis. In this review, we describe the complex pathophysiology that underlies the clinical phenotypes of sarcopenia and frailty, their association with decompensation, and provide an overview of tools to assess these conditions in patients with cirrhosis. When available, we highlight data focusing on patients with acutely decompensated cirrhosis, such as inpatients, as this is an area of unmet clinical need. Finally, we discuss management strategies to reverse and/or prevent the development of sarcopenia and frailty, which include adequate nutritional intake of calories and protein, as well as regular exercise of at least moderate intensity, with a mix of aerobic and resistance training. Key knowledge gaps in our understanding of sarcopenia and frailty in decompensated cirrhosis remain, including best methods to measure muscle mass and function in the inpatient setting, racial/ethnic variation in the development and presentation of sarcopenia and frailty, and optimal clinical metrics to assess response to therapeutic interventions that translate into a reduction in adverse outcomes associated with these conditions.
| S-EPMC9125684 | biostudies-literature
Project description:Objectives Non-invasive staging of decompensated cirrhosis is an unmeet clinical need. The aims of this study were to characterize and validate a novel miRNA signature to stage decompensated cirrhosis and predict the portal pressure and cardiac dysfunction response to non-selective beta-blockers (NSBB). Design 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 three miRNAs (miR-192-5p, miR-34a-5p and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, that was refractory in 18 (50%), and were placed on NSBB for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient (HVPG), and echocardiogram study was performed before and 1 month after NSBB. Results Cirrhotic patients 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). miR-452-5p and miR-429 expression were lower in NSBB responders (p=0.006). miR-181b-5p expression was greater in refractory- 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 (ρ=-0.46 p=0.007; and ρ=-0.41 p=0.01 respectively), and with diminished systolic contractility in patients with refractory ascites after NSBB (ρ=-0.55 p=0.02; and ρ=-0.55 p=0.02, respectively). Conclusion Analysis of a miRNA signature in serum distinguishes 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 NSBB.
2021-02-10 | GSE150867 | GEO
Project description:Patients with cirrhosis often develop malnutrition and micronutrient deficiencies, leading to a worse prognosis and increased mortality. Our main goal was to assess the prevalence of micronutrient deficiencies in patients with decompensated cirrhosis. This was a prospective single-center study including 125 consecutive patients hospitalized for acute decompensation of cirrhosis (mostly of alcoholic etiology). A blood test including trace elements and vitamins was performed on admission. The main micronutrient deficiencies observed were vitamin D (in 94.5%), vitamin A (93.5%), vitamin B6 (60.8%) and zinc (85.6%). Patients in Child-Pugh class C had lower levels of vitamin A (p < 0.0001), vitamin E (p = 0.01) and zinc (p < 0.001), and higher levels of ferritin (p = 0.002) and vitamin B12 (p < 0.001) than those in Child-Pugh class A and B. Patients with a higher model of end-stage liver disease (MELD) score had lower levels of vitamin A (p < 0.0001), vitamin E (p < 0.001), magnesium (p = 0.01) and zinc (p = 0.001), and higher levels of ferritin (p = 0.002) and vitamin B12 (p < 0.0001). Severe hepatic insufficiency correlated with lower levels of zinc, vitamin E and vitamin A, and higher levels of vitamin B12 and ferritin.
| S-EPMC8069759 | biostudies-literature
Project description:Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2-4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis. Treatment with albumin also counteracts the development of hepatorenal syndrome and spontaneous bacterial peritonitis. More recently, the positive impact of long-term albumin supplementation in liver disease, based on its pleiotropic non-oncotic activities, has been recognized. These include transport of endo- and exogenous substances, anti-inflammatory, antioxidant and immunomodulatory activities, and stabilizing effects on the endothelium. Besides the growing recognition that effective albumin therapy requires adjustment of the plasma level to normal physiological values, the search for substances with adjuvant activities is becoming increasingly important. More than 75% of patients with decompensated liver cirrhosis do not only present with hypoalbuminemia but also with zinc deficiency. There is a close relationship between albumin and the essential trace element zinc. First and foremost, albumin is the main carrier of zinc in plasma, and is hence critical for systemic distribution of zinc. In this review, we discuss important functions of albumin in the context of metabolic, immunological, oxidative, transport, and distribution processes, alongside crucial functions and effects of zinc and their mutual dependencies. In particular, we focus on the major role of chronic inflammatory processes in pathogenesis and progression of liver cirrhosis and how albumin therapy and zinc supplementation may affect these processes.
| S-EPMC8618355 | biostudies-literature
Project description:Malnutrition is a leading cause of morbidity and mortality in cirrhosis. There is no consensus as to the optimal approach for identifying malnutrition in end-stage liver disease. The aim of this study was to measure biochemical, serologic, hormonal, radiographic, and anthropometric features in a cohort of hospitalized cirrhotic patients to characterize biomarkers for identification of malnutrition.In this prospective observational cohort study, 52 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on mid-arm muscle circumference < 23 cm and dominant handgrip strength < 30 kg. Anthropometric measurements were obtained. Appetite was assessed using the Simplified Nutrition Appetite Questionnaire (SNAQ) score. Fasting levels of serum adipokines, cytokines, and hormones were determined using Luminex assays. Logistic regression analysis was used to determine features independently associated with malnutrition.Subjects with and without malnutrition differed in several key features of metabolic phenotype including wet and dry BMI, skeletal muscle index, visceral fat index and HOMA-IR. Serum leptin levels were lower and INR was higher in malnourished subjects. Serum leptin was significantly correlated with HOMA-IR, wet and dry BMI, mid-arm muscle circumference, skeletal muscle index, and visceral fat index. Logistic regression analysis revealed that INR and log-transformed leptin were independently associated with malnutrition.Low serum leptin and elevated INR are associated with malnutrition in hospitalized patients with end-stage liver disease.
| S-EPMC5008824 | biostudies-literature
Project description:Background: Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis. Data is, however, contradictory. Here we investigated whether levels of IL-6 and IL-8 putatively produced by myeloid cells in ascites are associated with systemic inflammation and whether inflammation depends on the presence of specific bacterial DNA. Methods and Materials: We enrolled 33 patients with decompensated liver cirrhosis from whom we collected paired samples of blood and ascites. IL-6 and IL-8 were measured in serum samples of all patients using ELISA. In a subset of 10 representative patients, bacterial DNA was extracted from ascites and whole blood, followed by 16S rRNA gene amplicon sequencing. Results: There were significantly higher levels of IL-6 in ascites fluid compared to blood samples in all patients. Interestingly, IL-6 levels in blood correlated tightly with disease severity and surrogates of systemic inflammation, while IL-6 levels in ascites did not. Moreover, patients with higher blood CRP levels showed greater SBP prevalence compared to patients with lower levels, despite similar positive culture results. Bacterial richness was also significantly higher in ascites compared to the corresponding patient blood. We identified differences in microbial composition and diversity between ascites and blood, but no tight relationship with surrogates of systemic inflammation could be observed. Discussion: In decompensated cirrhosis, markers of systemic inflammation and microbiota composition seem to be dysregulated in ascites and blood. While a relationship between systemic inflammation and microbiota composition seems to exist in blood, this is not the case for ascites in our hands. These data may suggest compartmentalization of the immune response and interaction of the latter with the microbiota especially in the blood compartment.
| S-EPMC6376951 | biostudies-literature
Project description:Liver disease is one of the leading causes of death worldwide. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE2-mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro. Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE2, reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus. Taken together, human albumin solution infusions may be used to reduce circulating PGE2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.
| S-EPMC5369639 | biostudies-literature