Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol‐related acute‐on‐chronic liver failure

Mehta, Gautam; Mookerjee, Rajeshwar P.; Sharma, Vikram; Jalan, Rajiv

doi:10.1111/liv.12559

Cited by 93 publications

(80 citation statements)

References 39 publications

(51 reference statements)

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“…Nitric oxide (NO) and carbon monoxide (CO) are the main vasodilators involved in arterial splanchnic vasodilation. In the context of bacterial infections and particularly in that of sepsis, circulating endotoxins and proinflammatory cytokines further impair portal hypertension and liver function, further increasing their negative effect on the cardiovascular dysfunction in patients with cirrhosis [9] (Fig. 3).…”

Section: Pathogenesis Of Sepsis Induced-akimentioning

confidence: 99%

Sepsis-induced acute kidney injury in patients with cirrhosis

et al. 2015

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Acute kidney injury (AKI) is a common and life-threatening complication in patients with cirrhosis. Recently, new criteria for the diagnosis of AKI have been proposed in patients with cirrhosis by the International Club of Ascites. Almost all types of bacterial infections can induce AKI in patients with cirrhosis representing its most common precipitating event. The bacterial infection-induced AKI usually meets the diagnostic criteria of hepatorenal syndrome (HRS). Well in keeping with the "splanchnic arterial vasodilation hypothesis", it has been stated that HRS develops as a consequence of a severe reduction of effective circulating volume related to splanchnic arterial vasodilation and to an inadequate cardiac output. Nevertheless, the role of bacterial infections in precipitating organ failures, including renal failure, is enhanced when their course is characterized by the development of a systemic inflammatory response syndrome (SIRS), thus, when sepsis occurs. Sepsis has been shown to be capable to induce "per se" AKI in animals as well as in patients conditioning also the features of renal damage. This observation suggests that when precipitated by sepsis, the pathogenesis and the clinical course of AKI also in patients with cirrhosis may differentiate to a certain extent from AKI with another or no precipitating factor. The purpose of this review is to describe the features of AKI precipitated by bacterial infections and to highlight whether infection and/or the development of SIRS may influence its clinical course, and, in particular, the response to treatment.

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Section: Pathogenesis Of Sepsis Induced-akimentioning

confidence: 99%

Sepsis-induced acute kidney injury in patients with cirrhosis

et al. 2015

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“…Nonetheless, despite these suggestive findings, there is very little information on the type of inflammatory mediators that are increased in ACLF and its relationship with outcomes. Moreover, the few studies published have investigated only either single or limited number of cytokines914; therefore neither a complete picture about the characteristics of the inflammatory reaction nor the types of pathways involved are known. Therefore, the current study was aimed at addressing the issue of the inflammatory response and its relationship with ACLF and survival in patients with cirrhosis.…”

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confidence: 99%

Characterization of Inflammatory Response in Acute-on-Chronic Liver Failure and Relationship with Prognosis

Solé

Solà

Morales-Ruíz

et al. 2016

Sci Rep

107

100

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ACLF is characterized by a systemic inflammatory response, but the cytokines involved in this process have not been well studied. The aim of this study was to characterize the systemic inflammatory response in patients with cirrhosis and ACLF and its relationship with prognosis. Fifty-five patients with cirrhosis, 26 with ACLF, were studied prospectively. Systemic inflammatory response was analyzed by measuring a large array of plasma cytokines by using a multiplex kit. A principal component analysis show noticeable differences between ACLF and decompensated cirrhosis without ACLF. Patients with ACLF had significant abnormal levels of 12 cytokines compared to those without ACLF, including: VCAM-1, VEGF-A, Fractalkine, MIP-1α, Eotaxin, IP-10, RANTES, GM-CSF, IL-1β, IL-2, ICAM-1, and MCP-1. Cytokines showing the most marked relationship with ACLF were VCAM-1 and VEGF-A (AUCROC 0.77; p = 0.001). There was a significant relationship between some of inflammatory mediators and 3-month mortality, particularly VCAM-1, ICAM-1, and GM-CSF (AUCROC>0.7; p < 0.05). Functional Enrichment Analysis showed that inflammatory markers differentially expressed in ACLF patients were enriched in leukocyte migration, particularly monocytes and macrophages, and chemotaxis pathways. In conclusion, ACLF is characterized by a marked inflammatory reaction with activation of mediators of adhesion and migration of leukocytes. The intensity of the inflammatory reaction correlates with prognosis.

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“…Furthermore, correlations between pro-inflammatory mediators C-reactive protein and IL-6 and portal pressure and mortality have been observed789. The influence of the resultant systemic inflammation on intra-hepatic resistance is most marked in patients with more advanced disease, in particular, acute on chronic liver failure (ACLF)10; yet little is understood regarding underlying mechanisms. More recently, LPS levels were shown to increase the mortality of patients with alcoholic hepatitis11 but the mechanisms of how LPS leads to increased mortality is unknown.…”

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confidence: 99%

Lipopolysaccharide-Induced Neutrophil Dysfunction Following Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS) Insertion is Associated with Organ Failure and Mortality

Macnaughtan

Mookerjee

Merwe

et al. 2017

Sci Rep

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Systemic lipopolysaccharide (LPS) is implicated in increasing mortality in patients with alcoholic hepatitis but the underlying mechanisms are not well characterised. The objective of this study was to characterise neutrophil function, LPS and cytokine concentrations within the splanchnic circulation of alcoholic cirrhotic patients undergoing TIPSS insertion for variceal haemorrhage and correlate this with outcome. 26 patients with alcoholic cirrhosis and variceal haemorrhage were studied prior to and 1-hour after TIPSS insertion. Neutrophil function, LPS and cytokine concentrations were determined in arterial, hepatic venous (HV) and portal venous blood (PV). Significantly higher LPS concentrations and neutrophil reactive oxidant species (ROS) production were observed in PV vs HV blood. Cross-incubation of HV plasma with PV neutrophils resulted in reduced ROS production. Insertion of TIPSS was associated with a significant increase in arterial LPS concentrations and deterioration in neutrophil phagocytosis. Number of organ failures and arterial IL-6 concentrations at presentation were associated with increased mortality. The portal circulation has a distinct immunological milieu characterised by a pathological neutrophil phenotype and an anti-inflammatory cytokine profile associated with heightened LPS levels. TIPSS insertion renders this neutrophil functional defect systemic, associated with an increase in arterial LPS and a susceptibility to sepsis.

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Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol‐related acute‐on‐chronic liver failure

Abstract: The disturbances in systemic and hepatic haemodynamics in alcohol-related ACLF are associated with dysregulated inflammation, multi-organ failure and marked activation of the sympathetic nervous system. These abnormalities predict high mortality rates in alcohol-related ACLF patients.

Cited by 93 publications

References 39 publications

Sepsis-induced acute kidney injury in patients with cirrhosis

Sepsis-induced acute kidney injury in patients with cirrhosis

Characterization of Inflammatory Response in Acute-on-Chronic Liver Failure and Relationship with Prognosis

Lipopolysaccharide-Induced Neutrophil Dysfunction Following Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS) Insertion is Associated with Organ Failure and Mortality

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