Gut microflora in the pathogenesis of the complications of cirrhosis

García–Tsao, Guadalupe; Wiest, Reiner

doi:10.1016/j.bpg.2003.10.005

Cited by 173 publications

(134 citation statements)

References 110 publications

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“…32 The highest levels of endotoxin reported in patients with liver disease are found in portal venous blood, 33,34 highlighting the importance of the bowel and altered gut permeability as a possible source of endotoxin. 35 However, the difficulties with the measurement of endotoxin are reflected in the wide range of values in the literature and make this an unreliable indicator on which to base further management. 33,34 Our data do support the notion that endotoxin may be the putative humoral factor in patients' plasma responsible for the activation of neutrophils by showing that endotoxin increased the resting burst in healthy neutrophils while reducing phagocytosis in neutrophils from patients with alcoholic cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

et al. 2007

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Mortality in patients with alcoholic hepatitis (AH) remains high, and although corticosteroids are widely used for treatment, the results vary considerably. In AH, neutrophils are primed and infiltrate the liver to produce injury, but paradoxically, the main cause of death in such patients is infection. Our prospective study addressed this paradox of primed neutrophils on the one hand and increased risk of infection on the other. We hypothesized that the full activation of neutrophils by a humoral factor such as endotoxin renders them unable to respond to further bacterial challenge. We analyzed neutrophil oxidative burst and phagocytosis in whole blood by fluorescence-activated cell sorting analysis in 63 alcoholic patients with cirrhosis and patients with cirrhosis with superimposed AH (cirrhosis؉AH). In 16 patients, ex vivo studies determined whether the removal of endotoxin restored neutrophil function. A resting burst greater than or equal to 5%, indicating neutrophil activation and a reduced phagocytic capacity lower than 42%, was associated with significantly greater risk of infection, organ failure, and mortality. This defective neutrophil function was transmissible through patients' plasma to normal neutrophils, and patients' neutrophil function could be restored by normal plasma. The ex vivo removal of endotoxin from patients' plasma decreased the resting burst and increased the phagocytic function. Conclusions: Our study provides the rationale for a goal-directed approach to the management of patients with cirrhosis and AH, in which the assessment of neutrophil function may be an important biomarker to select patients for immunosuppressive therapy. The neutrophil dysfunction in cirrhosis and AH is reversible, with endotoxin-removal strategies providing new targets for intervention. (HEPATOLOGY 2007;46:831-840.)

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Section: Discussionmentioning

confidence: 99%

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

et al. 2007

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“…Second, patients with liver cirrhosis have increased bowel permeability and decreased bowel motility, which can result in a bacterial contamination of the portal vein by translocation of gut bacteria to mesenteric lymph nodes. 24 Finally, patients with liver cirrhosis have an impaired immune system and may therefore frequently suffer from bacterial infections.…”

Section: Effects Of Lps Pretreatment On Portal Pressurementioning

confidence: 99%

“…17,18 In this study, the effects of intraperitoneal LPS on portal pressure and the involved pathways were investigated.…”

mentioning

confidence: 99%

Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis

Steib¹,

Hartmann²,

Hesler³

et al. 2010

Laboratory Investigation

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Recent studies have shown that the risk of variceal bleeding in patients with liver cirrhosis increases with infections such as spontaneous bacterial peritonitis (SBP). In this study, we hypothesized that pretreatment with intraperitoneal LPS may escalate portal hypertension. In fibrotic livers (4 weeks after bile duct ligation, BDL), the activation of Kupffer cells (KCs) by zymosan (150 mg/ml) in the isolated non-recirculating liver perfusion system resulted in a transient increase in portal perfusion pressure. Pretreatment with intraperitoneal LPS (1 mg/kg body weight (b.w.) for 3 h) increased basal portal perfusion pressure, and prolonged the zymosan-induced increase from transient to a long-lasting increase that was sustained until the end of the experiments in BDL but not in sham-operated animals. Pretreatment with gadolinium chloride (10 mg/kg b.w.), MK-886 (0.6 mg/kg b.w.), Ly171883 (20 mM) or BM 13.177 (20 mM) reduced the maximal and long-lasting pressure increase in BDL animals by approximately 50-60%. The change in portal perfusion pressure was paralleled by a long-lasting production of cysteinyl leukotriene (Cys-LT) and thromboxane (TX) after LPS pretreatment. However, the response to vasoconstrictors was not altered by intraperitoneal LPS. Western blot analyses showed an increased Toll-like receptor (TLR)4 and MyD88 expression after LPS pretreatment. In vivo experiments confirmed that intraperitoneal LPS increased basal portal pressure, and extended the portal pressure increase produced by intraportal zymosan or by LPS infusion. In conclusion, upregulation of TLR4 and MyD88 expression in fibrotic livers confers hypersensitivity to LPS. This may lead to escalation of portal hypertension by production of TX and Cys-LT after endotoxin-induced KC activation. Therefore, LT inhibitors may represent a promising treatment option in addition to early administration of antibiotics in SBP.

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“…The most frequent complications are jaundice, rupture of varicose veins, encephalopathy, ascites, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome [4].…”

Section: Introductionmentioning

confidence: 99%

Alterations in neutrophil extracellular traps is associated with the degree of decompensation of liver cirrhosis

Agraz‐Cibrián

Segura-Ortega

Delgado‐Rizo

et al. 2016

J Infect Dev Ctries

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Introduction: Liver cirrhosis (LC) constitutes one of the main 10 causes of death worldwide. LC has a characteristic asymptomatic compensated phase followed by a progressive decompensated phase, in which diverse complications are presented. LC patients are highly prone to bacterial infections. The neutrophils in these patients present defects in the production of oxygen radicals, which are essential for bacteria elimination as in the activation of neutrophil extracellular traps (NETs). The main objective of this work was to determine the NETs and neutrophil activation markers in LC patients. Methodology: Neutrophil purification was done with Ficoll Histopaque from a sample of the peripheral blood of patients with compensated and decompensated LC. Neutrophils were activated with Phorbol 12-myristate 13-acetate to evaluate the release of NETs by means of fluorescence microscopy and fluorometry, while expression of activation markers (CD69, CD80, perforin, and CAP-18) was evaluated by flow cytometry. Results: A significant decrease in the release capability of NETs was observed as the level of LC in the patient increased. When comparing serum levels in inflammatory cytokines among the different study groups, significant differences were observed. No significant differences were detected on neutrophil activation markers; nevertheless, there was a correlation between diminution of CD69 and CD80 expression in decompensated patients. Conclusions: We demonstrated that LC patients with neutrophil extracellular trap release deficiencies could have an increased rate of complications.

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Gut microflora in the pathogenesis of the complications of cirrhosis

Cited by 173 publications

References 110 publications

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis

Alterations in neutrophil extracellular traps is associated with the degree of decompensation of liver cirrhosis

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