The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90‐day and 1‐year mortality

Taylor, Nicholas; Vijay, Godhev K. Manakkat; Abeles, R.D.; Auzinger, G.; Bernal, William; Ma, Yuanfang; Wendon, Julia; Shawcross, Debbie L.

doi:10.1111/apt.12886

Cited by 72 publications

(86 citation statements)

References 27 publications

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“…'Paralysed' monocytes with reduced monocyte HLA-DR expression have been shown to be an independent predictor of poor outcome in patients with decompensated cirrhosis [17] and neutrophil bacteriocidal capability is impaired with the most significant dysfunction being observed in those with advanced disease and in those treated with propranolol. This circulating neutrophil dysfunction has been shown to predict the development of infection, organ dysfunction and survival at 90 days and 1 year [18]. Interestingly, it has been shown that ammonia itself can induce neutrophil malfunction with excessive and inappropriate release of reactive oxygen species and failure to move towards and phagocytose bacteria such as Escherichia coli, which may offer some insight as to why ammonia and inflammation may be synergistic partners in the pathogenesis of HE [19].…”

mentioning

confidence: 98%

Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy?

Shawcross

2015

Expert Review of Gastroenterology & Hepatology

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mentioning

confidence: 98%

Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy?

Shawcross

2015

Expert Review of Gastroenterology & Hepatology

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“…Functional defects include decreased phagocytic capacity [35] but preserved bacterial killing [36] and impaired chemotaxis and migration to sites of infection [37].…”

Section: Infection Related Mortality In Acute-on-chronic Liver Failurementioning

confidence: 99%

Immunotherapy in the Treatment and Prevention of Infection in Acute-on-chronic Liver Failure

et al. 2015

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Chronic liver disease, depicted by gradual destruction and fibrosis of the liver, is a condition with high and probably increasing prevalence worldwide. Its deterioration, acute-on-chronic liver failure (ACLF), is characterized by an in-hospital mortality of up to 65%. Infectious complications are the main precipitants eliciting ACLF and concurrently the main cause of death from ACLF. Patients have a marked susceptibility to bacterial infections, which is thought to arise a consequence of an inadequate immune response to microbial challenge, termed immuneparesis. The pathophysiologic mechanisms remain poorly understood. Treatments aimed at restoring the patients' immune function may prevent onset of ACLF and death from secondary infections. A number of drugs approved for patients with liver disease bear immunomodulatory potential such as albumin, glucocorticoids, N-acetylcysteine. Specific targets have been defined that may lead to development of new immunotherapeutic agents. Here, we summarize the pathophysiology of immuneparesis in ACLF and drug candidates to restore immune function and improve survival in the future.

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“…Exhaustion of immune effector cells is a plausible result of this overwhelming effect. Indeed, neutrophils demonstrate impaired bactericidal capacity in both ALF and cirrhosis and this predicts the development of organ dysfunction, infection and mortality (Taylor et al 2013(Taylor et al , 2014. Monocytes have also been shown to exhibit reduced antigen presenting capabilities and TNF-α production in liver failure (Berry et al 2011).…”

Section: Systemic Inflammation and Hepatic Encephalopathymentioning

confidence: 99%

Clinical science workshop: targeting the gut-liver-brain axis

et al. 2015

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A clinical science workshop was held at the ISHEN meeting in London on Friday 11th September 2014 with the aim of thrashing out how we might translate what we know about the central role of the gut-liver-brain axis into targets which we can use in the treatment of hepatic encephalopathy (HE). This review summarises the integral role that interorgan ammonia metabolism plays in the pathogenesis of HE with specific discussion of the roles that the small and large intestine, liver, brain, kidney and muscle assume in ammonia and glutamine metabolism. Most recently, the salivary and gut microbiome have been shown to underpin the pathophysiological changes which culminate in HE and patients with advanced cirrhosis present with enteric dysbiosis with small bowel bacterial overgrowth and translocation of bacteria and their products across a leaky gut epithelial barrier. Resident macrophages within the liver are able to sense bacterial degradation products initiating a pro-inflammatory response within the hepatic parenchyma and release of cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-8 into the systemic circulation. The endotoxemia and systemic inflammatory response that are generated predispose both to the development of infection as well as the manifestation of covert and overt HE. Co-morbidities such as diabetes and insulin resistance, which commonly accompany cirrhosis, may promote slow gut transit, promote bacterial overgrowth and increase glutaminase activity and may need to be acknowledged in HE risk stratification assessments and therapeutic regimens. Therapies are discussed which target ammonia production, utilisation or excretion at an individual organ level, or which reduce systemic inflammation and endotoxemia which are known to exacerbate the cerebral effects of ammonia in HE. The ideal therapeutic strategy would be to use an agent that can reduce hyperammonemia and reduce systemic inflammation or perhaps to adopt a combination of therapies that can address both.

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The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90‐day and 1‐year mortality

Abstract: SUMMARY BackgroundPatients with cirrhosis are susceptible to sepsis, pre-disposing to the development of encephalopathy, bleeding and organ dysfunction with associated high mortality.

Cited by 72 publications

References 27 publications

Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy?

Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy?

Immunotherapy in the Treatment and Prevention of Infection in Acute-on-chronic Liver Failure

Clinical science workshop: targeting the gut-liver-brain axis

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