Summary
Background
Mortality from chronic liver disease is rising exponentially. The liver is intimately linked to the gut via the portal vein, and exposure to gut microbiota and their metabolites ...translocating across the gut lumen may impact upon both the healthy and diseased liver. Modulation of gut microbiota could prove to be a potential therapeutic target.
Aim
To characterise the changes in the gut microbiome that occur in chronic liver disease and to assess the impact of manipulation of the microbiome on the liver.
Methods
We conducted a PubMed search using search terms including ‘microbiome’, ‘liver’ and ‘cirrhosis’ as well as ‘non‐alcoholic fatty liver disease’, ‘steatohepatitis’, ‘alcohol’ and ‘primary sclerosing cholangitis’. Relevant articles were also selected from references of articles and review of the ClinicalTrials.gov website.
Results
Reduced bacterial diversity, alcohol sensitivity and the development of gut dysbiosis are seen in several chronic liver diseases, including non‐alcoholic fatty liver disease, alcohol‐related liver disease and primary sclerosing cholangitis. Perturbations in gut commensals could lead to deficient priming of the immune system predisposing the development of immune‐mediated diseases. Furthermore, transfer of stool from an animal with the metabolic syndrome may induce steatosis in a healthy counterpart. Patients with cirrhosis develop dysbiosis, small bowel bacterial overgrowth and increased gut wall permeability, allowing bacterial translocation and uptake of endotoxin inducing hepatic and systemic inflammation.
Conclusions
Manipulation of the gut microbiota with diet, probiotics or faecal microbiota transplantation to promote the growth of “healthy” bacteria may ameliorate the dysbiosis and alter prognosis.
Aliment Pharmacol Ther 2011; 33: 739–747
Summary
Background The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this ...field.
Aims To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials.
Methods A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end‐points for assessing the treatment and secondary prevention of hepatic encephalopathy.
Results It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro‐cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter‐ and intravariability in the availability of some of the more objective surrogate performance markers.
Conclusions The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed.
Background & Aims Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and ...infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date. Methods We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan 2000 and March 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded. Results 46% of patients had positive cultures taken within ±48 h from admission to ICU 25% blood and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score ( p = 0.03) and SOFA score ( p = 0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive ( p <0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent of patients survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted. Conclusions These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival.
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with both acute and chronic liver dysfunction. It defines prognosis in acute liver injury in which patients can succumb with ...brain oedema and intracranial hypertension. In cirrhosis, it occurs insidiously, causing a range of neuropsychiatric disturbances. For over a century, we have known that ammonia is important in its pathogenesis and astrocytes are the cells that have been most commonly found to be affected neuropathologically. In this review we centre on the story of the 'sick astrocyte', focusing on the molecular pathogenesis of HE and the important role that inflammation has on its modulation. We describe new developments in this area with respect to potential targets for future therapies.
Linked Content
This article is linked to Goel et al and Goel and Nguyen papers. To view these articles visit https://doi.org/10.1111/apt.14361 and https://doi.org/10.1111/apt.14450.
Summary
Background
Patients with cirrhosis are susceptible to sepsis, pre‐disposing to the development of encephalopathy, bleeding and organ dysfunction with associated high mortality.
Aim
To ...characterise circulating neutrophil function in a cirrhotic cohort as a determinant of 90‐day and 1‐year mortality.
Methods
Sixty‐two patients with cirrhosis 49 stable (Child–Pugh A/B/C = 24%/39%/37%); 13 acute‐on‐chronic liver failure were prospectively studied and compared with 11 healthy controls. Neutrophil function was evaluated at baseline and repeated at critical points during the course of the patient's illness until death/transplantation. Neutrophil phenotype was determined using fluorochrome‐labelled antibodies to CD16/CD11b and assessed by flow cytometry. Neutrophil phagocytic activity (NPA) and capacity (NPC) were determined using FITC‐labelled opsonised Escherichia coli. Oxidative burst (OB) was quantified by the percentage of neutrophils producing reactive oxygen species (ROS) and mean fluorescence intensity at rest, and after stimulation with E. coli. Physiological variables, biochemistry, microbiology and outcomes were collected. Plasma pro‐ and anti‐inflammatory cytokine profiles were performed by ELISA.
Results
NPA/NPC was impaired in cirrhosis with the most significant dysfunction being observed in those with advanced disease and in those treated with propranolol. NPC predicted survival in stable cirrhosis AUROC 0.83 (95% CI 0.68–0.97); P = 0.021 and differentiated survivors from nonsurvivors (90‐day P = 0.01; 1 year P < 0.001). Resting OB ≥12% predicted 90‐day mortality with 80% sensitivity and 71% specificity AUROC 0.81 (95% CI 0.64–0.97); P = 0.026 and differentiated survivors from nonsurvivors; P = 0.015.
Conclusion
Circulating neutrophils in patients with cirrhosis are dysfunctional and predict the development of infection, organ dysfunction and survival at 90 days and 1 year.
Linked Content
This article is linked to Støy et al and Patel and Muir papers. To view these articles visit https://doi.org/10.1111/apt.14600 and https://doi.org/10.1111/apt.14654.
Summary
Background
Thrombocytopenia and circulating dysfunctional immune cells are commonly observed in patients with cirrhosis. Platelets may form complexes with neutrophils, monocytes and T cells ...modulating their function. We recently reported increased frequencies of platelet‐complexed neutrophils in cirrhosis with evidence of neutrophil activation upon contact with healthy platelets in vitro. Whether this occurs in vivo following platelet transfusion and contributes to systemic inflammation and endothelial activation is unknown.
Aims
To characterise platelet‐leucocyte aggregation in cirrhosis and to determine whether elective platelet transfusion results in perturbations associated with changes in markers of haemostasis, inflammation or endothelial activation.
Methods
We collected blood from cirrhotics (n = 19) before and following elective platelet transfusion. We measured platelet‐leucocyte aggregation, activation and function, and markers of platelet activation, systemic inflammation and endothelial activation by flow cytometry. Haemostasis was assessed by thromboelastometry and plasma haemostatic proteins.
Results
We observed a 2.5‐fold increase in platelet‐complexed neutrophils in patients with cirrhosis compared with healthy subjects and twofold more platelets attached per monocyte and T cell. All platelet‐complexed leucocytes expressed higher levels of activation markers and platelet‐complexed neutrophils had higher resting oxidative burst and phagocytic capacity than their nonplatelet‐complexed counterparts (P < 0.001); most pronounced in patients with cirrhosis. Paradoxically, platelet‐complexed leucocyte frequency decreased with increasing MELD score. Platelet transfusion increased soluble CD40 ligand (platelet activation marker), the frequency of platelet‐complexed monocytes (P < 0.05) and improved haemostatic status.
Conclusion
Cirrhotic patients have activated circulating platelet‐complexed leucocytes with increased platelet‐monocyte aggregation following elective platelet transfusion. Elective platelet transfusion might therefore exacerbate immune dysfunction in cirrhosis.
Linked ContentThis article is linked to Patel and Muir, and Støy and Shawcross papers. To view these articles visit https://doi.org/10.1111/apt.14654 and https://doi.org/10.1111/apt.14671.
Guidelines for the treatment of hepatic encephalopathy suggest ammonia reduction as the main focus, based on strategies to reduce ammonia's generation and absorption in the colon by using lactulose ...and a reduced protein diet.
Two studies provide compelling and provocative data questioning the relevance of these interventions. Bodils Als-Nielsen and colleagues, in a systematic review of randomised trials, found insufficient evidence about whether non-absorbable disaccharides are beneficial (BMJ 2004; 328: 1046-50). In a small randomised study, Juan Cordoba and colleagues showed that diets with normal protein content can be administered safely during episodic hepatic encephalopathy due to cirrhosis and that protein restriction does not have any beneficial effect during such episodes (J Hepatol 2004; 41: 38-43).
Two approaches to new therapies for hepatic encephalopathy are needed. First, it is important to focus on the interorgan metabolism of ammonia. The small intestine and kidneys might be important producers of ammonia, and muscle is an important organ that can remove ammonia. Novel therapies targeting these organs reduce ammonia. Second, research is needed to explore factors other than ammonia that might be important in hepatic encephalopathy, including the synergistic role of inflammation. The lack of conclusive data about the efficacy of any treatment supports the view that placebo-controlled trials of newer agents are needed and ethical. The emphasis should shift to aggressive management of the precipitating event.
Minimal hepatic encephalopathy (MHE) is common in cirrhosis but its pathophysiologic basis remains undefined. We evaluated whether the presence of MHE was associated with severity of liver disease, ...ammonia levels or the presence of inflammation and assessed factors determining neuropsychological deterioration accompanying induction of hyperammonemia.
Eighty four cirrhotics were studied. A neuropsychological test battery was performed and blood taken for ammonia, WCC, CRP, nitrate/nitrite, IL-6 and amino acids, before and after, induction of hyperammonemia by administration of a solution mimicking the amino acid composition of haemoglobin (60) or placebo (24).
The presence and severity of MHE were independent of severity of liver disease and ammonia concentration but markers of inflammation were significantly higher in those with MHE compared with those without. Induction of hyperammonemia produced deterioration in one or more neuropsychological tests by > or =1 SD in 73.3%. This was independent of the magnitude of change in plasma ammonia and severity of liver disease but was significantly greater in those with more marked inflammation.
Our data show that inflammation is an important determinant of the presence and severity of MHE. The change in neuropsychological function following induced hyperammonemia is greater in those with more severe inflammation.
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