Publications by authors named "Debbie L Shawcross"

68 Publications

The rise and fall and rise again of ammonia as a therapeutic target in HE.

Hepatology 2022 Jan 7. Epub 2022 Jan 7.

Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1002/hep.32319DOI Listing
January 2022

An 18-year-old girl with retrosternal burning discomfort: a bitter pill to swallow.

BMJ Open Gastroenterol 2021 Dec;8(1)

Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.

Caustic injury secondary to impaction of ingested batteries is a potentially severe cause of oesophageal injury with an increasing incidence that reflects consumer trends and the utilisation of compact electronic devices. Delays to recognition and management are associated with increased risk of complications, morbidity and mortality. In this manuscript, we describe a case presentation and literature review of a patient presenting with upper oesophageal odynophagia after the deliberate ingestion of multiple foreign bodies.
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http://dx.doi.org/10.1136/bmjgast-2021-000767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718464PMC
December 2021

Statins: A Panacea to Reduce Mortality in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma?

Liver Transpl 2021 Nov 27. Epub 2021 Nov 27.

Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK.

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http://dx.doi.org/10.1002/lt.26381DOI Listing
November 2021

Gut-derived systemic inflammation as a driver of depression in chronic liver disease.

J Hepatol 2021 Nov 17. Epub 2021 Nov 17.

Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.

Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.
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http://dx.doi.org/10.1016/j.jhep.2021.11.008DOI Listing
November 2021

Implications and Management of Cirrhosis-Associated Immune Dysfunction Before and After Liver Transplantation.

Liver Transpl 2021 Nov 5. Epub 2021 Nov 5.

Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.

Cirrhosis-associated immune dysfunction (CAID) describes a panacea of innate and adaptive deficits that result from the sequelae of cirrhotic portal hypertension that is similar in its manifestations regardless of etiology of chronic liver injury. CAID is associated with synchronous observations of dysregulated priming of innate immune effector cells that demonstrate a proinflammatory phenotype but are functionally impaired and unable to adequately prevent invading pathogens. CAID is mainly driven by gut-barrier dysfunction and is associated with deficits of microbial compartmentalization and homeostasis that lead to tonic activation, systemic inflammation, and exhaustion of innate-immune cells. CAID leads to a high frequency of bacterial and fungal infections in patients with cirrhosis that are often associated with acute decompensation of chronic liver disease and acute-on-chronic liver failure and carry a high mortality rate. Understanding the deficits of mucosal and systemic immunity in the context of chronic liver disease is essential to improving care for patients with cirrhosis, preventing precipitants of acute decompensation of cirrhosis, and improving morbidity and survival. In this review, we summarize the detailed dynamic immunological perturbations associated with advanced chronic liver disease and highlight the importance of recognizing immune dysregulation as a sequela of cirrhosis. Furthermore, we address the role of screening, prevention, and early treatment of infections in cirrhosis in improving patient outcomes in transplant and nontransplant settings.
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http://dx.doi.org/10.1002/lt.26353DOI Listing
November 2021

Diarrhoea and preadmission antibiotic exposure in COVID-19: a retrospective cohort study of 1153 hospitalised patients.

BMJ Open Gastroenterol 2021 09;8(1)

King's College Hospital NHS Foundation Trust, London, UK.

Objective: The aims of this study were to describe community antibiotic prescribing patterns in individuals hospitalised with COVID-19, and to determine the association between experiencing diarrhoea, stratified by preadmission exposure to antibiotics, and mortality risk in this cohort.

Design/methods: Retrospective study of the index presentations of 1153 adult patients with COVID-19, admitted between 1 March 2020 and 29 June 2020 in a South London NHS Trust. Data on patients' medical history (presence of diarrhoea, antibiotic use in the previous 14 days, comorbidities); demographics (age, ethnicity, and body mass index); and blood test results were extracted. Time to event modelling was used to determine the risk of mortality for patients with diarrhoea and/or exposure to antibiotics.

Results: 19.2% of the cohort reported diarrhoea on presentation; these patients tended to be younger, and were less likely to have recent exposure to antibiotics (unadjusted OR 0.64, 95% CI 0.42 to 0.97). 19.1% of the cohort had a course of antibiotics in the 2 weeks preceding admission; this was associated with dementia (unadjusted OR 2.92, 95% CI 1.14 to 7.49). After adjusting for confounders, neither diarrhoea nor recent antibiotic exposure was associated with increased mortality risk. However, the absence of diarrhoea in the presence of recent antibiotic exposure was associated with a 30% increased risk of mortality.

Conclusion: Community antibiotic use in patients with COVID-19, prior to hospitalisation, is relatively common, and absence of diarrhoea in antibiotic-exposed patients may be associated with increased risk of mortality. However, it is unclear whether this represents a causal physiological relationship or residual confounding.
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http://dx.doi.org/10.1136/bmjgast-2020-000593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423520PMC
September 2021

Regulation, risk and safety of Faecal Microbiota Transplant.

Infect Prev Pract 2020 Sep 9;2(3):100069. Epub 2020 Jun 9.

Centre for Clinical Infection and Diagnostics Research (CIDR), King's College, London and Guy's & St. Thomas' NHS Foundation Trust, UK.

From its origins as a left-field, experimental, and even "maverick" intervention, faecal microbiota transplantation (FMT) is now a well-recognised, accepted, and potentially life-saving therapeutic strategy, for the management of recurrent Clostridiodes difficile infection (rCDI). It is being investigated as a treatment for a growing number of diseases including hepatic encephalopathy and eradication of antimicrobial resistant organisms, and the list of indications will likely expand in the future. There is no universally accepted definition of what FMT is, and its mechanism of action remains incompletely understood; this has likely contributed to the breadth of approaches to regulation depending on interpretation. In the UK FMT is considered a medicinal product, in North America, a biological product, whereas in parts of Europe, it is considered a human cell/tissue product. Regulation seeks to improve quality and safety, however, lack of standardisation creates confusion, and overly restrictive regulation may hamper widespread access and discourage research using FMT. FMT is generally considered safe, especially if rigorous donor screening and testing is conducted. Most short-term risks are associated with the delivery method (e.g. colonoscopy). Longer term risks are less well described but longitudinal follow-up of treated cohorts is in place to assess for this, and no signal towards harm has been found to date. Rarely it has been associated with adverse outcomes including the transmission of antibiotic resistant bacteria, and even death. It is vital patients undergoing FMT are well informed to the currently appreciated risks and benefits before proceeding.
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http://dx.doi.org/10.1016/j.infpip.2020.100069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280140PMC
September 2020

Severe alcohol-related liver disease admissions post-COVID-19 lockdown: canary in the coal mine?

Frontline Gastroenterol 2021 26;12(4):354-355. Epub 2020 Oct 26.

Institute of Liver Studies, King's College Hospital Liver Unit, London, London, UK.

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http://dx.doi.org/10.1136/flgastro-2020-101693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231423PMC
October 2020

Meeting the Challenge of Antimicrobial Resistance in Cirrhosis: The Invisible Threat That Lies Within.

Gastroenterology 2021 08 25;161(2):413-415. Epub 2021 May 25.

Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London and, Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.05.043DOI Listing
August 2021

The microbiota in cirrhosis and its role in hepatic decompensation.

J Hepatol 2021 07;75 Suppl 1:S67-S81

Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, VA, USA.

Cirrhosis - the common end-stage of chronic liver disease - is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.
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http://dx.doi.org/10.1016/j.jhep.2020.11.013DOI Listing
July 2021

Erroneous Ammonia Measurement is Not Synonymous With a Lack of Efficacy of Ammonia-Lowering Therapies in Hepatic Encephalopathy.

Clin Gastroenterol Hepatol 2021 11 29;19(11):2456-2457. Epub 2021 Jan 29.

Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.

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http://dx.doi.org/10.1016/j.cgh.2021.01.046DOI Listing
November 2021

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.

J Hepatol 2021 05 20;74(5):1097-1108. Epub 2020 Nov 20.

Medical University of Innsbruck, Innsbruck, Austria.

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes.

Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome.

Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality.

Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis.

Lay Summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.
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http://dx.doi.org/10.1016/j.jhep.2020.11.019DOI Listing
May 2021

Foreword.

Br J Nurs 2020 09;29(Sup17):S3

Professor of Hepatology and Chronic Liver Failure, Liver Sciences, Faculty of Life Sciences and Medicine, King's College London.

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http://dx.doi.org/10.12968/bjon.2020.29.Sup17.S3DOI Listing
September 2020

Intestinal Virome in Patients With Alcoholic Hepatitis.

Hepatology 2020 12 10;72(6):2182-2196. Epub 2020 Oct 10.

Department of Medicine, University of California San Diego, La Jolla, CA.

Background And Aims: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD.

Approach And Results: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality.

Conclusions: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.
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http://dx.doi.org/10.1002/hep.31459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159727PMC
December 2020

Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus.

Am J Gastroenterol 2020 07;115(7):989-1002

Department of Medicine, University of Padova, Padova, Italy.

Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.
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http://dx.doi.org/10.14309/ajg.0000000000000603DOI Listing
July 2020

Faecal microbiota transplant to ERadicate gastrointestinal carriage of Antibiotic Resistant Organisms (FERARO): a prospective, randomised placebo-controlled feasibility trial.

BMJ Open 2020 05 25;10(5):e038847. Epub 2020 May 25.

Centre for Clinical Infection and Diagnostics Research, Guy's and Saint Thomas' Hospitals NHS Trust, London, UK

Introduction: Antimicrobial resistance is rising, largely due to the indiscriminate use of antimicrobials. The human gut is the largest reservoir of antibiotic resistant bacteria (ARB). Individuals colonised with ARB have the potential to spread these organisms both in the community and hospital settings. Infections with ARB such as extended spectrum beta-lactamase producing enterobacteriales (ESBL-E) and carbapenemase producing enterobacteriales (CPE) are more difficult to treat and are associated with an increased morbidity and mortality. Presently, there is no effective decolonisation strategy for these ARB. Faecal microbiota transplant (FMT) has emerged as a potential strategy for decolonisation of ARB from the human gut, however there is significant uncertainty about the feasibility, effectiveness and safety of using this approach.

Methods And Analysis: Prospective, randomised, patient-blinded, placebo-controlled feasibility trial of FMT to eradicate gastrointestinal carriage of ARB. Eighty patients with a recent history of invasive infection secondary to ESBL-E or CPE and persistent gastrointestinal carriage will be randomised 1:1 to receive encapsulated FMT or placebo. The primary outcome measure is consent rate (as a proportion of patients who fulfil inclusion/exclusion criteria); this will be used to determine if a substantive trial is feasible. Participants will be followed up at 1 week, 1 month, 3 months and 6 months and monitored for adverse events as well as gastrointestinal carriage rates of ARB after intervention.

Ethics And Dissemination: Research ethics approval was obtained by London-City and East Research Ethics Committee (ref 20/LO/0117). Trial results will be published in a peer-reviewed journal and presented at international conferences.

Trial Registration Number: ISRCTN registration number 34 467 677 and EudraCT number 2019-001618-41.
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http://dx.doi.org/10.1136/bmjopen-2020-038847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252984PMC
May 2020

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Nature 2019 11 13;575(7783):505-511. Epub 2019 Nov 13.

Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.
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http://dx.doi.org/10.1038/s41586-019-1742-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872939PMC
November 2019

Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list.

Aliment Pharmacol Ther 2019 08 6;50(4):435-441. Epub 2019 Jun 6.

Institute of Liver Studies and Transplantation, King's College Hospital, London, UK.

Background: Rifaximin reduces the risk of overt hepatic encephalopathy (HE) and is associated with significant reductions in hospitalisations and 30-day readmissions.

Aim: To examine the outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug.

Methods: Patient records of those listed for liver transplantation over a 2-year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment.

Results: Of the 622 patients listed for transplantation, 101 had HE. Sixty-six patients were treated with rifaximin and 35 were naïve at listing. The use of concurrent lactulose was not significantly different between groups. Median MELD score was similar (15 [14-16)] rifaximin-treated and 16 [14-18] rifaximin-naïve). Patients on the waiting list treated with rifaximin had reduced all-cause admissions, episodes of spontaneous bacterial peritonitis and variceal bleeding. Mean length of stay was 9 days (95% CI 6-12) in the rifaximin-treated group vs 14 (95% CI 7-21) in the rifaximin-naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in average days to readmission (adjusted effect estimate 71, 95% CI 3-140 days) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89-0.93).

Conclusion: Rifaximin prescribed for HE in patients listed for liver transplantation improved outcomes with significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and variceal bleeding.
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http://dx.doi.org/10.1111/apt.15326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816014PMC
August 2019

Serum and Fecal Oxylipins in Patients with Alcohol-Related Liver Disease.

Dig Dis Sci 2019 07 10;64(7):1878-1892. Epub 2019 May 10.

Department of Medicine, University of California San Diego, La Jolla, CA, USA.

Background: Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease.

Aims: (1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease.

Methods: We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid, and docosahexaenoic acid in a patient cohort with alcohol-related liver disease.

Results: Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease score. Especially, higher level of serum 20-HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality.

Conclusions: Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.
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http://dx.doi.org/10.1007/s10620-019-05638-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588282PMC
July 2019

Is treating the gut microbiome the key to achieving better outcomes in cirrhosis?

Expert Rev Gastroenterol Hepatol 2019 Jan 13;13(1):1-2. Epub 2018 Nov 13.

a Liver Sciences, School of Immunology and Microbial Science, Faculty of Life Sciences and Medicine , King's College London , London , UK.

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http://dx.doi.org/10.1080/17474124.2019.1543587DOI Listing
January 2019

In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis.

Liver Int 2018 11 30;38(11):1988-1996. Epub 2018 May 30.

Liver Intensive Care Unit, Institute of Liver Studies, King College Hospital, London, UK.

Background & Aims: A simultaneous decline in pro- and anticoagulant drivers in patients with liver diseases results in a "rebalanced" haemostatic system, even in acutely ill patients. Nevertheless, both bleeding and thrombotic events are common. Here, we explored efficacy of pro- and antihaemostatic strategies in compensated and acutely ill cirrhotics which may be unpredictable given the profound haemostatic changes.

Methods: We tested the effects in vitro of the addition of clinically relevant doses of commonly used pro- and antihaemostatic strategies in plasma from healthy individuals (n = 30) and patients with compensated (n = 18) and acutely decompensated cirrhosis (n = 18), and acute-on-chronic liver failure (n = 10). We used thrombin generation tests and fibrin clot permeability assays to assess potency of various approaches.

Results: Fresh frozen plasma and recombinant factor VIIa modestly increased thrombin generation (10%-20%). Prothrombin complex concentrate increased thrombin generation two-fold in controls and 2-4-fold in patients. Clot permeability decreased after addition of fibrinogen concentrate by 51% in controls and by 50%-60% in patients. Low molecular weight heparin decreased thrombin generation by 18% in controls and by 23%-54% in patients. Similarly, dabigatran decreased thrombin generation by 33% in controls and by 47%-100% in patients. In contrast, rivaroxaban decreased thrombin generation by 55% in controls, but only by 11%-38% in patients.

Conclusions: These in vitro data suggest little prohaemostatic effect of fresh frozen plasma and recombinant factor VIIa in acutely ill cirrhotics, whereas prothrombin complex concentrate and fibrinogen concentrate clearly improved haemostasis. Furthermore, our data suggest the requirement for dose adjustments of commonly used anticoagulants in these patients.
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http://dx.doi.org/10.1111/liv.13882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220788PMC
November 2018

Diagnosis and management of hepatic encephalopathy.

Br J Nurs 2018 Feb;27(Sup3):S7-S13

Reader and Honorary Consultant Hepatologist, Institute of Liver Studies, School of Immunity and Microbial Science, Faculty of Life Sciences and Medicine, King's College Hospital, London.

Overt and covert hepatic encephalopathy (HE) are debilitating complications of cirrhosis. HE results in a poor quality of life for patients and their caregivers and, unless there is access to liver transplantation, the prognosis is poor. The development of overt HE is often unpredictable, and its management, particularly in the ward, remains challenging. There is an urgent need for novel approaches to treat HE. Until recently, therapies for this complication were disappointing, with frequently intolerable side effects such as diarrhoea and faecal incontinence. However, a non-absorbable antibiotic, rifaximin, * has been approved for the prevention of recurrent overt HE. It aims to reduce hospitalisation and resource use, as well as improve patients' quality of life. This article describes the practical aspects of diagnosing, classifying and managing HE. It reviews the pharmacological options for the treatment and prophylaxis of overt HE, and explores the evidence base demonstrating that rifaximin reduces the recurrence of overt HE.
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http://dx.doi.org/10.12968/bjon.2018.27.Sup3.S7DOI Listing
February 2018

The impact of rifaximin-α on the hospital resource use associated with the management of patients with hepatic encephalopathy: a retrospective observational study (IMPRESS).

Frontline Gastroenterol 2017 Oct 7;8(4):243-251. Epub 2017 Apr 7.

Department of Gastroenterology & Hepatology, Queen Alexandra Hospital, Portsmouth, UK.

Objective: To compare all-cause and liver-related hospital resource use in the 6 and 12 months pre-rifaximin-α and post-rifaximin-α initiation in UK patients with hepatic encephalopathy (HE).

Design: A UK multicentre, retrospective, observational study. Patients' medical records were reviewed for demographics, clinical outcomes and adverse events (AEs) to rifaximin-α. Details of hospital admissions/attendances in the 6 and 12 months pre-rifaximin-α and post-rifaximin-α initiation were extracted from hospital electronic databases.

Setting: 13 National Health Service centres.

Patients: 207 patients with HE who initiated rifaximin-α between July 2008 and May 2014. Hospital resource use data were available for 145/207 patients.

Main Outcome Measure: Change in mean number of liver-related hospital bed days/patient (total and critical care) between the 6 months pre-rifaximin-α and post-rifaximin-α initiation.

Results: Comparing the 6 months pre-rifaximin-α and post-rifaximin-α initiation in alive patients at the end of the observation period (N=114): there were significant reductions in the mean number of hospitalisations/patient (liver-related 1.3 to 0.5, p<0.001; all-cause 1.9 to 0.9, p<0.001), hospital bed days/patient (liver-related 17.8 to 6.8, p<0.001; all-cause 25.4 to 10.6, p<0.001), 30-day hospital readmissions/patient (liver-related 0.5 to 0.2, p=0.039; all-cause 0.8 to 0.4, p=0.024) and emergency department (ED) attendances/patient (all-cause, 1.0 to 0.5, p<0.001). The mean critical care bed days/patient reduced significantly for all-cause admissions (1.3 to 0.3, p=0.049); non-significant reduction for liver-related admissions. 4% of patients (9/207) developed AEs.

Conclusions: In UK clinical practice, treatment with rifaximin-α for HE is well-tolerated and associated with significant reductions in hospitalisations, bed days (including critical care), ED attendances and 30-day readmissions.
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http://dx.doi.org/10.1136/flgastro-2016-100792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641856PMC
October 2017

Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure.

J Crit Care 2018 Feb 17;43:54-60. Epub 2017 Aug 17.

Liver Intensive Care Unit, Institute of Liver Studies, King College Hospital, London, United Kingdom. Electronic address:

Background: Cirrhotic patients have complex haemostatic abnormalities. Current evidence suggests stable cirrhotic (SC) patients have a "re-balanced" haemostatic state. However, limited data exists in acute decompensated (AD) or acute on chronic liver failure (ACLF) patients.

Methods: We utilised thrombin generation analysis, fibrinolysis assessment, and evaluation of haemostatic parameters to assess haemostasis in liver disease of progressive severity.

Results: The study cohorts were comprised of: SC, n=8; AD n=44; ACLF, n=17; and Healthy Control (HC), n=35. There was a progressive increase across the cohorts in INR (p=0.0001), Factor VIII (p=0.0001) and VWF levels (p=0.0001) and a correspondingly decrease in anti-thrombin (p=0.0001), ADAMTS-13 (p=0.01) and fibrinogen levels (p=0.0001). In the presence of thrombomodulin, thrombin generation was equivalent or significantly higher in all the cohorts compared to HC (p=0.0001). Compared to AD, ACLF had a lower ETP (p=0.002) and thrombin peak (p=0.0001). There was no significant difference across the cohorts in clot lysis time (p=0.07), although compared to HC, AD had a significantly shorter lysis time (p=0.001).

Conclusions: Our cohorts, despite significant differences in haemostatic parameters, displayed intact thrombin generation but progressive hypo-functional clot stability and potentially but not universal hyper-functional haemostasis.
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http://dx.doi.org/10.1016/j.jcrc.2017.07.053DOI Listing
February 2018

Dysfunctional neutrophil effector organelle mobilization and microbicidal protein release in alcohol-related cirrhosis.

Am J Physiol Gastrointest Liver Physiol 2017 Sep 22;313(3):G203-G211. Epub 2017 Jun 22.

Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, United Kingdom

Patients with alcohol-related cirrhosis (ALD) are prone to infection. Circulating neutrophils in ALD are dysfunctional and predict development of sepsis, organ dysfunction, and survival. Neutrophil granules are important effector organelles containing a toxic array of microbicidal proteins, whose controlled release is required to kill microorganisms while minimizing inflammation and damage to host tissue. We investigated the role of these granular responses in contributing to immune disarray in ALD. Neutrophil granular content and mobilization were measured by flow cytometric quantitation of cell-surface/intracellular markers, [secretory vesicles (CD11b), secondary granules (CD66b), and primary granules (CD63; myeloperoxidase)] before and after bacterial stimulation in 29 patients with ALD cirrhosis (15 abstinent; 14 actively drinking) compared with healthy controls (HC). ImageStream Flow Cytometry characterized localization of granule subsets within the intracellular and cell-surface compartments. The plasma cytokine environment was analyzed using ELISA/cytokine bead array. Circulating neutrophils were primed in the resting state with upregulated surface expression of CD11b ( = 0.0001) in a cytokine milieu rich in IL-8 ( < 0.001) and lactoferrin ( = 0.035). Neutrophils showed exaggerated mobilization to the cell surface of primary granules at baseline ( = 0.001) and in response to -formyl-l-methionyl-l-leucyl-l-phenylalanine ( = 0.009) and ( = 0.0003) in ALD. There was no deficit in granule content or mobilization to the cell membrane in any granule subset observed. Paradoxically, active alcohol consumption abrogated the hyperresponsive neutrophil granular responses compared with their abstinent counterparts. Neutrophils are preprimed at baseline with augmented effector organelle mobilization in response to bacterial stimulation; neutrophil degranulation is not a mechanism leading to innate immunoparesis in ALD. Neutrophil granule release is dysregulated in patients with alcohol-related cirrhosis (ALD) with augmented effector organelle mobilization and microbiocidal protein release. Neutrophil granules are upregulated in ALD at baseline and demonstrate augmented responses to bacterial challenge. The granular responses in ALD did not contribute to the observed functional deficit in innate immunity but rather were dysregulated and hyperresponsive, which may induce bystander damage to host tissue. Paradoxically, active alcohol consumption abrogated the excessive neutrophil granular responses to bacterial stimulus compared with their abstinent counterparts.
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http://dx.doi.org/10.1152/ajpgi.00112.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625135PMC
September 2017

The changing face of hepatic encephalopathy: A projection for the next 5 years.

Clin Liver Dis (Hoboken) 2016 Dec 30;8(6):156-159. Epub 2016 Dec 30.

Institute of Liver Studies and Transplantation King's College London School of Medicine at King's College Hospital Denmark Hill United Kingdom.

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http://dx.doi.org/10.1002/cld.603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490241PMC
December 2016

Reversal of acquired hepatocerebral degeneration with living donor liver transplantation.

Liver Transpl 2016 05;22(5):693

Institute of Liver Studies, King's College Hospital, King's College London School of Medicine, London, UK.

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http://dx.doi.org/10.1002/lt.24423DOI Listing
May 2016

Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase.

Gut 2017 03 9;66(3):519-529. Epub 2016 Feb 9.

Department of Hepatology and Gastroenterology, Imperial College, London, UK.

Objective: In order to explain the increased susceptibility to serious infection in alcoholic hepatitis, we evaluated monocyte phagocytosis, aberrations of associated signalling pathways and their reversibility, and whether phagocytic defects could predict subsequent infection.

Design: Monocytes were identified from blood samples of 42 patients with severe alcoholic hepatitis using monoclonal antibody to CD14. Phagocytosis and monocyte oxidative burst (MOB) were measured ex vivo using flow cytometry, luminometry and bacterial killing assays. Defects were related to the subsequent development of infection. Intracellular signalling pathways were investigated using western blotting and PCR. Interferon-γ (IFN-γ) was evaluated for its therapeutic potential in reversing phagocytic defects. Paired longitudinal samples were used to evaluate the effect of in vivo prednisolone therapy.

Results: MOB, production of superoxide and bacterial killing in response to were markedly impaired in patients with alcoholic hepatitis. Pretreatment MOB predicted development of infection within two weeks with sensitivity and specificity that were superior to available clinical markers. Accordingly, defective MOB was associated with death at 28 and 90 days. Expression of the gp91 subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was reduced in patients with alcoholic hepatitis demonstrating defective MOB. Monocytes were refractory to IFN-γ stimulation and showed high levels of a negative regulator of cytokine signalling, suppressor of cytokine signalling-1. MOB was unaffected by 7 days in vivo prednisolone therapy.

Conclusions: Monocyte oxidative burst and bacterial killing is impaired in alcoholic hepatitis while bacterial uptake by phagocytosis is preserved. Defective MOB is associated with reduced expression of NADPH oxidase in these patients and predicts the development of infection and death.
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http://dx.doi.org/10.1136/gutjnl-2015-310378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534772PMC
March 2017

Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis.

J Hepatol 2016 May 18;64(5):1058-1067. Epub 2016 Jan 18.

Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom.

Background & Aims: Predicting survival in decompensated cirrhosis (DC) is important in decision making for liver transplantation and resource allocation. We investigated whether high-resolution metabolic profiling can determine a metabolic phenotype associated with 90-day survival.

Methods: Two hundred and forty-eight subjects underwent plasma metabotyping by (1)H nuclear magnetic resonance (NMR) spectroscopy and reversed-phase ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS; DC: 80-derivation set, 101-validation; stable cirrhosis (CLD) 20 and 47 healthy controls (HC)).

Results: (1)H NMR metabotyping accurately discriminated between surviving and non-surviving patients with DC. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities. This was confirmed on external validation (area under the receiver operating curve [AUROC]=0.96 (95% CI 0.90-1.00, sensitivity 98%, specificity 89%). UPLC-TOF-MS confirmed that lysophosphatidylcholines and phosphatidylcholines [LPC/PC] were downregulated in non-survivors (UPLC-TOF-MS profiles AUROC of 0.94 (95% CI 0.89-0.98, sensitivity 100%, specificity 85% [positive ion detection])). LPC concentrations negatively correlated with circulating markers of cell death (M30 and M65) levels in DC. Histological examination of liver tissue from DC patients confirmed increased hepatocyte cell death compared to controls. Cross liver sampling at time of liver transplantation demonstrated that hepatic endothelial beds are a source of increased circulating total cytokeratin-18 in DC.

Conclusion: Plasma metabotyping accurately predicts mortality in DC. LPC and amino acid dysregulation is associated with increased mortality and severity of disease reflecting hepatocyte cell death.
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http://dx.doi.org/10.1016/j.jhep.2016.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876170PMC
May 2016

How to diagnose and manage hepatic encephalopathy: a consensus statement on roles and responsibilities beyond the liver specialist.

Eur J Gastroenterol Hepatol 2016 Feb;28(2):146-52

aInstitute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital bInstitute of Liver and Digestive Health, Royal Free Hospital, London cDepartment of Gastroenterology, Eastbourne District General Hospital, Eastbourne d4C Consultants International, Hemel Hempstead eDepartment of Gastroenterology, Hampshire Hospitals Foundation Trust, Basingstoke, UK fClinic for Gastroenterology Hepatology and Infectious Disease, University Hospital, Dusseldorf gDepartment of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany hDepartment of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands iDepartment of Liver and Biliopancreatic Disorders, University Hospitals Leuven - KU LEUVEN, Leuven, Belgium.

Introduction: Hepatic encephalopathy is defined as brain dysfunction caused by liver insufficiency and/or portosystemic shunting. Symptoms include nonspecific cognitive impairment, personality changes and changes in consciousness. Overt (symptomatic) hepatic encephalopathy is a common complication of cirrhosis that is associated with a poor prognosis. Patients with hepatic encephalopathy may present to healthcare providers who do not have primary responsibility for management of patients with cirrhosis. Therefore, we developed a series of 'consensus points' to provide some guidance on management.

Methods: Using a modified 'Delphi' process, consensus statements were developed that summarize our recommendations for the diagnosis and management of patients with hepatic encephalopathy. Points on which full consensus could not be reached are also discussed.

Results: Our recommendations emphasize the role of all healthcare providers in the identification of cognitive impairment in patients with cirrhosis and provide guidance on steps that might be considered to make a diagnosis of overt hepatic encephalopathy. In addition, treatment recommendations are summarized. Minimal hepatic encephalopathy can have a significant impact on patients; however, in most circumstances identification and management of minimal hepatic encephalopathy remains the responsibility of specialists in liver diseases.

Conclusion: Our opinion statements aim to define the roles and responsibilities of all healthcare providers who at times care for patients with cirrhosis and hepatic encephalopathy. We suggest that these recommendations be considered further by colleagues in other disciplines and hope that future guidelines consider the management of patients with cirrhosis and with a 'suspicion' of cognitive impairment through to a formal diagnosis of hepatic encephalopathy.
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http://dx.doi.org/10.1097/MEG.0000000000000529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885589PMC
February 2016
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