Publications
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Artru F, Atkinson S, Trovato F, et al., 2022, Untargeted lipidomics unveils a specific plasma signature of severe alcoholic hepatitis, International Liver Congress, Publisher: ELSEVIER, Pages: S135-S135, ISSN: 0168-8278
Bailey P, Vergis N, Allison M, et al., 2021, Psychosocial Evaluation of Candidates for Solid Organ Transplantation, TRANSPLANTATION, Vol: 105, Pages: E292-E302, ISSN: 0041-1337
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Vergis N, Patel V, Bogdanowicz K, et al., 2021, IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis, Trials, Vol: 22, Pages: 1-16, ISSN: 1745-6215
Background: Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1β antibody, Canakinumab, in the treatment of AH.Methods: This is multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the United Kingdom. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is reduction in lobular inflammation, comparing histological appearances at baseline with appearances at 28 days. Patients with evidence of ongoing disease activity will receive a second infusion of Canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days. Discussion: This phase II study will explore the benefits of the IL-1β antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1β signaling may improve histology and survival for patients with AH. Trial registration: Prospectively registered with EudraCT 2017-003724-79.
Tyson L, Thursz PM, Forrest E, et al., 2021, INCIDENT ACUTE KIDNEY INJURY HAS A WORSE PROGNOSIS THAN BASELINE IN SEVERE ALCOHOLIC HEPATITIS, Publisher: BMJ PUBLISHING GROUP, Pages: A25-A26, ISSN: 0017-5749
Dhanda A, Allison M, Bodger K, et al., 2021, INCREASING BURDEN OF ALCOHOL-RELATED LIVER DISEASE IN THE UK ASSOCIATED WITH THE CORONAVIRUS PANDEMIC, Publisher: BMJ PUBLISHING GROUP, Pages: A26-A26, ISSN: 0017-5749
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Middleton P, Vergis N, 2021, Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation, Therapeutic Advances in Gastroenterology, Vol: 14, Pages: 1-19, ISSN: 1756-2848
Mitochondria are key organelles involved in energy production as well as numerous metabolic processes. There is a growing interest in the role of mitochondrial dysfunction in the pathogenesis of common chronic diseases as well as in cancer development. This review will examine the role mitochondria play in the pathophysiology of common liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, chronic hepatitis B and hepatocellular carcinoma. Mitochondrial dysfunction is described widely in the literature in studies examining patient tissue and in disease models. Despite significant differences in pathophysiology between chronic liver diseases, common mitochondrial defects are described, including increased mitochondrial reactive oxygen species production and impaired oxidative phosphorylation. We review the current literature on mitochondrial-targeted therapies, which have the potential to open new therapeutic avenues in the management of patients with chronic liver disease.
Rhodes F, Vergis N, Thursz M, et al., 2021, The combination of ABIC plus ELF as a single marker outperforms ABIC alone in predicting 90-day survival in alcoholic hepatitis., Publisher: ELSEVIER, Pages: S324-S325, ISSN: 0168-8278
Lett A, Lim A, Skinner C, et al., 2021, Rapid, non-invasive measurement of gastric emptying rate using transcutaneous fluorescence spectroscopy, Biomedical Optics Express, Vol: 12, Pages: 4249-4264, ISSN: 2156-7085
Gastric emptying rate (GER) signifies the rate at which the stomach empties following ingestion of a meal and is relevant to a wide range of clinical conditions. GER also represents a rate limiting step in small intestinal absorption and so is widely assessed for research purposes. Despite the clinical and physiological importance of gastric emptying, methods used to measure GER possess a series of limitations (including being invasive, slow or unsuitable for certain patient populations). Here, we present a new technique based on transcutaneous (through-the-skin) fluorescence spectroscopy that is fast, non-invasive, and does not require the collection of samples or laboratory-based analysis. Thus, this approach has the potential to allow immediate reporting of clinical results. Using this new method, participants receive an oral dose of a fluorescent contrast agent and a wearable probe detects the uptake of the agent from the gut into the blood stream. Analysis of the resulting data then permits the calculation of GER. We compared our spectroscopic technique to the paracetamol absorption test (a clinically approved GER test) in a clinical study of 20 participants. Results demonstrated good agreement between the two approaches and, hence, the clear potential of transcutaneous fluorescence spectroscopy for clinical assessment of GER.
Vergis N, Phillips R, Cornelius V, et al., 2021, Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial, Trials, Vol: 22, ISSN: 1745-6215
OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease C
Tyson L, Forlano R, Ulucay E, et al., 2021, Automated quantitation of histological features could predictmortality in patients with severe alcoholic hepatitis, ILC 2021, Publisher: Elsevier, ISSN: 0168-8278
Vergis N, 2021, Trends in Alcohol-Induced Deaths in the United States by Sex, Age, and Ethnicity Suggest a Need for Targeted Health Interventions, HEPATOLOGY, Vol: 73, Pages: 856-857, ISSN: 0270-9139
Forrest E, Petts G, Austin A, et al., 2021, The diagnostic and prognostic significance of liver histology in alcoholic hepatitis, Alimentary Pharmacology and Therapeutics, Vol: 53, Pages: 426-431, ISSN: 0269-2813
BackgroundLiver biopsy may be of diagnostic and prognostic value but its role in alcoholic hepatitis (AH) has been controversial.AimTo assess the utility of liver biopsy in the assessment of clinically severe AHMethodsThe histological features of alcoholic steatohepatitis (ASH) were recorded and scored in patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial who underwent liver biopsy. These features were then assessed relative to outcome and established clinical prognostic scores.ResultsThe STOPAH trial recruited 1068 patients; biopsies were obtained in 182 (17%). One hundred and sixty‐one biopsies were adequate for histological assessment and 140 (87%) were diagnostic for ASH. Only three biopsies (2%) did not have histological features of alcohol‐related liver injury. In biopsies performed prior to randomisation, ASH was identified in 92.5% of patients meeting clinical trial definitions of severe AH. In biopsies with ASH, taken before or within 48 hours of randomisation, survival differences between Alcoholic Hepatitis Histological Score (AHHS) groups were not significant: comparison of mild / moderate (91%: 21 of 23 patients) with severe (78%: 29 of 37 patients) groups: P = 0.18. The AHHS was not superior to clinical scores of prognosis: area under the curve for 28‐day mortality was 0.728, compared with 0.799 for the Glasgow alcoholic hepatitis score and 0.728 for the MELD score.ConclusionLiver histology taken before treatment rarely changes the diagnosis in patients meeting strict criteria for a clinical diagnosis of AH. The AHHS is similar to clinical scores in determining prognosis.Clinical trial registrationEudraCT reference number: 2009‐013897‐42.ISRCTN reference number: 88782125.MREC number: 09/MRE09/59.UKCRIN ID: 9143.
Middleton P, Thursz M, Vergis N, 2021, P204 Mitochondrial dysfunction may explain innate immunoparesis and susceptibility to infection of patients with alcoholic hepatitis, BSG Campus
Cemente A, Atkinson S, Tyson LD, et al., 2020, EARLY ALCOHOL RELAPSE AFTER AN EPISODE OF ALCOHOL-INDUCED HEPATITIS (AH): PREVALENCE, IMPACT ON LIVER FUNCTION, GENETIC AND NON -GENETIC FACTORS AND IDENTIFICATION OF DISTINCT RISK PROFILES., Liver Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY, Pages: 158A-159A, ISSN: 0270-9139
Atkinson SR, Grove JI, Liebig S, et al., 2020, In severe alcoholic hepatitis, serum keratin-18 fragments are diagnostic, prognostic, and theragnostic biomarkers., American Journal of Gastroenterology, Vol: 115, Pages: 1857-1868, ISSN: 0002-9270
INTRODUCTION: Up to 40% of patients with severe alcoholic hepatitis (AH) die within 6 months of presentation, making prompt diagnosis and appropriate treatment essential. We determined the associations between serum keratin-18 (K18) and histological features, prognosis, and differential response to prednisolone in patients with severe AH. METHODS: Total (K18-M65) and caspase-cleaved K18 (K18-M30) were quantified in pretreatment sera from 824 patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (87 with suitable histological samples) and disease controls. RESULTS: K18 fragments were markedly elevated in severe AH and strongly predicted steatohepatitis (alcoholic steatohepatitis) on biopsy (area under receiver operating characteristics: 0.787 and 0.807). Application of published thresholds to predict alcoholic steatohepatitis would have rendered biopsy unnecessary in 84% of all AH cases. K18-M30 and M65 were associated with 90-day mortality, independent of age and Model for End-stage Liver Disease score in untreated patients. The association for K18-M65 was independent of both age and Model for End-stage Liver Disease in prednisolone-treated patients. Modelling of the effect of prednisolone on 90-day mortality as a function of pretreatment serum K18 levels indicated benefit in those with high serum levels of K18-M30. At low pretreatment serum K18 levels, prednisolone was potentially harmful. A threshold of K18-M30 5 kIU/L predicted therapeutic benefit from prednisolone above this level (odds ratio: 0.433, 95% confidence interval: 0.19-0.95, P = 0.0398), but not below (odds ratio: 1.271, 95% confidence interval: 0.88-1.84, P = 0.199). Restricting prednisolone usage to the former group would have reduced exposure by 87%. DISCUSSION: In a large cohort of patients with severe AH, serum K18 strongly correlated with histological severity, independently associated with 90-day mortality, and predicted response to prednisolone therapy. Quantificati
Skinner C, Thompson AJ, Thursz MR, et al., 2020, Intestinal permeability and bacterial translocation in patients with liver disease, focusing on alcoholic aetiology: methods of assessment and therapeutic intervention, Therapeutic Advances in Gastroenterology, Vol: 13, Pages: 1-16, ISSN: 1756-2848
Increased bacterial translocation (BT) across the gut barrier due to greater intestinal permeability (IP) is seen across a range of conditions, including alcohol-related liver disease (ArLD). The phenomenon of BT may contribute to both the pathogenesis and the development of complications in ArLD. There are a number of methods available to assess IP and in this review we look at their various advantages and limitations. The knowledge around BT and IP in ArLD is also reviewed, as well as the therapeutic strategies currently in use and in development.
Kim JU, Majid A, Judge R, et al., 2020, Effect of COVID-19 lockdown on alcohol consumption in patients with pre-existing alcohol use disorder, LANCET GASTROENTEROLOGY & HEPATOLOGY, Vol: 5, Pages: 886-+
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Maurice J, Lett A, Skinner C, et al., 2020, Transcutaneous fluorescence spectroscopy as a tool for non-invasive monitoring of gut function: first clinical experiences, Scientific Reports, Vol: 10, ISSN: 2045-2322
Gastro-intestinal function plays a vital role in conditions ranging from inflammatory bowel disease and HIV through to sepsis and malnutrition. However, the techniques that are currently used to assess gut function are either highly invasive or unreliable. Here we present an alternative, non-invasive sensing modality for assessment of gut function based on fluorescence spectroscopy. In this approach, patients receive an oral dose of a fluorescent contrast agent and a fibre-optic probe is used to make fluorescence measurements through the skin. This provides a readout of the degree to which fluorescent dyes have permeated from the gut into the blood stream. We present preliminary results from our first measurements in human volunteers demonstrating the potential of the technique for non-invasive monitoring of multiple aspects of gastro-intestinal health.
Nathwani R, Mukherjee S, Forlano R, et al., 2020, Letter: liver disease and COVID-19 - not the perfect storm, Alimentary Pharmacology and Therapeutics, Vol: 52, Pages: 572-574, ISSN: 0269-2813
This article is linked to Garrido et al papers. To view these articles, visit https://doi.org/10.1111/apt.15813 and https://doi.org/10.1111/apt.15886.
Dhanda A, Atkinson S, Vergis N, et al., 2020, Trace element deficiency is highly prevalent and associated with infection and mortality in patients with alcoholic hepatitis, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol: 52, Pages: 537-544, ISSN: 0269-2813
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Rhodes F, Cococcia S, Vergis N, et al., 2019, AN ALGORITHM COMBINING HYALURONIC ACID, PROCOLLAGEN III AMINO-TERMINAL PEPTIDE AND THE GLASGOW ALCOHOLIC HEPATITIS SCORE IN A SINGLE NUMBER PREDICTS 90-DAY MORTALITY IN ALCOHOL-RELATED HEPATITIS., Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Publisher: WILEY, Pages: 817A-818A, ISSN: 0270-9139
Vergis N, Thursz M, Atkinson S, 2019, Assessment and management of infection in alcoholic hepatitis, Seminars in Liver Disease, Vol: 40, Pages: 11-19, ISSN: 0272-8087
Severe alcoholic hepatitis (SAH) is a condition characterized by jaundice and liver failure that develops after heavy and prolonged alcohol consumption. Infection frequently complicates the natural history of the disease and is independently associated with mortality. Objective recognition and recording of infection are therefore essential in the evaluation of therapeutic interventions and for antibiotic stewardship. This review will evaluate infections that complicate SAH at admission and beyond. Factors that associate with the development of infection will be identified and clinical and laboratory techniques available to identify infection will be discussed. Common pathogens and frequently used antibiotics will be reviewed and recommendations will be made for the management of infection for SAH patients. New techniques to assess infection earlier and more precisely may improve diagnosis and treatment of this important driver of mortality in SAH.
Forrest EH, Storey N, Sinha R, et al., 2019, Baseline neutrophil-to-lymphocyte ratio predicts response to corticosteroids and is associated with infection and renal dysfunction in alcoholic hepatitis., Alimentary Pharmacology and Therapeutics, Vol: 50, Pages: 442-453, ISSN: 0269-2813
BACKGROUND: Treating severe alcoholic hepatitis involves the exposure of patients to corticosteroids for 7 days to assess "response". AIM: To assess the prognostic and therapeutic implications of baseline Neutrophil-to-Lymphocyte ratio (NLR) in patients with severe alcoholic hepatitis. METHODS: Patients recruited to the STOPAH trial and an independent validation group were analysed retrospectively. Area under the Receiver Operating Curve (AUC) analysis was performed. Kaplan-Meier analysis was used to assess survival. Log-rank test and Odds ratio (OR) were used for comparative analysis. RESULTS: Baseline NLR was available for 789 STOPAH patients. The AUC for NLR was modest for 90-day outcome (0.660), but it was associated with infection, acute kidney injury (AKI) and severity of alcoholic hepatitis. Ninety-day survival was not affected by prednisolone treatment if NLR < 5 or > 8 < 5 but mortality was reduced with prednisolone treatment when the NLR was 5-8:21.0% cf. 34.5%; P = 0.012. Prednisolone treatment increased the chance of Lille response if the NLR was ≥ 5 (56.5% cf. 41.1%: P = 0.01; OR 1.86) but increased the risk of Day 7 infection (17.3% cf. 7.4%: P = 0.006; OR 2.60) and AKI (20.8% cf. 7.0%: P = 0.008; OR 3.46) if the NLR was > 8. Incorporation of NLR into a modified Glasgow Alcoholic Hepatitis Score (mGAHS) improved the AUC to 0.783 and 0.739 for 28-day and 90-day outcome, respectively. CONCLUSION: The NLR is associated with AKI and infection in severe alcoholic hepatitis. The NLR identifies those most likely to benefit from corticosteroids at baseline (NLR 5-8). The mGAHS has a good predictive value for 28- and 90-day outcomes.
Parker R, Kim SJ, Im GY, et al., 2019, Obesity in acute alcoholic hepatitis increases morbidity and mortality, EBioMedicine, Vol: 45, Pages: 511-518, ISSN: 2352-3964
BackgroundAlcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH) and the underlying inflammatory crosstalk between adipose tissue (AT) and the liver.MethodsA cohort of 233 patients with AH from the UK and USA provided data to analyse the effects of obesity in AH. Body mass index was corrected for the severity of ascites, termed cBMI. Inflammatory and metabolic profiling was undertaken by proteome analysis of human serum samples. The effect of alcohol on adipose tissue and CXCL11 expression was studied in 3 T3-derived adipocytes and in mice using the high-fat diet-plus-binge ethanol model.FindingsObesity was common amongst patients with AH, seen in 19% of individuals. Obesity (HR 2.22, 95%CI 1.1–4.3, p = .022) and underweight (HR 2.38, 1.00–5.6, p = .049) were independently associated with mortality at 3 months. Proteome analysis demonstrated multiple metabolic and inflammatory factors differentially expressed in obese AH verse lean AH, with CXCL11 being the most elevated factor in obese AH. In vitro analysis of cultured adipocytes and in vivo analysis of mouse models showed that alcohol induced CXCL11 expression in AT, but not in liver.InterpretationObesity is common in AH and associated with a greater than two-fold increase in short-term mortality. Obese AH is associated with a different inflammatory phenotype, with the greatest elevation in CXCL11. These data confirm that adiposity is clinically important in acute alcohol-related liver disease and illustrate the adipose-liver inflammatory axis in AH.FundThis work was supported in part by an EASL Sheila Sherlock Physician Scientist Fellowship. The funder played no role in gathering or analysing data or writing the manuscript. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the U
Forrest E, Storey N, Sinha R, et al., 2019, A modified Glasgow alcoholic hepatitis score incorporating the neutrophil-to-lymphocyte ratio is superior to other baseline scores of prognosis in alcoholic hepatitis, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E277-E278, ISSN: 0168-8278
Forrest E, Storey N, Sinha R, et al., 2019, Baseline neutrophil-to-lymphocyte ratio indicates both prevalent and incident infection and acute kidney injury, and is related to corticosteroid Lille response in alcoholic hepatitis, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E47-E47, ISSN: 0168-8278
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Tyson LD, Atkinson S, Pechlivanis A, et al., 2019, Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis, International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: E108-E108, ISSN: 0168-8278
Vergis N, Atkinson S, Thursz M, 2019, The future of therapy for alcoholic hepatitis - beyond corticosteroids, Journal of Hepatology, Vol: 70, Pages: 785-787, ISSN: 0168-8278
Corticosteroids are the only treatment proven to reduce mortality from severe alcoholic hepatitis (SAH), though the benefit is short-lived.1 Several potential therapies are currently under evaluation in human clinical trials (Table 1). These therapies target: i) malnutrition; ii) intestinal dysbiosis and its portal translocation; iii) bile acid production; iv) hepatocyte death; v) hepatocyte regeneration; and vi) life-threatening complications of the disease itself.
Vergis N, Scarborough AJ, Morris JA, et al., 2018, Prone or Left for Colonoscopy? A Randomized Controlled Trial of Prone Versus Left-sided Starting Position for Colonoscopy, JOURNAL OF CLINICAL GASTROENTEROLOGY, Vol: 52, Pages: E82-E86, ISSN: 0192-0790
Atkinson SR, Vergis N, Louvet A, et al., 2017, Universal screening of acute medical admissions for excess alcohol consumption: What's the misuse?, JOURNAL OF HEPATOLOGY, Vol: 67, Pages: 448-450, ISSN: 0168-8278
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