Recent Submissions

  • Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease

    Barwell, Julian; Gupta, Pankaj; Neal, Christopher P; Tobin, Martin D; Vemala, Vishwaray M (2023-04-23)
    Background & aims: Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods: Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. Results: We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. Conclusions: We have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and implications: A rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.
  • Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease

    Barwell, Julian; Gupta, Pankaj; Vemala, Vishwaraj; Grant, Allister (21/04/2023)
    Background & aims: Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods: Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. Results: We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. Conclusions: We have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and implications: A rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.
  • Improving polyp detection at colonoscopy: Non-technological techniques

    Thayalasekaran, Sreedhari (2023-05-16)
    Colonoscopy and polypectomy remain the gold standard investigation for the detection and prevention of colorectal cancer. Halting the progression of colonic adenoma through adequate detection of pre-cancerous lesions interrupts the progression to carcinoma. The adenoma detection rate is a key performance indicator. Increasing adenoma detection rates are associated with reducing rates of interval colorectal cancer. Endoscopists with high baseline adenoma detection rate have a meticulous technique during colonoscopy withdrawal that improves their adenoma detection. This minireview article summarizes the evidence on the following simple operator techniques and their effects on the adenoma detection rate; minimum withdrawal times, dynamic patient position change and proximal colon retroflexion.
  • Investigating the relationship between home parenteral support and needs-based quality of life in patients with chronic intestinal failure: A national multi-centre longitudinal cohort study

    Rogers, Daniel; Muggridge, Rebecca (2023-01-25)
    Home parenteral support (HPS) is an essential but potentially burdensome treatment that can affect quality of life (QoL). The aims of this longitudinal study were to understand whether any changes in HPS over time were associated with QoL. The Parenteral Nutrition Impact Questionnaire (PNIQ) was used, and data were collected on HPS prescribed at three time points. Data were analysed using multi-level mixed regression models presented as effect size and were adjusted for confounders. Study recruited 572 participants from 15 sites. Of these, 201 and 145 completed surveys at second and third time-points, respectively. PNIQ score was out of 20 with a higher score indicating poorer QoL. Any reduction in HPS infusions per week was associated with an improved PNIQ score of -1.10 (95% CI -2.17, -0.02) unadjusted and -1.34 (95% CI -2.45, -0.24) adjusted. Per day change to the number of infusions per week was associated with a change in the PNIQ score of 0.32 (95% CI -0.15, 0.80) unadjusted and 0.34 (95% CI -0.17, 0.85) adjusted. This is the largest national study to demonstrate improvements in QoL associated with HPS reduction over time using an HPS-specific and patient-centric tool, adding unique data for use of therapies in intestinal failure.
  • Use of a non-endoscopic immunocytological device (Cytosponge™) for post chemoradiotherapy surveillance in patients with oesophageal cancer in the UK (CYTOFLOC): A multicentre feasibility study

    Kadri, Sudarshan (2022-09-23)
    Background: Effective surveillance strategies are required for patients diagnosed with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC) for whom chemoradiotherapy (CRT) is used as a potentially-curative, organ-sparing, alternative to surgery. In this study, we evaluated the safety, acceptability and tolerability of a non-endoscopic immunocytological device (the Cytosponge™) to assess treatment response following CRT. Methods: This multicentre, single-arm feasibility trial took place in 10 tertiary cancer centres in the UK. Patients aged at least 16 years diagnosed with OSCC or OAC, and who were within 4-16 weeks of completing definitive or neo-adjuvant CRT, were included. Participants were required to have a Mellow-Pinkas dysphagia score of 0-2 and be able to swallow tablets. All patients underwent a single Cytosponge™ assessment in addition to standard of care (which included post-treatment endoscopic evaluation with biopsy for patients undergoing definitive CRT; surgery for those who received neo-adjuvant CRT). The primary outcome was the proportion of consented, evaluable patients who successfully underwent Cytosponge™ assessment. Secondary and tertiary outcomes included safety, study consent rate, acceptance rate, the suitability of obtained samples for biomarker analysis, and the comparative efficacy of Cytosponge™ to standard histology (endoscopy and biopsy or post-resection specimen) in assessing for residual disease. The trial is registered with ClinicalTrials.gov, NCT03529669. Findings: Between 18th April 2018 and 16th January 2020, 41 (42.7%; 95% confidence interval (CI) 32.7-53.2) of 96 potentially eligible patients consented to participate. Thirty-nine (95.1%, 95% CI 83.5-99.4) successfully carried out the Cytosponge™ procedure. Of these, 37 (95%) would be prepared to repeat the procedure. There were only two grade 1 adverse events attributed to use of the Cytosponge™. Thirty-five (90%) of the completed Cytosponge™ samples were suitable for biomarker analysis; 29 (83%) of these were concordant with endoscopic biopsies, three (9%) had findings suggestive of residual cancer on Cytosponge™ not found on endoscopic biopsies, and three (9%) had residual cancer on endoscopic biopsies not detected by Cytosponge™. Interpretation: Use of the CytospongeTM is safe, tolerable, and acceptable for the assessment of treatment response following CRT in OAC and OSCC. Further evaluation of Cytosponge™ in this setting is warranted. Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council.
  • Faecal immunochemical testing (FIT) in patients with signs or symptoms of suspected colorectal cancer (CRC): a joint guideline from the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the British Society of Gastroenterology (BSG)

    Stephenson, James (2022-07-12)
    Faecal immunochemical testing (FIT) has a high sensitivity for the detection of colorectal cancer (CRC). In a symptomatic population FIT may identify those patients who require colorectal investigation with the highest priority. FIT offers considerable advantages over the use of symptoms alone, as an objective measure of risk with a vastly superior positive predictive value for CRC, while conversely identifying a truly low risk cohort of patients. The aim of this guideline was to provide a clear strategy for the use of FIT in the diagnostic pathway of people with signs or symptoms of a suspected diagnosis of CRC. The guideline was jointly developed by the Association of Coloproctology of Great Britain and Ireland/British Society of Gastroenterology, specifically by a 21-member multidisciplinary guideline development group (GDG). A systematic review of 13 535 publications was undertaken to develop 23 evidence and expert opinion-based recommendations for the triage of people with symptoms of a suspected CRC diagnosis in primary care. In order to achieve consensus among a broad group of key stakeholders, we completed an extended Delphi of the GDG, and also 61 other individuals across the UK and Ireland, including by members of the public, charities and primary and secondary care. Seventeen research recommendations were also prioritised to inform clinical management.
  • Infliximab: a single-centre, prospective, observational evaluation of TDM data in patients with IBD

    Gadsby, Jessica; Hall, Karen; Shah, Fatima; Pattni, Sanjeev; Gethins, Sharon; Mulla, Hussain
    Objectives: Therapeutic drug monitoring of infliximab (IFX) is important to optimise treatment of inflammatory bowel disease (IBD). A recent IBD consensus statement recommends targeting trough serum concentrations of >3 μg/mL, higher than our local recommendation of >1 μg/mL. We therefore investigated the relationship between IFX trough concentrations and C reactive protein (CRP), faecal calprotectin (FCP), clinical outcomes and anti-IFX antibody (AB) development as well as the influence of concomitant thiopurine treatment. Methods: Observational data, prospectively collected in a cohort of adult patients with IBD newly initiated on IFX at a single centre. Results: IFX concentrations >3 μg/mL were associated with a greater reduction in CRP (% change from baseline) and lower FCP; mean (SD) 47 (33.8) % vs 102.3 (136.9) % and 233.9 (505.1) μg/g vs 416.3 (613.5) μg/g, respectively. Lower IFX concentrations were observed in patients who developed AB than those who did not, mean (range) 6.2 (1.1-10) μg/mL vs 0.9 (0.4-4.9) μg/mL, respectively, and also in patients who stopped/switched therapy compared with those who continued, 2.4 (2.9) μg/mL vs 6.5 (2.8) μg/mL; p=0.0002. Patients taking a concomitant thiopurine were found to have higher IFX concentrations; mean (range) 6.4 (0.7-10) μg/mL vs 3.9 (0.4-10) μg/mL. Conclusions: IFX concentrations are correlated with biomarkers, clinical response and AB development in patients with IBD. Concomitant thiopurine therapy appears to be associated with higher IFX concentrations and reduced likelihood of AB development.
  • Immunosuppressive regimens and outcomes of inflammatory bowel disease patients requiring kidney transplantation

    Singh, Baljit (2022-02)
    Patients with inflammatory bowel disease (IBD) can develop extra-renal complications and as a result, suffer from end stage renal failure requiring kidney transplantation (KT). A brief review of available literature revealed that IBD patients undergoing KT have shorter overall survival rates compared to their controls. Literature reporting steroid regimens and survival outcomes specific to IBD and post kidney transplant are scarce and these studies have small sample sizes thus making it difficult to draw accurate conclusions. Further research is required in the form of a randomized controlled study to clarify the effect and mechanism of steroid immunosuppression on the prognosis of renal transplant recipients and explore new treatment schemes.
  • A Multicenter Study of Patient Acceptability of the IBD Disk Tool and Patient-Reported Disabilities

    Pattni, Sanjeev (2022-02)
    Background: IBD, both Crohn's disease and ulcerative colitis, is associated with significant functional disability. Gastrointestinal symptoms alone are not the sole purpose of the interaction between patients and providers. In order to ascertain patients' disabilities, we utilized the recently developed IBD Disk to help determine their functional concerns and initiate relevant conversation. We aimed to ascertain patient acceptability and their major disabilities. Patients and methods: In this multicenter study, IBD patients at their outpatient visit were given the paper version of the IBD Disk. Patients were asked to score their level of disability for each item of the IBD Disk. The completed scores were then shared with their healthcare provider to act as a focus of discussion during the consultation. Patients and clinicians were also asked to provide informal qualitative feedback as to the benefits of the IBD Disk and areas for improvement. Results: A total of 377 (female 60%) patients completed the questionnaires over the study period. Patient acceptability scored on a 0-10 Likert scale was excellent. All patients scored all domains of disability. Sleep, energy, and joint pain were the highest scoring domains of the IBD Disk, scoring higher than digestive symptoms. Clinicians and patients agreed that the IBD Disk allowed for ease of communication about disability symptoms and relevance to their day-to-day functioning. Conclusion: The IBD Disk is a novel easy-to-use tool to assess the functional disability of patients. We next plan to utilize it in the form of an electronic app internationally and in relation to treatment commencement and escalation.
  • Unexplained peripheral blood eosinophilia with gastrointestinal symptoms

    Wardlaw, Andrew; Myers, Bethan; Rathbone, Barrie; Siddiqui, Salman; Wurm, Peter (2021)
    No abstract available.
  • Impact of home parenteral nutrition on family members: A national multi-centre cross-sectional study

    Rogers, Daniel
    Background & aims: Home parenteral nutrition (HPN) is a necessary treatment for patients with chronic, type 3, intestinal failure (IF). HPN often requires lifestyle adaptations, which are likely to affect quality of life (QoL) in both patients and family members. The aim of this study was to identify the level of burden on family members who are involved with HPN care and to understand specific factors that contribute to any burden. Methods: Patients over the age of 18 and receiving HPN were identified in IF clinics from multiple centres across the U.K. Eligible patients were asked to complete the parenteral nutrition impact questionnaire (PNIQ) to assess their QoL, while family members were asked to complete the burden scale for family caregivers (BSFC). Logistical regression was undertaken giving adjusted odds ratios (aOR). Results: 678 participants completed the survey representing 339 patients with their appointed family member. Mean PNIQ score was 11.53 (S.D. 5.5), representing a moderate impact of HPN on patients' QoL. On the BSFC scale, 23% of family members reported a moderate to very severe subjective burden indicating an increased risk of psychosomatic symptoms. After adjusting for age and gender, predictors of BSFC included: family members self-reported health status using the EuroQol visual analogue scale (aOR 19.91, 95% CI 1.69, 233.99, p = 0.017) and support received by health services (aOR = 5.83, 95% CI = 1.93, 17.56, p = 0.002). Employment status, disease type, number of nights on HPN and length of time on HPN were not associated with BSFC. Conclusions: Family members with a poor health status or lack of support by health service were more likely to have a moderate to very severe subjective burden. Tailored support from the multi-professional IF team may reduce the burden experienced by family members of people dependent on HPN.
  • Microbiomes in physiology: Insights into 21st century global medical challenges

    Suzuki, Toru (2022)
    New findings: What is the topic of this review? This review summarises the role of the gut microbiome in physiology and how it can be targeted as an effective strategy against two of the most important global medical challenges of our time namely, metabolic diseases and antibacterial resistance. What advances does it highlight? We outline the critical roles of the microbiome in regulating host physiology and discuss how microbiome analysis is useful for disease stratification to enable informed clinical decisions and develop interventions such as faecal microbiota transplantation (FMT), prebiotics, and probiotics. We also discuss the limitations of microbiome modulation, including the potential for probiotics to enhance antimicrobial resistance gene reservoirs, and that currently a "healthy microbiome" that can be used as a biobank for transplantation is yet to be defined. Abstract: The human gut microbiome plays a key factor in the development of metabolic diseases and antimicrobial resistance which are among the greatest global medical challenges of the 21st century. The symposium aimed to highlight state-of-the-art evidence for the role of the gut microbiome in physiology, from childhood to adulthood, and the impact this has on global disease outcomes, ageing and antimicrobial resistance. Although the gut microbiome is established early in life, over time the microbiome and their components including metabolites can become perturbed due to changes such as dietary habits, use of antibiotics and age. As gut microbial metabolites, including short chain fatty acids (SCFAs), secondary bile acids and trimethylamine-N-Oxide (TMAO), can interact with host receptors including G protein coupled receptors (GPCRs), and can alter host metabolic fluxes, they can significantly affect physiological homeostasis leading to metabolic diseases. These metabolites can be used to stratify disease phenotypes such as irritable bowel syndrome (IBS) and adverse events after heart failure and provide informed decisions on clinical management and treatment. While strategies such as probiotics, prebiotics, and faecal microbiota transplantation (FMT) have been proposed as interventions to treat and prevent metabolic diseases and antimicrobial resistance, caution must be exercised; first due to the potential of probiotics to enhance antimicrobial resistance gene reservoirs and second, a "healthy gut microbiome" that can be used as a biobank for transplantation is yet to be defined. We highlight that sampling other parts of the GI tract may produce more representative data than the faecal microbiome alone. This article is protected by copyright. All rights reserved.