Analysis of genotyping for predicting liver injury marker, procollagen III in persons at risk of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at-risk patients in primary care using non-invasive methods has the potential to address this by identifying those likely to progress. We, therefore, evaluated variant alleles at loci associated with non-alcoholic fatty liver disease as genetic determinants of substantial liver injury in patients with disease risk factors. METHODS: Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI > 27.3 (identified from registration with general practitioners) in this observational cross-sectional study. Patients were genotyped for characterised risk alleles in PNPLA3 (rs738409), GCKR (rs1260326) and TM6SF2 (rs58542926) and associations with PIIINP assessed. RESULTS: The risk alleles in PNPLA3, GCKR or TM6SF2 were not found to be individually associated with the presence of a disease risk factor and were not significantly more common in patients with raised serum PIIINP. The prevalence of possession of both PNPLA3 and GCKR variant alleles combined was significantly higher in at-risk patients with clinically significant liver disease indicated by serum PIIINP above 11 ng/mL (P = .014). CONCLUSIONS: Genotyping, therefore, has limited value for predicting severe liver disease in at-risk individuals identified in a community setting.

Narrow band imaging and serology in the assessment of premalignant gastric pathology.

BACKGROUND: Patient outcomes in gastric adenocarcinoma are poor due to late diagnosis. Detecting and treating at the premalignant stage has the potential to improve this. Helicobacter pylori is also a strong risk factor for this disease. AIMS: Primary aims were to assess the diagnostic accuracy of magnified narrow band imaging (NBI-Z) endoscopy and serology in detecting normal mucosa, H. pylori gastritis and gastric atrophy. Secondary aims were to compare the diagnostic accuracies of two classification systems using both NBI-Z and white light endoscopy with magnification (WLE-Z) and evaluate the inter-observer agreement. METHODS: Patients were prospectively recruited. Images of gastric mucosa were stored with histology and serum for IgG H. pylori and Pepsinogen (PG) I/II ELISAs. Blinded expert endoscopists agreed on mucosal pattern. Mucosal images and serological markers were compared with histology. Kappa statistics determined inter-observer variability for randomly allocated images among four experts and four non-experts. RESULTS: 116 patients were prospectively recruited. Diagnostic accuracy of NBI-Z for determining normal gastric mucosa was 0.87(95%CI 0.82-0.92), H. pylori gastritis 0.65(95%CI 0.55-0.75) and gastric atrophy 0.88(95%CI 0.81-0.94). NBI-Z was superior to serology at detecting gastric atrophy: NBI-Z gastric atrophy 0.88(95%CI 0.81-0.94) vs PGI/II ratio < 3 0.74(95%CI 0.62-0.85) p<.0001. Overall NBI-Z was superior to WLE-Z in detecting disease using two validated classifications. Inter-observer agreement was 0.63(95%CI 0.51-0.73). CONCLUSIONS: NBI-Z accurately detects changes in the GI mucosa which currently depend on histology. NBI-Z is useful in the detection of precancerous conditions, potentially improving patient outcomes with early intervention to prevent gastric cancer.

The hepatitis C revolution part 1: antiviral treatment options.

PURPOSE OF REVIEW: The rapid evolution in the therapeutic landscape of hepatitis C presents a minefield to clinicians seeking to optimize therapy for their patients. Efficacy, evidence-base, side-effects, and drug combinations must be tailored to individual patients, taking into account comorbidities, degree of fibrosis, evidence of hepatic decompensation, and life expectancy. The review article aims to discuss novel hepatitis C virus (HCV) treatments with an overview of recent breakthrough research validating their potential. It is hoped that this systematic evaluation will clarify best available evidence for clinicians treating patients with HCV on a regular basis. RECENT FINDINGS: With greater understanding of the HCV life cycle and viral genome, the last decade has seen the emergence of novel direct-acting antiviral (DAA) agents, which specifically target proteins responsible for viral replication. Landmark clinical trials have offered robust evidence supporting the use of DAA agents as pioneer treatments, alone, or in combination with standard pegylated interferon (peg-IFN) and ribavirin (RBV)-based regimens. DAAs have proved highly efficacious, with pan-genotypic activity, shortened treatment duration, and an improved side-effect profile when compared with historical peg-IFN/RBV treatment. Recent phase 3 studies have provided proof-of-concept that all-oral, IFN-free DAA regimens can yield high rates of sustained virological response across most HCV genotypes. SUMMARY: The ability of DAAs to dramatically improve virological clearance heralds a new era in clinical therapeutics, as the unprecedented prospect of cure for a chronic viral infection becomes tangible. However, myriad clinical challenges remain before global eradication of HCV can become reality.

The hepatitis C revolution part 2: difficult-to-treat groups and experimental approaches.

PURPOSE OF REVIEW: Novel direct-acting antiviral (DAA) agents are highly effective in the treatment of hepatitis C, achieving unprecedented rates of sustained virological response, a functional cure. However, a significant minority of patients belong to 'difficult-to-treat' groups, in which efficacy of DAAs appears less robust. The review article aims to discuss additional treatment strategies which may be employed in these patient cohorts, as well as evidence for the potential role of experimental DAAs. RECENT FINDINGS: Patients with genotype 3 infection have consistently lower rates of virological clearance following DAA therapy when compared with other genotypes. However, in combination with sofosbuvir, the novel nonstructural protein 5A inhibitor daclatasvir has demonstrated high efficacy in the treatment of noncirrhotic genotype 3 infection. Recent data from phase 2 and 3 clinical studies support the use of currently approved DAA regimens in the treatment of patients with hepatitis C virus and human immunodeficiency virus (HIV) coinfection. Sustained virological response rates in coinfected patients are analogous to those observed in monoinfection, such that HIV infection itself does not pose a barrier to DAA efficacy. In posttransplant populations, DAAs have again shown great potential, with trial data validating use of sofosbuvir/ledipasvir. SUMMARY: Unmet need persists in certain subsets of the hepatitis C patient population. The arrival on scene of novel DAAs is likely to further expand the repertoire of available therapy for these 'difficult-to-treat' groups.

Why is there a change in patterns of GE cancer?

Recent decades have seen a worrying trend in incidence rates of distal oesophageal and proximal gastric cancers. Fuelled by radical changes in lifestyle, diet, physical activity and environmental exposures, as well as an ageing population and host genetic predisposition, the incidence of oesophageal adenocarcinoma (OAC) is on the rise in Western populations. While overall incidence of gastric cancers is declining, the ageing of society means that an increase in absolute numbers is expected over coming years. Both cancers tend to present at an advanced stage, hence prognosis remains poor despite increasingly effective screening and treatment strategies. The development of gastric and oesophageal malignancies is influenced by myriad factors, not least geographical, racial and socioeconomic differences in addition to lifestyle choices. The multidimensional nature of these risk factors requires a holistic understanding of their net influence in the development of malignancy. This review explores the evidence base for established and putative risk factors in the development of gastric and oesophageal cancers. It is hoped that with a clear understanding of important risk factors, a multidisciplinary approach including effective primary prevention, regular screening of high-risk groups and continued research into the molecular biology of gastrointestinal carcinogenesis may facilitate a reduction in incidence rates, as well as early detection and optimal management of upper gastrointestinal malignancies.

Quality standards for the management of non-alcoholic fatty liver disease (NAFLD): consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group.

Non-alcoholic fatty liver disease (NAFLD) is common, affecting approximately 25% of the general population. The evidence base for the investigation and management of NAFLD is large and growing, but there is currently little practical guidance to support development of services and delivery of care. To address this, we produced a series of evidence-based quality standard recommendations for the management of NAFLD, with the aim of improving patient care. A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group produced the recommendations, which cover: management of people with, or at risk of, NAFLD before the gastroenterology or liver clinic; assessment and investigations in secondary care; and management in secondary care. The quality of evidence for each recommendation was evaluated by the Grading of Recommendation Assessment, Development and Evaluation tool. An anonymous modified Delphi voting process was conducted individually by each member of the group to assess the level of agreement with each statement. Statements were included when agreement was 80% or greater. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice. It is hoped that services will review their practice against our recommendations and key performance indicators and institute service development where needed to improve the care of patients with NAFLD.

Metabolic Imaging in Non-Alcoholic Fatty Liver Disease: Applications of Magnetic Resonance Spectroscopy.

Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an integrated approach to uncover molecular mediators, key pathogenic milestones and response to intervention at the metabolic level. The advent of precision imaging has yielded unprecedented insights into these processes. Quantitative imaging biomarkers such as magnetic resonance imaging (MRI), spectroscopy (MRS) and elastography (MRE) present robust, powerful tools with which to probe NAFLD metabolism and fibrogenesis non-invasively, in real time. Specific advantages of MRS include the ability to quantify static metabolite concentrations as well as dynamic substrate flux in vivo. Thus, a vast range of key metabolic events in the natural history of NAFLD can be explored using MRS. Here, we provide an overview of MRS for the clinician, as well as key pathways exploitable by MRS in vivo. Development, optimisation and validation of multinuclear MRS, in combination with other quantitative imaging techniques, may ultimately provide a robust, non-invasive alternative to liver biopsy for observational and longitudinal studies. Through enabling deeper insight into inflammatory and fibrogenic cascades, MRS may facilitate identification of novel therapeutic targets and clinically meaningful endpoints in NAFLD. Its widespread use in future could conceivably accelerate study design, data acquisition and availability of disease-modifying therapies at a population level.

Detecting chronic liver disease: are liver function tests the solution?

By 2020, chronic liver disease will have eclipsed ischaemic heart disease as the leading cause of working life years lost in the UK. As mortality from chronic liver disease continues to rise, the landscape of aetiology has shifted from infectious to non-communicable causes. In parallel with the growing prevalence of obesity and type 2 diabetes, non-alcoholic fatty liver disease is estimated to affect 25% of the UK adult population. Simultaneously, escalating alcohol consumption has fuelled public health and economic concerns regarding its widespread impact on working-age adults. Given that chronic liver disease remains clinically silent until its advanced stages, there is an urgent unmet need to identify affected individuals earlier in the disease process, enabling targeted intervention strategies which may improve prognosis. Robust epidemiological data have shown that liver fibrosis is the strongest predictor of clinically meaningful outcomes, including decompensation, liver cancer and overall mortality. Detecting fibrosis among at-risk individuals, in a manner that is reproducible, non-invasive, safe and cost effective, has become a major challenge of our time. This article addresses the pitfalls of the standard panel of liver function tests, discusses other non-invasive biomarkers and reviews imaging technologies which may revolutionise community-based diagnosis and stratification of chronic liver disease.

Drug Development for Nonalcoholic Fatty Liver Disease: Landscape and Challenges.

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in industrialized economies. With no licensed treatment currently available, together with a growing prevalence that parallels global increases in obesity and type 2 diabetes, NAFLD will dominate the landscape of hepatology for the foreseeable future. A multifaceted etiopathogenesis, paucity of reproducible preclinical models that effectively recreate human NAFLD, and lack of robust surrogate trial endpoints have presented major hurdles in drug discovery and development. Smooth collaboration between bench scientists, biotechnology, pharmaceutical industries, and clinicians will be pivotal to target identification, development of effective therapies, biomarker discovery, and ultimately to bring pipeline drugs to market. This review examines the key challenges remaining in NAFLD drug development, outlines early and late phase clinical trials of candidate treatments, and discusses the journey toward biomarker discovery which may facilitate development of novel endpoints in NAFLD clinical trials, enabling meaningful response to be determined noninvasively.

Mapping transactional analysis to clinical leadership models.

Leaders in today's NHS face the unenviable task of reconciling rising demand, frozen resource allocation and increasing accountability. As the NHS itself stands at the nexus of an unstable political and socioeconomic landscape, its future success relies largely on its ability to nurture excellence, to encourage open communication within and across health-care teams, and to inspire its workforce through exemplary leadership and followership. Key to these endeavours are clinicians on the 'shop floor', whose daily interactions with patients and staff help to shape prevailing culture and drive progress through quality improvement and leadership initiatives. This article considers how transactional analysis can be incorporated into professional development to help doctors develop insight into and optimize the use of different communication styles. The authors propose that a working knowledge of the transactional analysis ego state model can enhance effective communication, leadership and followership within and across health-care teams, with a view to optimizing patient outcomes and workforce interactions.

Structured approach in improving weekend handovers in a medical high dependency unit.

Weekend admissions to hospital have been associated with adverse patient outcomes, including higher morbidity and mortality risk in general medicine and surgery. The reasons behind this are likely to be multifactorial and include reduced senior clinician-led care, decreased overall workforce, and ineffective or incomplete handover. With the advent of shift-work patterns, robust handover between medical teams is of paramount importance, particularly before weekends. This has been reflected in recent publications by Royal College of Physicians (acute care toolkit 1: handover, May 2011), that identified handover as an error-prone process and issued guidelines designed to optimise its effectiveness. The aim of this project was to evaluate weekend patient mortality and success of handover on the medical high dependency unit of a large teaching hospital in the United Kingdom, before and after introduction of a structured handover tool on Friday afternoons during May 2013. This unit is registrar-led at weekends. Weekend mortality decreased from 43% in March 2013 to 22% in May 2013 (odds ratio 0.37, 95% CI 0.19-0.68, p=0.07). Documentation of resuscitation status and escalation plans increased from 75% in March 2013 to 93% in May 2013. There was universal positive feedback from registrars involved with the handover tool, who provided senior cover during the weekends in May 2013. It is hoped that structured, written handover will ultimately become commonplace in this unit and will improve patient safety at weekends.

Aspirin and NSAIDs; benefits and harms for the gut.

Despite modern advances in cancer research, screening and treatment options, gastrointestinal tumours remain a leading cause of death worldwide. Both oesophageal and colorectal malignancies carry high rates of morbidity and mortality, presenting a challenge to clinicians in search of effective management strategies. In recent years, the increasing burden of disease has led to a paradigm shift in our approach from treatment to prevention. Among several agents postulated as having a chemopreventive effect on the gastrointestinal tract, aspirin has been most widely studied and has gained universal acknowledgement. There is an expanding evidence base for aspirin as a key mediator in the prevention of dysplastic change in Barrett's oesophagus and colorectal adenomas. Its cardioprotective effects also impact positively on the patient population in question, many of whom have ischaemic vascular disease. The major side effects of aspirin have been well-characterised and may cause significant morbidity and mortality in their own right. Complications such as peptic ulceration, upper gastrointestinal bleeding and haemorrhagic stroke pose serious threats to the routine administration of aspirin and hence a balance between the risks and benefits must be struck if chemoprevention is to be effective on a large scale. In this review, we address the current evidence base for aspirin use in gastrointestinal oncology, as well as several key questions surrounding its safety, cost effectiveness and optimal dose.