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ObjectiveWe aimed to determine (1) the temporal trends of liver enzyme testing in UK general practice and (2) how these vary among different subgroups at risk of chronic liver disease (CLD).DesignRetrospective cohort study.SettingUK primary care database (Clinical Practice Research Datalink (CPRD)), 2004–2016.ParticipantsPatients aged 18 years or over, registered in the CPRD from 1 January 2004 to 31 December 2016.Outcome measuresThe frequency of testing recorded within the study period in general practice was calculated for: alanine aminotransferase (ALT); aspartate aminotransferase (AST); gamma glutamyl transferase (GGT); alkaline phosphatase (ALP); bilirubin and platelets. Analyses were conducted in subgroups of patients at high risk of developing liver disease.ResultsThe study cohort included 2 912 066 individuals with median follow-up of 3.2 years. The proportion of patients with at least one measurement for ALT, ALP, bilirubin or platelet test gradually increased over the course of the study period and fell for AST and GGT. By 2016, the proportion of the population receiving one of more tests in that year was: platelet count 28.0%, ALP 26.2%, bilirubin 25.6%, ALT 23.7%, GGT 5.1% and AST 2.2%. Those patients with risk factors for CLD had higher proportions receiving liver marker assessments than those without risk factors.ConclusionsThe striking finding that AST is now only measured in a fraction of the population has significant implications for routine guidance which frequently expects it. A more nuanced approach where non-invasive markers are targeted towards individuals with risk factors for CLD may be a solution.

ObjectivesScreening in selected high risk populations for Barrett’s oesophagus (BO) and oesophageal varices (OVs) has been proposed, but there are obstacles with conventional oesophagogastroduodenoscopy (C-OGD), including patient acceptability. Portable and disposable office-based transnasal endoscopy (TNE) is a feasible and accurate alternative to C-OGD that may have use in primary and secondary care. This article outlines a qualitative analysis of patient experiences of TNE and C-OGD in order to gain an insight into an acceptable delivery of an endoscopic screening service.DesignPurposeful sampling identified 23 participants who then underwent semi-structured interviews to determine their experiences of both procedures. Thematic analysis was conducted to derive meaning from their lived experiences.SettingA secondary care endoscopy unit, clinic room and interview room.ParticipantsPatients referred for BO or OV surveillance and for endoscopy to investigate dyspepsia underwent unsedated TNE using the EG Scan II device followed by C-OGD with or without sedation (patient choice), as part of a clinical trial.ResultsThe themes that arose from our analysis were: inclusivity in one’s own healthcare, comfort level and convenience, validity of the procedure and application to a screening population and a sense of altruism and reciprocity. Positive aspects of TNE included participant empowerment, reduced discomfort and avoidance of conscious sedation. Participants felt that if TNE screening was of proven efficacy it would be welcomed, though views on use in a community setting were mixed.ConclusionsMost patients preferred TNE to unsedated C-OGD and the reasons they gave featured strongly in the emerging themes. Preferences between TNE and sedated C-OGD were more subtle, with equivalent comfort scores but merits and drawbacks of both being discussed. This information identifies opportunities and challenges in establishing an endoscopic screening service. Trial registration number ISRCTNregistry identifier: 70595405; Pre-results.

ObjectivesTo assess the feasibility of a novel diagnostic algorithm targeting patients with risk factors for chronic liver disease in a community setting.DesignProspective cross-sectional study.SettingTwo primary care practices (adult patient population 10 479) in Nottingham, UK.ParticipantsAdult patients (aged 18 years or over) fulfilling one or more selected risk factors for developing chronic liver disease: (1) hazardous alcohol use, (2) type 2 diabetes or (3) persistently elevated alanine aminotransferase (ALT) liver function enzyme with negative serology.InterventionsA serial biomarker algorithm, using a simple blood-based marker (aspartate aminotransferase:ALT ratio for hazardous alcohol users, BARD score for other risk groups) and subsequently liver stiffness measurement using transient elastography (TE).Main outcome measuresDiagnosis of clinically significant liver disease (defined as liver stiffness ≥8 kPa); definitive diagnosis of liver cirrhosis.ResultsWe identified 920 patients with the defined risk factors of whom 504 patients agreed to undergo investigation. A normal blood biomarker was found in 62 patients (12.3%) who required no further investigation. Subsequently, 378 patients agreed to undergo TE, of whom 98 (26.8% of valid scans) had elevated liver stiffness. Importantly, 71/98 (72.4%) patients with elevated liver stiffness had normal liver enzymes and would be missed by traditional investigation algorithms. We identified 11 new patients with definite cirrhosis, representing a 140% increase in the number of diagnosed cases in this population.ConclusionsA non-invasive liver investigation algorithm based in a community setting is feasible to implement. Targeting risk factors using a non-invasive biomarker approach identified a substantial number of patients with previously undetected cirrhosis.Trial registration numberThe diagnostic algorithm utilised for this study can be found on clinicaltrials.gov (NCT02037867), and is part of a continuing longitudinal cohort study.

Circadian rhythm governs many aspects of liver physiology and its disruption exacerbates chronic disease. CLOCKΔ19 mice disrupted circadian rhythm and spontaneously developed obesity and metabolic syndrome, a phenotype that parallels the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD represents an increasing health burden with an estimated incidence of around 25% and is associated with an increased risk of progression towards inflammation, fibrosis and carcinomas. Excessive extracellular matrix deposition (fibrosis) is the key driver of chronic disease progression. However, little attention was paid to the impact of disrupted circadian rhythm in hepatic stellate cells (HSCs) which are the primary mediator of fibrotic ECM deposition. Here, we showed in vitro and in vivo that liver fibrosis is significantly increased when circadian rhythm is disrupted by CLOCK mutation. Quiescent HSCs from CLOCKΔ19 mice showed higher expression of RhoGDI pathway components and accelerated activation. Genes altered in this primed CLOCKΔ19 qHSC state may provide biomarkers for early liver disease detection, and include AOC3, which correlated with disease severity in patient serum samples. Integration of CLOCKΔ19 microarray data with ATAC-seq data from WT qHSCs suggested a potential CLOCK regulome promoting a quiescent state and downregulating genes involved in cell projection assembly. CLOCKΔ19 mice showed higher baseline COL1 deposition and significantly worse fibrotic injury after CCl4 treatment. Our data demonstrate that disruption to circadian rhythm primes HSCs towards an accelerated fibrotic response which worsens liver disease.

ObjectivesThe increasing incidence of chronic liver disease (CLD) in the UK may be attributed to a rise in preventable risk factors, including hazardous alcohol use and type 2 diabetes. Transient elastography (TE) can rapidly stratify risk of CLD in primary care populations and provide an opportunity to raise patient awareness of risk factors.This study explores patients’ experiences of TE screening in a primary care setting. In addition, patient awareness of CLD risk is explored.Study design and settingThis study used a qualitative process evaluation of a community screening pathway for CLD (Nottingham, UK). Participants completed semistructured interviews, which were audio-recorded, transcribed verbatim and analysed thematically.ParticipantsTwenty adults were purposively recruited 6 months to 2 years after TE screening. Inclusion criteria included (1) hazardous alcohol use, (2) type 2 diabetes and/or (3) persistently elevated liver enzymes without known cause.ResultsUndergoing TE in primary care was seen as acceptable to most participants. Hazardous alcohol use was identified as the primary cause of CLD; no participants were aware of metabolic risk factors. TE improved understanding of personal risk factors and prompted contemplation of lifestyle changes across all TE stratifications. However, participants’ perceptions of risk were altered by the healthcare providers’ communication of TE scores.ConclusionsHigh acceptability of TE, regardless of the risk factor, provides strong support for inclusion of TE stratification in primary care. Findings highlight the positive impact of receiving TE on risk awareness. Future clinical iterations should improve the structure and communication of TE results to patients.

Chronic liver disease (CLD) is an ignored epidemic. Premature mortality is considerable and in the United Kingdom (UK) liver disease is in the top three for inequitable healthcare alongside heart and respiratory disease. Fifty percentage of patients with CLD are first diagnosed with cirrhosis after an emergency presentation translating to poorer patient outcomes. Traditional models of care have been based in secondary care when the need is at community level. Investigating patients for disease based on their risk factors at a population level in the community will identify its presence early when there is potential reversibility. Innovation is needed in three broad areas to improve clinical care in this area: better access to diagnostics within the community, integrating diagnostics across primary and secondary care and utilizing digital healthcare to enhance patient care. In this article, we describe how the Integrated Diagnostics for Early Detection of Liver Disease (ID-LIVER) project, funded by UK Research and Innovation, is developing solutions in Greater Manchester to approach the issue of diagnosis of liver disease at a population level. The ambition is to build on innovative pathways previously established in Nottingham by bringing together NHS organizations, academic partners and commercial organizations. The motivation is to co-create and implement a commercial solution that integrates multimodal diagnostics via cutting edge data science to drive growth and disrupt the currently inadequate model. The ambitious vision is for this to be widely adopted for early diagnosis and stratification of liver disease at a population level within the NHS.

Background We annually monitored stable compensated cirrhosis (CC) patients to evaluate serial variation in blood serum, liver stiffness, and multiparametric magnetic resonance imaging (mpMRI) measures to provide reference change values (RCV) and sample size measures for future studies. Methods Patients were recruited from a prospectively followed CC cohort, with assessments at baseline and annually over three years. We report on blood markers, transient elastography liver stiffness measures (LSM) and noninvasive mpMRI (volume, T1 mapping, blood flow, perfusion) of the liver, spleen, kidneys, and heart in a stable CC group and a healthy volunteer (HV) group. Coefficient of variation over time (CoV T ) and RCV are reported, along with hazard ratio to assess disease progression. Sample size estimates to power future trials of cirrhosis regression on mpMRI are presented. Results Of 60 CC patients enrolled, 28 with stable CC were followed longitudinally and compared to 10 HVs. CoV T in mpMRI measures was comparable between CC and HV groups. CoV T of Enhanced Liver Fibrosis score was low (< 5%) compared to Fibrosis-4 index (17.9%) and Aspartate Aminotransferase-to-Platelet-Ratio Index (19.4%). A large CoV T (20.7%) and RCV (48.3%) were observed for LSM. CoV T and RCV were low for liver, spleen, and renal T1 values (CoV T < 5%, RCV < 8%) and volume (CoV T < 10%, RCV < 16%); haemodynamic measures were high (CoV T 12–25%, RCV 16–47%). Conclusions Evidence of low CoV T and RCV in multiorgan T1 values. RCV and sample size estimates are provided for future longitudinal multiorgan monitoring in CC patients. Trial registration ClinicalTrials.gov identifier: NCT02037867 , Registered: 05/01/2013.

Introduction: Alcohol is the leading cause of cirrhosis in Western populations. The early identification of high-risk drinkers followed by intervention is an effective way to reduce harm. We aim to assess the feasibility of integrating transient elastography (TE) into community alcohol services, and to determine its impact on modifying drinking behaviours. Method: A prospective cohort study was conducted at a community alcohol clinic in Nottingham, UK (April 2012 to March 2014). Patients (>18 years) with a primary alcohol problem were recruited. Those known to liver services or those known to have chronic liver disease were excluded. Significant liver fibrosis was defined by a liver stiffness of >8 kilopascal (kPa). Follow-up was for a minimum of six months. Data were descriptively analysed for significant differences between patients with a normal liver stiffness versus raised liver stiffness. Results: 156 patients were invited; n = 87 attended and n = 86 underwent successful TE. The majority were male (n = 53, 70.0%), and the mean age was 46.3 years (SD ± 9.8). Median liver stiffness was 6.9 kPa (range 3.1–75.0kPa). Clinically significant liver fibrosis was identified in n = 33 (38.4%), of which n = 6 were in the cirrhotic range (≥15 kPa). The baseline median self-reported alcohol intake for normal stiffness was 126 units per week (range 24–378) and in raised stiffness was 149.0 units per week (range 39.0–420.0); this difference was nonsignificant (p = 0.338). The median reduction in self-reported alcohol intake in the whole cohort was 65.0 units per week (range 27.0–88.0, p < 0.001); in the normal liver stiffness group it was 25.0 units per week (range 18.0–75.0, p = 0.154), and in the raised liver stiffness group it was 78.5 units per week (range 36.0–126.0, p < 0.001). Conclusion: The study demonstrated that transient elastography is a feasible tool to stratify clinically significant liver disease in community alcohol services. It can stimulate a change in high-risk drinking behaviour and a normal liver stiffness result does not provide false reassurance to participants.

IntroductionThere is an unmet need for simple tools to predict development of hepatic decompensation among patients with compensated cirrhosis. We applied machine learning to several international datasets to develop and validate a straightforward predictive model of decompensation.MethodsWe used routinely available clinical and laboratory data from 575 patients with compensated cirrhosis from the training cohorts in Nottingham (United Kingdom) and Modena (Italy), followed up for a median of 4 years. Based on this data, we developed a predictive model using a random forest classifier and validated it across independent international populations involving over 2,100 patients from Dublin (Ireland), Menoufia (Egypt), Leeds (UK) and Ogaki (Japan).ResultsIn the training cohorts, 22% of patients developed liver decompensation. Using machine learning, we developed RODIC (Risk of Decompensation in Cirrhosis), a well-calibrated model based on albumin, bilirubin and the Fib-4 value (AUC-ROC = 0.86; weighted F1 score = 0.82) which predicts the risk of decompensation within 3 years. RODIC performed well across all validation sets pointing to the generalisability of the model, with AUC-ROC scores ranging from 0.67 to 0.80 and weighted F1 scores from 0.70 to 0.81. Moreover, the model was effective regardless of cirrhosis aetiology. For HCV-positive patients, RODIC remained reliable irrespective of whether they achieved sustained virologic response.ConclusionsOur validated machine learning model based on readily available clinical, and laboratory features accurately quantitates the risk of liver decompensation in patients with compensated hepatic cirrhosis.

BackgroundNinety percent of chronic liver disease is caused by lifestyle related risk factors which are readily coded in electronic health records. Higher prevalence of these risk factors is associated with a lower socioeconomic status which is itself strongly associated with liver disease mortality.Nottingham City is the 11th most socioeconomically deprived of 317 districts nationally. The Nottingham and Nottinghamshire Integrated Care System (ICS) including Nottingham University Hospitals collaborated to address health inequality using a Population Health Management approach.We aimed to target specific Primary Care Networks (PCN) with high socioeconomic deprivation and risk factor prevalence to implement a novel community-based model to identify patients at risk of undiagnosed chronic liver disease.MethodsIdentification of adult patients (≥18 years) at high risk (hazardous alcohol use and/or Diabetes + BMI ≥30kg/m2) was completed using General Practice Repository for Clinical Care (GPRCC) via eHealthScope; a unique and secure online integrated database of primary, secondary and social care data of patients in Nottingham. Patients were excluded if known to have chronic liver disease, housebound, severely frail or receiving end of life care. At risk patients were invited to attend for a liver health check at a community location using transient elastography (TE). All patients received a brief lifestyle intervention.ResultsAcross the ICS, 21055 patients were identified to be at high risk of liver disease. Nottingham City East PCN (population 66,800) was nominated as the first implementation site. 1057 patients were identified to be at risk (hazardous alcohol use = 152, Type 2 Diabetes and BMI ≥30kg/m2 = 905). Sixty two percent of the population within this PCN live in areas defined as the most deprived in England. Black and Minority Ethnic groups form 35% of the resident population.Three-hundred and forty patients (32.2%) attended and were risk stratified using TE. Forty-seven percent of this cohort were female, the average age was 59 years and 35.3% were of non-white ethnicity (Asian 20.0%, Black/African/Caribbean 10.6%, Mixed ethnicity 3.5%, other ethnic group 1.2%, White 62.7%, not recorded 2.0%).TE identified 79.4% (n=270) to be low risk (TE<8kPa), 15.9% (n=54) to be intermediate risk (TE 8–14.9kPa) and 4.7% (n=16) to be high risk (TE≥15kPa) (figure 1).Abstract P96 Figure 1Results of implementing a novel community-based pathway in an area of high social deprivation using population health data[Figure omitted. See PDF]ConclusionA collaborative partnership within a newly evolving health infrastructure (ICS) has enabled the development and implementation of a community pathway that directly addresses health inequality in the early diagnosis of chronic liver disease.