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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.

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.

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.

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.

Background Type 2 diabetes (T2D) is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non‐alcoholic fatty liver disease (NAFLD). However, the absolute risk of progression is low. So, it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk‐stratification tools are suboptimal and perform worse in people with diabetes. Aims To determine whether the addition of complementary biomarker(s) to current NAFLD risk‐stratification tools in people with T2D could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC. Methods The Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with T2D (n = 1066, age 60–75 at baseline). Cases of cirrhosis and HCC were identified over 11 years of follow‐up. Biomarkers were measured at baseline and year 1 and association with incident disease was assessed using logistic regression. Results Of existing risk‐stratification scores tested, the Fibrosis‐4 (FIB‐4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut‐point ≥ 50 μ g/L) to FIB‐4 (cut‐point ≥ 1.3) maintained a false negative rate of ≤25% and reduced the number of people incorrectly identified as “high risk” for incident disease by ∼50%. Conclusions The addition of hyaluronic acid to FIB‐4 reduced the proportion of people inappropriately identified as “high risk” for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with T2D. These findings require a validation in independent cohorts.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic liver disease worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort of 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering the complete MASLD severity spectrum, and created a secure, searchable, open resource (SteatoSITE). In 668 cases and 39 controls, we generated hepatic bulk RNA sequencing data and performed differential gene expression and pathway analysis, including exploration of gender-specific differences. A web-based gene browser was also developed. We integrated histopathological assessments, transcriptomic data and 5.67 million days of time-stamped longitudinal electronic health record data to define disease-stage-specific gene expression signatures, pathogenic hepatic cell subpopulations and master regulator networks associated with adverse outcomes in MASLD. We constructed a 15-gene transcriptional risk score to predict future hepatic decompensation events (area under the receiver operating characteristic curve 0.86, 0.81 and 0.83 for 1-, 3- and 5-year risk, respectively). Additionally, thyroid hormone receptor beta regulon activity was identified as a critical suppressor of disease progression. SteatoSITE supports rational biomarker and drug development and facilitates precision medicine approaches for patients with MASLD. SteatoSITE is an open resource that integrates histopathologic assessments, transcriptomic data and longitudinal electronic health records for a cohort of 940 patients with metabolic dysfunction-associated steatotic liver disease.

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. 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. 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%. 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. Quantification of serum K18 levels could assist in clinical decision-making.

IntroductionAlcohol is the leading cause of cirrhosis in western populations. 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.MethodA prospective cohort study was conducted at a community alcohol clinic in Nottingham (April-2012 to March-2014). Patients (>18years) with a primary alcohol problem were recruited. Those known to liver services or to have chronic liver disease were excluded. Significant liver fibrosis was defined by a liver stiffness measure (LSM) of >8 kilopascals (kPa). Follow-up was for a minimum of six months. Data were descriptively analysed for significant differences between patients with a normal LSM versus raised LSM.Results156 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 6.9kPa. Clinically significant liver fibrosis was identified in n=33 (38.4%), of which n=6 were in cirrhotic range (≥15 kPa). Baseline median self-reported alcohol intake for normal stiffness was 126 units per week and in raised stiffness was 149.0 units per week the difference was non-significant (p=0.338). Median reduction in self-report alcohol intake in whole cohort was 65.0 units per week (p=<0.001), in normal liver stiffness group was 25.0 units per week (p=0.154), and in raised liver stiffness group was 78.5 units per week (p<0.001).ConclusionThe 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.Abstract P97 Table 1Comparison of cohorts Whole cohort (n=86) Raised liver stiffness (n=33) Normal liver stiffness (n=53) P* Age (years) 46.3 (+/- 9.8) 46.6 (+/- 8.6) 46.0 (+/-10.9) 0.79 Gender (male) 53 (70.0) 17 (51.2) 35 (66.0) Liver stiffness score (kPa) 6.9 (3.1-75.0) 13.5 (8.1-75) 5.8 (3.1-8) <0.01 ALT (units/litre) 64.5 (+/- 52.5) 83.1 (+/- 60.8) 53.0 (+/- 43.4) 0.01 GGT (units/litre) 568.6 (+/- 757.4) 1033.6 (+/- 949.7) 226.7 (+/- 260.8) <0.01 Alcohol intake (units/week) Baseline (n=57) 145 (24-420) 149 (39-420) 126 (24-378) 0.338 ≥ Six months (n=47) 80 (0-315) 65 (0-300) 90.7 (0-315) Alcohol intake ≥ 6 months (change in proportions ) n=26 n=21 Reduced 17 (65.4%) 14 (66.7%) 1.00 Increased 1 (3.8%) 5 (23.8%) 0.08 Abstinence 7 (26.0%) 4 (19.0%) 0.73 Mean (SD), median (range), number(%) *p for significance of difference between normal liver stiffness (<8kPa) versus raised liver stiffness (>8kPa) group