Implementation of a liver health check in people with type 2 diabetes.

As morbidity and mortality related to potentially preventable liver diseases are on the rise globally, early detection of liver fibrosis offers a window of opportunity to prevent disease progression. Early detection of non-alcoholic fatty liver disease allows for initiation and reinforcement of guidance on bodyweight management, risk stratification for advanced liver fibrosis, and treatment optimisation of diabetes and other metabolic complications. Identification of alcohol-related liver disease provides the opportunity to support patients with detoxification and abstinence programmes. In all patient groups, identification of cirrhosis ensures that patients are enrolled in surveillance programmes for hepatocellular carcinoma and portal hypertension. When considering early detection strategies, success can be achieved from applying ad-hoc screening for liver fibrosis in established frameworks of care. Patients with type 2 diabetes are an important group to consider case findings of advanced liver fibrosis and cirrhosis, as up to 19% have advanced fibrosis (which is ten times higher than the general population) and almost 70% have non-alcoholic fatty liver disease. Additionally, patients with type 2 diabetes with alcohol use disorders have the highest proportion of liver-related morbidity of people with type 2 diabetes generally. Patients with type 2 diabetes receive an annual diabetes review as part of their routine clinical care, in which the health of many organs are considered. Yet, liver health is seldom included in this review. This Viewpoint argues that augmenting the existing risk stratification strategy with an additional liver health check provides the opportunity to detect advanced liver fibrosis, thereby opening a window for early interventions to prevent end-stage liver disease and its complications, including hepatocellular carcinoma.

An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease.

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.

Mortality rates among patients successfully treated for hepatitis C in the era of interferon-free antivirals: population based cohort study.

OBJECTIVES: To quantify mortality rates for patients successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals and compare these rates with those of the general population. DESIGN: Population based cohort study. SETTING: British Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only). PARTICIPANTS: 21 790 people who were successfully treated for hepatitis C in the era of interferon-free antivirals (2014-19). Participants were divided into three liver disease severity groups: people without cirrhosis (pre-cirrhosis), those with compensated cirrhosis, and those with end stage liver disease. Follow-up started 12 weeks after antiviral treatment completion and ended on date of death or 31 December 2019. MAIN OUTCOME MEASURES: Crude and age-sex standardised mortality rates, and standardised mortality ratio comparing the number of deaths with that of the general population, adjusting for age, sex, and year. Poisson regression was used to identify factors associated with all cause mortality rates. RESULTS: 1572 (7%) participants died during follow-up. The leading causes of death were drug related mortality (n=383, 24%), liver failure (n=286, 18%), and liver cancer (n=250, 16%). Crude all cause mortality rates (deaths per 1000 person years) were 31.4 (95% confidence interval 29.3 to 33.7), 22.7 (20.7 to 25.0), and 39.6 (35.4 to 44.3) for cohorts from British Columbia, Scotland, and England, respectively. All cause mortality was considerably higher than the rate for the general population across all disease severity groups and settings; for example, all cause mortality was three times higher among people without cirrhosis in British Columbia (standardised mortality ratio 2.96, 95% confidence interval 2.71 to 3.23; P<0.001) and more than 10 times higher for patients with end stage liver disease in British Columbia (13.61, 11.94 to 15.49; P<0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates. CONCLUSION: Mortality rates among people successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals are high compared with the general population. Drug and liver related causes of death were the main drivers of excess mortality. These findings highlight the need for continued support and follow-up after successful treatment for hepatitis C to maximise the impact of direct acting antivirals.

Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study.

BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes. METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort). FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4. INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care. FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

PRO-C3 is a predictor of clinical outcomes in distinct cohorts of patients with advanced liver disease.

Background & Aims: Fibroblast activity is a key feature of fibrosis progression and organ function loss, leading to liver-related complications and mortality. The fibrogenesis marker, PRO-C3, has been shown to have prognostic significance in relation to fibrosis progression and as a treatment efficacy marker. We investigated whether PRO-C3 was prognostic for clinical outcome and mortality in two distinct cohorts of compensated cirrhosis. Methods: Cohort 1 was a rapid fibrosis progression cohort including 104 patients with HCV and biopsy-proven Ishak fibrosis stage ≥3 without prior clinical events. Cohort 2 was a prospective cohort including 172 patients with compensated cirrhosis of mixed aetiology. Patients were assessed for clinical outcomes. PRO-C3 was assessed in serum at baseline in cohorts 1 and 2, and compared with model for end-stage liver disease and albumin-bilirubin (ALBI) scores. Results: In cohort 1, a 2-fold increase in PRO-C3 was associated with 2.7-fold increased hazard of liver-related events (95% CI 1.6-4.6), whereas a one unit increase in ALBI score was associated with a 6.5-fold increased hazard (95% CI 2.9-14.6). In cohort 2, a 2-fold increase in PRO-C3 was associated with a 2.7-fold increased hazard (95% CI 1.8-3.9), whereas a one unit increase in ALBI score was associated with a 6.3-fold increased hazard (95% CI 3.0-13.2). A multivariable Cox regression analysis identified PRO-C3 and ALBI as being independently associated with the hazard of liver-related outcomes. Conclusions: PRO-C3 and ALBI were independent prognostic factors for predicting liver-related clinical outcomes. Understanding the dynamic range of PRO-C3 might enhance its use for both drug development and clinical practice. Impact and Implications: We tested novel proteins of liver scarring (PRO-C3) in two groups of liver patients with advanced disease to see if they could predict clinical events. We found that this marker and an established test called ALBI were both independently associated with future liver-related clinical outcomes.

Circadian Disruption Primes Myofibroblasts for Accelerated Activation as a Mechanism Underpinning Fibrotic Progression in Non-Alcoholic Fatty Liver Disease.

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.

Delivery of biannual ultrasound surveillance for individuals with cirrhosis and cured hepatitis C in the UK.

BACKGROUND: Previous studies show the uptake of biannual ultrasound (US) surveillance in patients with cirrhosis is suboptimal. Here, our goal was to understand in broader terms how surveillance is being delivered to cirrhosis patients with cured hepatitis C in the UK. METHODS: Hepatitis C cirrhosis patients achieving a sustained viral response (SVR) to antiviral therapies were identified from the national Hepatitis-C-Research-UK resource. Data on (i) liver/abdominal US examinations, (ii) HCC diagnoses, and (iii) HCC curative treatment were obtained through record-linkage to national health registries. The rate of US uptake was calculated by dividing the number of US episodes by follow-up time. RESULTS: A total of 1908 cirrhosis patients from 31 liver centres were followed for 3.8 (IQR: 3.4-4.9) years. Overall, 10 396 liver/abdominal USs were identified. The proportion with biannual US was 19% in the first 3 years after SVR and 9% for all follow-up years. Higher uptake of biannual US was associated with attending a liver transplant centre; older age and cirrhosis decompensation. Funnel plot analysis indicated significant inter-centre variability in biannual US uptake, with 6/29 centres outside control limits. Incident HCC occurred in 133 patients, of which 49/133 (37%) were treated with curative intent. The number of US episodes in the two years prior to HCC diagnosis was significantly associated with higher odds of curative-intent treatment (aOR: 1.53; 95% CI: 1.12-2,09; p = .007). CONCLUSIONS: This study provides novel data on the cascade of care for HCC in the UK. Our findings suggest biannual US is poorly targeted, inefficient and is not being delivered equitably to all patients.

Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Comparing magnetic resonance liver fat fraction measurements with histology in fibrosis: the difference between proton density fat fraction and tissue mass fat fraction.

OBJECTIVE: Magnetic resonance spectroscopy (MRS) provides a powerful method of measuring fat fraction. However, previous studies have shown that MRS results give lower values compared with visual estimates from biopsies in fibrotic livers. This study investigated these discrepancies and considered whether a tissue water content correction, as assessed by MRI relaxometry, could provide better agreement. MATERIALS AND METHODS: 110 patients were scanned in a 1.5 T Philips scanner and biopsies were obtained. Multiple echo MRS (30 × 30 × 30 mm volume) was used to determine Proton Density Fat Fraction (PDFF). Biopsies were assessed by visual assessment for fibrosis and steatosis grading. Digital image analysis (DIA) was also used to quantify fat fraction within tissue samples. T1 relaxation times were then used to estimate tissue water content to correct PDFF for confounding factors. RESULTS: PDFF values across the four visually assessed steatosis grades were significantly less in the higher fibrosis group (F3-F4) compared to the lower fibrosis group (F0-F2). The slope of the linear regression of PDFF vs DIA fat fraction was ~ 1 in the low fibrosis group and 0.77 in the high fibrosis group. Correcting for water content based on T1 increased the gradient but it did not reach unity. DISCUSSION: In fibrotic livers, PDFF underestimated fat fraction compared to DIA methods. Values were improved by applying a water content correction, but fat fractions were still underestimated.

Variability of noninvasive MRI and biological markers in compensated cirrhosis: insights for assessing disease progression.

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 (CoVT) 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. CoVT in mpMRI measures was comparable between CC and HV groups. CoVT 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 CoVT (20.7%) and RCV (48.3%) were observed for LSM. CoVT and RCV were low for liver, spleen, and renal T1 values (CoVT < 5%, RCV < 8%) and volume (CoVT < 10%, RCV < 16%); haemodynamic measures were high (CoVT 12-25%, RCV 16-47%). CONCLUSIONS: Evidence of low CoVT 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.

LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries.

BACKGROUND: The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease. METHODS: This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program. DISCUSSION: This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country. TRIAL REGISTRATION: This study is registered on Clinicaltrials.gov ( NCT03789825 ).

Performance of routine risk scores for predicting cirrhosis-related morbidity in the community.

BACKGROUND & AIMS: Models predicting an individual's 10-year risk of cirrhosis complications have not been developed for a community setting. Our objectives were to assess the performance of existing risk scores - both with and without genetic data - for predicting cirrhosis complications in the community. METHODS: We used a 2-stage study design. In stage 1, a systematic review was conducted to identify risk scores derived from routine liver blood tests that have demonstrated prior ability to predict cirrhosis-related complication events. Risk scores identified from stage 1 were tested in a UK Biobank subgroup, comprising participants with a risk factor for chronic liver disease (stage 2). Cirrhosis complications were defined as hospitalisation for liver cirrhosis or presentation with hepatocellular carcinoma. Discrimination of risk scores with and without genetic data was assessed using the Wolbers C-index, Harrell's adequacy index, and cumulative incidence curves. RESULTS: Twenty risk scores were identified from the stage-1 systematic review. For stage-2, 197,509 UK biobank participants were selected. The cumulative incidence of cirrhosis complications at 10 years was 0.58%; 95% CI 0.54-0.61 (1,110 events). The top performing risk scores were aspartate aminotransferase-to-platelet ratio index (APRI: C-index 0.804; 95% CI 0.788-0.820) and fibrosis-4 index (FIB-4: C-index 0.780; 95% CI 0.764-0.795). The 10-year cumulative incidences of cirrhosis complications for participants with an APRI score exceeding the 90th, 95th and 99th percentile were 3.30%, 5.42% and 14.83%, respectively. Inclusion of established genetic risk loci associated with cirrhosis added <5% of new prognostic information to the APRI score and improved the C-index only minimally (i.e. from 0.804 to 0.809). CONCLUSIONS: Accessible risk scores derived from routine blood tests (particularly APRI and FIB-4) can be repurposed to estimate 10-year risk of cirrhosis morbidity in the community. Genetic data improves performance only minimally. LAY SUMMARY: New approaches are needed in community settings to reduce the late diagnosis of chronic liver disease. Thus, in a community cohort, we assessed the ability of 20 routine risk scores to predict 10-year risk of cirrhosis-related complications. We show that 2 routine risk scores in particular - "APRI" and "FIB-4" - could be repurposed to estimate an individual's 10-year risk of cirrhosis-related morbidity. Adding genetic risk factor information to these scores only modestly improved performance.

Transient Elastography in Community Alcohol Services: Can It Detect Significant Liver Disease and Impact Drinking Behaviour?

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.

Health Technology Adoption in Liver Disease: Innovative Use of Data Science Solutions for Early Disease Detection.

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.

Comprehensive Comparative Analysis of Standard Validated, Genetic, and Novel Biomarkers to Enhance Prognostic Risk-Stratification in Patients With Hepatitis C Virus Cirrhosis.

INTRODUCTION: Risk-stratifying patients with hepatitis C virus (HCV) cirrhosis according to medium-term prognosis will inform clinical decision-making. It is unclear which biomarkers/models are optimal for this purpose. We quantified the discriminative ability of 14 diverse biomarkers for prognosis prediction over a 4-year time. METHODS: We recruited 1196 patients with HCV cirrhosis from the United Kingdom for a prospective study. Genetic risk score, collagen (e.g., PROC3), comorbidity (e.g., CirCom), and validated biomarkers from routine data were measured at enrollment. Participants were linked to UK hospital admission, cancer, and mortality registries. Primary endpoints were (i) liver-related outcomes for patients with compensated cirrhosis and (ii) all-cause mortality for decompensated cirrhosis. The discriminative ability of all biomarkers was quantified individually and also by the fraction of new prognostic information provided. RESULTS: At enrollment, 289 (24%) and 907 (76%) had decompensated and compensated cirrhosis, respectively. Participants were followed for 3-4 years on average, with >70% of the follow-up time occurring post-HCV cure. Seventy-five deaths in the decompensated subgroup and 98 liver-related outcomes in the compensated subgroup were reported. The discriminative ability of the albumin-bilirubin-fibrosis-4 index (C-index: 0.71-0.72) was superior to collagen biomarkers (C-index = 0.58-0.67), genetic risk scores (C-index = 0.50-0.57), and comorbidity markers (0.53-0.60). Validated biomarkers showed the greatest prognostic improvement when combined with a comorbidity or a collagen biomarker (generally >30% of new prognostic information added). DISCUSSION: Inexpensive biomarkers such as the albumin-bilirubin-fibrosis-4 index predict medium-term cirrhosis prognosis moderately well and outperform collagen, genetic, and comorbidity biomarkers. Improvement of performance was greatest when a validated test was combined with comorbidity or collagen biomarker.

The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis.

The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E (APOE), rs2642438 in mitochondrial amidoxime reducing component 1 (MARC1), rs2792751 in glycerol-3-phosphate acyltransferase (GPAM), and rs187429064 in transmembrane 6 superfamily member 2 (TM6SF2), previously associated with progressive alcohol-related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case-control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP-HCV), and one alcohol-related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed-effect meta-analysis was used to determine the pooled effect size across all data sets. Across four case-control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele (APOE) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61-0.84; P = 2.9 × 10-5 ). Rs187429064:G (TM6SF2) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45-2.86; P = 3.1 × 10-6 ). In contrast, rs2792751:T (GPAM) was not associated with HCC (OR, 1.01; 95% CI, 0.90-1.13; P = 0.89), whereas rs2642438:A (MARC1) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84-1.00; P = 0.043). Conclusion: This study associates carriage of rs429358:C (APOE) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis.

Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population.

BACKGROUND & AIMS: Fibrosis-4 (FIB-4) and the nonalcoholic fatty liver disease fibrosis score (NFS) are the 2 most popular noninvasive blood-based serum tests proposed for widespread fibrosis screening. We therefore aimed to describe the accuracy of FIB-4 and NFS to detect elevated liver stiffness as an indicator of hepatic fibrosis in low-prevalence populations. METHODS: This study included a total of 5129 patients with concomitant measurement of FIB-4, NFS, and liver stiffness measurement (LSM) by Fibroscan (Echosens, France) from 5 independent population-based cohorts from Spain, Hong Kong, Denmark, England, and France; 3979 participants from the general population and 1150 from at-risk cohorts due to alcohol, diabetes, or obesity. We correlated LSM with FIB-4 and NFS, and calculated pre- and post-test predictive values of FIB-4 and NFS to detect elevated LSM at 8 kPa and 12 kPa cutoffs. The mean age was 53 ± 12 years, the mean body mass index was 27 ± 5 kg/m2, and 2439 (57%) were women. One in 10 patients (552; 11%) had liver stiffness ≥8 kPa, but 239 of those (43%) had a normal FIB-4, and 171 (31%) had normal NFS. The proportion of false-negatives was higher in at-risk patients than the general population. FIB-4 was false-negative in 11% of diabetic subjects, compared with 2.5% false-negatives with NFS. Waist circumference outperformed FIB-4 and NFS for detecting LSM ≥8 kPa in the general population. Almost one-third (28%-29%) of elevated FIB-4/NFS were false-positive in both the general population and at-risk cohorts. CONCLUSIONS: FIB-4 and NFS are suboptimal for screening purposes due to a high risk of overdiagnosis and a non-negligible percentage of false-negatives, especially in patients with risk factors for chronic liver disease. Waist circumference emerged as a potential first step to identify patients at risk for liver fibrosis in the general population.

Population screening for liver fibrosis: Toward early diagnosis and intervention for chronic liver diseases.

Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease and alcohol-related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18% to 27%-in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression.