Cost-Effectiveness of Hepatocellular Carcinoma Surveillance Strategies in Patients With Compensated Liver Cirrhosis in the United Kingdom.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness (CE) of 4 hepatocellular carcinoma (HCC) surveillance strategies in the United Kingdom, the GAAD algorithm, which combines Gender (biological sex) and Age with Elecsys® biomarker assays, alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (previously Des-γ-carboxy prothrombin); ultrasound (US); US + AFP and GAAD + US. METHODS: A de novo microsimulation state-transition Markov model was developed in Microsoft Excel® from the perspective of the United Kingdom National Health Service to calculate life-years, quality-adjusted life-years (QALYs), costs, incremental CE ratios, and net monetary benefits. Parameters were sourced from peer-reviewed published literature, national guidelines, and public cost databases. Sensitivity and scenario analyses were performed to evaluate the impact of parameter and structural uncertainty on the results. RESULTS: In a simulated cohort of 100 000 patients, discounted costs and QALYs per patient were £8663 and 6·066 for US, £9095 and 6·076 for US + AFP, £8719 and 6·078 for GAAD alone, and £9114 and 6·086 for GAAD + US. At a CE threshold of £20 000/QALY, GAAD was the most cost-effective strategy; however, although most costly, GAAD + US was the most clinically effective. Sensitivity and scenario analyses indicated that HCC incidence along with costs associated with diagnostic performance influence CE. CONCLUSION: Considering the cost of US and low incidence of HCC in the United Kingdom, this study suggests that GAAD alone or in combination with US are cost-effective surveillance strategies compared with US and US + AFP. Although GAAD + US showed the highest QALY increase, GAAD alone is considered preferable regarding CE; however, better performance estimates for GAAD + US are needed to confirm.

A roadmap for clinical trials in MASH-related compensated cirrhosis.

Although metabolic dysfunction-associated steatohepatitis (MASH) is rapidly becoming a leading cause of cirrhosis worldwide, therapeutic options are limited and the number of clinical trials in MASH-related compensated cirrhosis is low as compared to those conducted in earlier disease stages. Moreover, designing clinical trials in MASH cirrhosis presents a series of challenges regarding the understanding and conceptualization of the natural history, regulatory considerations, inclusion criteria, recruitment, end points and trial duration, among others. The first international workshop on the state of the art and future direction of clinical trials in MASH-related compensated cirrhosis was held in April 2023 at Vall d'Hebron University Hospital in Barcelona (Spain) and was attended by a group of international experts on clinical trials from academia, regulatory agencies and industry, encompassing expertise in MASH, cirrhosis, portal hypertension, and regulatory affairs. The presented Roadmap summarizes important content of the workshop on current status, regulatory requirements and end points in MASH-related compensated cirrhosis clinical trials, exploring alternative study designs and highlighting the challenges that should be considered for upcoming studies on MASH cirrhosis.

Accurate prediction of all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease using electronic health records.

INTRODUCTION AND OBJECTIVES: Despite the huge clinical burden of MASLD, validated tools for early risk stratification are lacking, and heterogeneous disease expression and a highly variable rate of progression to clinical outcomes result in prognostic uncertainty. We aimed to investigate longitudinal electronic health record-based outcome prediction in MASLD using a state-of-the-art machine learning model. PATIENTS AND METHODS: n = 940 patients with histologically-defined MASLD were used to develop a deep-learning model for all-cause mortality prediction. Patient timelines, spanning 12 years, were fully-annotated with demographic/clinical characteristics, ICD-9 and -10 codes, blood test results, prescribing data, and secondary care activity. A Transformer neural network (TNN) was trained to output concomitant probabilities of 12-, 24-, and 36-month all-cause mortality. In-sample performance was assessed using 5-fold cross-validation. Out-of-sample performance was assessed in an independent set of n = 528 MASLD patients. RESULTS: In-sample model performance achieved AUROC curve 0.74-0.90 (95 % CI: 0.72-0.94), sensitivity 64 %-82 %, specificity 75 %-92 % and Positive Predictive Value (PPV) 94 %-98 %. Out-of-sample model validation had AUROC 0.70-0.86 (95 % CI: 0.67-0.90), sensitivity 69 %-70 %, specificity 96 %-97 % and PPV 75 %-77 %. Key predictive factors, identified using coefficients of determination, were age, presence of type 2 diabetes, and history of hospital admissions with length of stay >14 days. CONCLUSIONS: A TNN, applied to routinely-collected longitudinal electronic health records, achieved good performance in prediction of 12-, 24-, and 36-month all-cause mortality in patients with MASLD. Extrapolation of our technique to population-level data will enable scalable and accurate risk stratification to identify people most likely to benefit from anticipatory health care and personalized interventions.

Effect of recipient age on prioritisation for liver transplantation in the UK: a population-based modelling study.

BACKGROUND: Following the introduction of an algorithm aiming to maximise life-years gained from liver transplantation in the UK (the transplant benefit score [TBS]), donor livers were redirected from younger to older patients, mortality rate equalised across the age range and short-term waiting list mortality reduced. Understanding age-related prioritisation has been challenging, especially for younger patients and clinicians allocating non-TBS-directed livers. We aimed to assess age-related prioritisation within the TBS algorithm by modelling liver transplantation prioritisation based on data from a UK transplant unit and comparing these data with other regions. METHODS: In this population-based modelling study, serum parameters and age at liver transplantation assessment of patients attending the Scottish Liver Transplant Unit, Edinburgh, UK, between December, 2002, and November, 2023, were combined with representative synthetic data to model TBS survival predictions, which were compared according to age group (25-49 years vs ≥60 years), chronic liver disease severity, and disease cause. Models for end-stage liver disease (UKELD [UK], MELD [Eurotransplant region], and MELD 3.0 [USA]) were used as validated comparators of liver disease severity. FINDINGS: Of 2093 patients with chronic liver disease, 1808 (86%) had complete datasets and liver disease parameters consistent with eligibility for the liver transplant waiting list in the UK (UKELD ≥49). Disease severity as assessed by UKELD, MELD, and MELD 3.0 did not differ by age (median UKELD scores of 56 for patients aged ≥60 years vs 56 for patients aged 25-49 years; MELD scores of 16 vs 16; and MELD 3.0 scores of 18 vs 18). TBS increased with advancing age (R=0·45, p<0·0001). TBS predicted that transplantation in patients aged 60 years or older would provide a two-fold greater net benefit at 5 years than in patients aged 25-49 years (median TBS 1317 [IQR 1116-1436] in older patients vs 706 [411-1095] in younger patients; p<0·0001). Older patients were predicted to have shorter survival without transplantation than younger patients (263 days [IQR 144-473] in older patients vs 861 days [448-1164] in younger patients; p<0·0001) but similar survival after transplantation (1599 days [1563-1628] vs 1573 days [1525-1614]; p<0·0001). Older patients could reach a TBS for which a liver offer was likely below minimum criteria for transplantation (UKELD <49), whereas many younger patients were required to have high-urgent disease (UKELD >60). US and Eurotransplant programmes did not prioritise according to age. INTERPRETATION: The UK liver allocation algorithm prioritises older patients for transplantation by predicting that advancing age increases the benefit from liver transplantation. Restricted follow-up and biases in waiting list data might limit the accuracy of these benefit predictions. Measures beyond overall waiting list mortality are required to fully capture the benefits of liver transplantation. FUNDING: None.

Routes to diagnosis for hepatocellular carcinoma patients: predictors and associations with treatment and mortality.

BACKGROUND: Hepatocellular carcinoma (HCC) incidence has increased rapidly, and prognosis remains poor. We aimed to explore predictors of routes to diagnosis (RtD), and outcomes, in HCC cases. METHODS: HCC cases diagnosed 2006-2017 were identified from the National Cancer Registration Dataset and linked to Hospital Episode Statistics and the RtD metric. Multivariable logistic regression was used to explore associations between RtD, diagnosis year, 365-day mortality and receipt of potentially curative treatment. RESULTS: 23,555 HCC cases were identified; 36.1% via emergency presentation (EP), 30.2% GP referral (GP), 17.1% outpatient referral, 11.0% two-week wait and 4.6% other/unknown routes. Odds of 365-day mortality was >70% lower via GP or OP routes than EP, and odds of curative treatment 3-4 times higher. Further adjustment for cancer/cirrhosis stage attenuated the associations with curative treatment. People who were older, female, had alcohol-related liver disease, or were more deprived, were at increased risk of an EP. Over time, diagnoses via EP decreased, and via GP increased. CONCLUSIONS: HCC RtD is an important predictor of outcomes. Continuing to reduce EP and increase GP and OP presentations, for example by identifying and regularly monitoring patients at higher risk of HCC, may improve stage at diagnosis and survival.

The future of International Classification of Diseases coding in steatotic liver disease: An expert panel Delphi consensus statement.

BACKGROUND: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. METHODS: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. RESULTS: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). CONCLUSIONS: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Quantifying the benefit of nonselective beta-blockers in the prevention of hepatic decompensation: A Bayesian reanalysis of the PREDESCI trial.

BACKGROUND AND AIMS: Beta-blockers have been studied for the prevention of variceal bleeding and, more recently, for the prevention of all-cause decompensation. Some uncertainties regarding the benefit of beta-blockers for the prevention of decompensation remain. Bayesian analyses enhance the interpretation of trials. The purpose of this study was to provide clinically meaningful estimates of both the probability and magnitude of the benefit of beta-blocker treatment across a range of patient types. APPROACH AND RESULTS: We undertook a Bayesian reanalysis of PREDESCI incorporating 3 priors (moderate neutral, moderate optimistic, and weak pessimistic). The probability of clinical benefit was assessed considering the prevention of all-cause decompensation. Microsimulation analyses were done to determine the magnitude of the benefit. In the Bayesian analysis, the probability that beta-blockers reduce all-cause decompensation was >0.93 for all priors. The Bayesian posterior hazard ratios (HR) for decompensation ranged from 0.50 (optimistic prior, 95% credible interval 0.27-0.93) to 0.70 (neutral prior, 95% credible interval 0.44-1.12). Exploring the benefit of treatment using microsimulation highlights substantial treatment benefits. For the neutral prior derived posterior HR and a 5% annual incidence of decompensation, at 10 years, an average of 497 decompensation-free years per 1000 patients were gained with treatment. In contrast, at 10 years 1639 years per 1000 patients were gained from the optimistic prior derived posterior HR and a 10% incidence of decompensation. CONCLUSIONS: Beta-blocker treatment is associated with a high probability of clinical benefit. This likely translates to a substantial gain in decompensation-free life years at the population level.

Cost of hepatocellular carcinoma to the national health service in England: a registry-based analysis.

OBJECTIVE: Hepatocellular carcinoma (HCC) incidence in the UK trebled between 1997 and 2017. With increasing numbers requiring treatment, understanding the likely impact on healthcare budgets can inform service planning and commissioning. The aim of this analysis was to use existing registry data to describe the direct healthcare costs of current treatments for HCC and estimate the impact on National Health Service (NHS) budgets. DESIGN: A retrospective data analysis based on the National Cancer Registration and Analysis Service cancer registry informed a decision-analytic model for England comparing patients by cirrhosis compensation status and those on palliative or curative treatment pathways. Potential cost drivers were investigated by undertaking a series of one-way sensitivity analyses. RESULTS: Between 1 January 2010 and 31 December 2016, 15 684 patients were diagnosed with HCC. The median cost per patient over 2 years was £9065 (IQR: £1965 to £20 491), 66% did not receive active therapy. The cost of HCC treatment for England over 5 years was estimated to be £245 million. CONCLUSION: The National Cancer Registration Dataset and linked data sets have enabled a comprehensive analysis of the resource use and costs of secondary and tertiary healthcare for HCC, providing an overview of the economic impact to the NHS England of treating HCC.

Extra-hepatic morbidity and mortality in alcohol-related liver disease: Systematic review and meta-analysis.

BACKGROUND: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol-related liver disease (ALD) are therefore at risk from both extra-hepatic and hepatic disease. AIMS: This review synthesises information about non-liver-related mortality in persons with ALD. METHODS: A systematic literature review was performed to identify studies describing non-liver outcomes in ALD. Information about overall non-liver mortality was extracted from included studies and sub-categorised into major causes: cardiovascular disease (CVD), non-liver cancer and infection. Single-proportion meta-analysis was done to calculate incidence rates (events/1000 patient-years) and relative risks (RR) compared with control populations. RESULTS: Thirty-seven studies describing 50 302 individuals with 155 820 patient-years of follow-up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol-related fatty liver the rate of non-liver mortality was 43.4/1000 patient-years, whereas in alcoholic hepatitis the rate of non-liver mortality was 22.5/1000 patient-years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6-3.8), from non-hepatic cancer 2.2 (1.6-2.9) and from infection 8.2 (4.7-14.3). CONCLUSION: Persons with ALD are at high risk of death from non-liver causes such as cardiovascular disease and non-hepatic cancer.

Meta-analysis: Enhanced liver fibrosis test to identify hepatic fibrosis in chronic liver diseases.

BACKGROUND & AIMS: Patients with liver disease can be stratified for risk of liver-related ill health by degree of hepatic fibrosis. The Enhanced liver fibrosis (ELF) test was developed to quantify hepatic fibrosis non-invasively and is widely used. The objective of this review was to identify and synthesise the evidence on the diagnostic accuracy of the ELF test for staging of hepatic fibrosis. APPROACH & RESULTS: Searches of PubMed and EMBASE were conducted between October 2020 and November 2021 to identify studies reporting the diagnostic accuracy of the ELF test compared to histology in liver disease patients. QUADAS-2 was used to assess risk of bias in each study. Meta-analysis using the multiple thresholds model described by Steinhauser S, Schumacher M, Rücker G. Modelling multiple thresholds in meta-analysis of diagnostic test accuracy studies. BMC Med. Res. Methodol. 2016;16. 10.1186/s12874-016-0196-1 allowed synthesis of 2 × 2 data at different cut-offs. Sixty-three studies were included in this review. These studies included 19,285 patients with or at risk of liver disease from viral hepatitis, Non-Alcoholic Fatty Liver Disease, Alcohol-related Liver Disease and other mixed chronic liver diseases. The prevalence of significant fibrosis, advanced fibrosis and cirrhosis was 47.5%, 39.2% and 4.4%, respectively. Cut-offs with maximal Youden index were generated with AUROC = 0.811 (95% CI: 0.736-0.870), 0.812 (95% CI: 0.758-0.856) and 0.810 (95% CI: 0.694-0.888) to detect significant fibrosis, advanced fibrosis or cirrhosis, respectively. Diagnostic accuracy of the ELF test varied between different liver diseases and cut-offs to detect each stage with 95% sensitivity or specificity were also generated. CONCLUSIONS: Meta-analysis revealed considerable variability in the ability of ELF to stage fibrosis across disease aetiologies. Research has mostly focused on viral hepatitis and NAFLD. There is currently a lack of data on the value of the ELF test in Alcohol-related liver disease and patients in primary care settings.

The Natural History of Advanced Chronic Liver Disease Defined by Transient Elastography.

BACKGROUND & AIMS: The clinical course of cirrhosis does not follow a predictable trajectory. Transient elastography (TE) is commonly used in clinical practice to diagnose liver fibrosis and increasingly to risk stratify patients. The aim of this study was to assess the natural history of advanced chronic liver disease (ACLD) defined by TE using electronic health record (EHR) data in a multistate framework. METHODS: TE data were collected between 2008 and 2019. Patients with a liver stiffness measurement (LSM) >10 kPa were included. Disease and procedure code information held in EHR was analyzed. Clinical events including decompensation, hepatocellular carcinoma (HCC), and death were identified. Outcomes were described in a multistate model using flexible parametric survival methods including LSM and the albumin bilirubin (ALBI) score. RESULTS: Three thousand and twenty eight patients were included. Median follow up was 3.1 years. LSM and ALBI were associated with the development of varices and decompensation, and ALBI, age, sex, and viral liver disease were associated with the development of HCC from the compensated state. The cumulative incidence of HCC before decompensation was low for patients with alcohol-related liver disease (3.8%) and nonalcoholic fatty liver disease (1.3%) at 5 years after TE. Importantly, death was predicted to occur before decompensation or HCC in most cases. CONCLUSIONS: Liver stiffness, ALBI score, and disease etiology are each associated with outcomes in a large contemporary cohort with ACLD. EHR data can be used to define clinical progression in these patients, facilitating large clinical effectiveness trials and cost-effectiveness analyses.

Community pathways for the early detection and risk stratification of chronic liver disease: a narrative systematic review.

Patients with chronic liver disease are often diagnosed during an index presentation to hospital with decompensated cirrhosis or liver-related events, and these presentations are associated with high mortality. However, there is often a long asymptomatic phase, in which there is an opportunity for earlier diagnosis and interventions to prevent progression to advanced disease. Therefore, strategies for early diagnosis and interventions (including behavioural changes and pharmacological treatments) that prevent patients progressing to cirrhosis and its associated complications probably have substantial benefits for patients and health-care services. Many community pathways have been generated. Some pathways focus on abnormal liver function tests as a starting point to diagnose liver disease. Other pathways target groups at greater risk of chronic liver disease-particularly people with harmful alcohol consumption, type 2 diabetes, and obesity. This systematic review summarises the existing strategies available for the early detection or risk stratification of liver disease, focusing primarily on alcohol-related liver disease and non-alcoholic fatty liver disease. Conducting randomised clinical trials that compare different strategies will be essential to elucidate which pathways are acceptable to patients, feasible, provide high diagnostic accuracy for the detection of liver disease, improve liver-related outcomes, and are most cost-effective at the population level.

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.