Pharmacological treatments for alcohol dependence: Evidence on uptake, inequalities and comparative effectiveness from a UK population-based cohort.

INTRODUCTION: We assessed the prevalence of prescribing of certain medications for alcohol dependence and the extent of any inequalities in receiving prescriptions for individuals with such a diagnosis. Further, we compared the effectiveness of two of the most prescribed medications (acamprosate and disulfiram) for alcohol dependence and assessed whether there is inequality in prescribing either of them. METHODS: We used a nationwide dataset on prescriptions and hospitalisations in Scotland, UK (N = 19,748). We calculated the percentage of patients receiving alcohol dependence prescriptions after discharge, both overall and by socio-economic groups. Binary logistic regressions were used to assess the odds of receiving any alcohol-dependence prescription and the comparative odds of receiving acamprosate or disulfiram. Comparative effectiveness in avoiding future alcohol-related hospitalisations (N = 11,239) was assessed using Cox modelling with statistical adjustment for potential confounding. RESULTS: Upto 7% of hospitalised individuals for alcohol use disorder received prescriptions for alcohol dependence after being discharged. Least deprived socio-economic groups had relatively more individuals receiving prescriptions. Inequalities in prescribing for alcohol dependence existed, especially across sex and comorbidities: males had 12% (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81-0.96) and those with a history of mental health hospitalisations had 10% (OR 0.90, 95% CI 0.82-0.98) lower odds of receiving prescriptions after an alcohol-related hospitalisation. Prescribing disulfiram was superior to prescribing acamprosate in preventing alcohol-related hospitalisations (hazard ratio ranged between 0.60 and 0.81 across analyses). Disulfiram was relatively less likely prescribed to those from more deprived areas. DISCUSSION AND CONCLUSIONS: Inequalities in prescribing for alcohol dependence exists in Scotland with lower prescribing to men and disulfiram prescribed more to those from least deprived areas.

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.

The rs72613567:TA polymorphism in HSD17B13 is associated with survival benefit after development of hepatocellular carcinoma.

BACKGROUND: The influence of genetic factors on survival following a diagnosis of hepatocellular carcinoma (HCC) remains unclear. AIM: To assess whether genetic polymorphisms influencing the susceptibility to develop HCC are also associated with HCC prognosis. METHODS: We included United Kingdom Biobank (UKB) participants diagnosed with HCC after study enrolment. The primary outcome was all-cause mortality. Patients were followed from the date of HCC diagnosis to death or the registry completion date. Five HCC susceptibility loci were investigated: rs738409 (PNPLA3), rs58542926 (TM6SF2); rs72613567 (HSD17B13); rs2242652 (TERT) and rs708113 (WNT3A). The associations between these genetic variants and HCC mortality risk were assessed using Cox regression, adjusted for age, sex, ethnicity, aetiology, severity of the underlying liver disease and receipt of curative HCC treatment. RESULTS: The final sample included 439 patients; 74% had either non-alcoholic fatty liver disease or alcohol-related liver disease. There were 321 deaths during a mean follow-up of 1.9 years per participant. Kaplan-Meier survival estimates at 1, 3 and 5 years were 53.2%, 31.2% and 22.6% respectively. In multivariate analysis, rs72613567:TA (HSD17B13) was the only genetic susceptibility variant significantly associated with all-cause mortality risk (aHR: 0.74; 95% CI: 0.61-0.90; p = 0.003). Other associated factors were Baveno stage 3-4 (aHR: 1.65; 95% CI: 1.05-2.59; p = 0.03) and HCC treatment with curative intent (aHR: 0.25; 95% CI: 0.17-0.37; p < 0.001). CONCLUSIONS: The rs72613567:TA polymorphism in HSD17B13 is not only associated with a reduction in the risk of developing HCC but with a survival benefit in HCC once established. Therapeutic inhibition of HSD17B13 may augment survival in individuals with HCC.

Disparities in care and outcomes for primary liver cancer in England during 2008-2018: a cohort study of 8.52 million primary care population using the QResearch database.

Background: Liver cancer has one of the fastest rising incidence and mortality rates among all cancers in the UK, but it receives little attention. This study aims to understand the disparities in epidemiology and clinical pathways of primary liver cancer and identify the gaps for early detection and diagnosis of liver cancer in England. Methods: This study used a dynamic English primary care cohort of 8.52 million individuals aged ≥25 years in the QResearch database during 2008-2018, followed up to June 2021. The crude and age-standardised incidence rates, and the observed survival duration were calculated by sex and three liver cancer subtypes, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and other specified/unspecified primary liver cancer. Regression models were used to investigate factors associated with an incident diagnosis of liver cancer, emergency presentation, late stage at diagnosis, receiving treatments, and survival duration after diagnosis by subtype. Findings: 7331 patients were diagnosed with primary liver cancer during follow-up. The age-standardised incidence rates increased over the study period, particularly for HCC in men (increased by 60%). Age, sex, socioeconomic deprivation, ethnicity, and geographical regions were all significantly associated with liver cancer incidence in the English primary care population. People aged ≥80 years were more likely to be diagnosed through emergency presentation and in late stages, less likely to receive treatments and had poorer survival than those aged <60 years. Men had a higher risk of being diagnosed with liver cancer than women, with a hazard ratio (HR) of 3.9 (95% confidence interval 3.6-4.2) for HCC, 1.2 (1.1-1.3) for CCA, and 1.7 (1.5-2.0) for other specified/unspecified liver cancer. Compared with white British, Asians and Black Africans were more likely to be diagnosed with HCC. Patients with higher socioeconomic deprivation were more likely to be diagnosed through the emergency route. Survival rates were poor overall. Patients diagnosed with HCC had better survival rates (14.5% at 10-year survival, 13.1%-16.0%) compared to CCA (4.4%, 3.4%-5.6%) and other specified/unspecified liver cancer (12.5%, 10.1%-15.2%). For 62.7% of patients with missing/unknown stage in liver cancer, their survival outcomes were between those diagnosed in Stages III and IV. Interpretation: This study provides an overview of the current epidemiology and the disparities in clinical pathways of primary liver cancer in England between 2008 and 2018. A complex public health approach is needed to tackle the rapid increase in incidence and the poor survival of liver cancer. Further studies are urgently needed to address the gaps in early detection and diagnosis of liver cancer in England. Funding: The Early Detection of Hepatocellular Liver Cancer (DeLIVER) project is funded by Cancer Research UK (Early Detection Programme Award, grant reference: C30358/A29725).

Statistical perspectives on using hepatocellular carcinoma risk models to inform surveillance decisions.

More than 50,000 people are diagnosed with hepatocellular carcinoma (HCC) every year in Europe. Many cases are known to specialist liver centres years before they present with HCC. Despite this, HCC is usually detected at a late stage, when prognosis is very poor. For more than two decades, clinical guidelines have recommended uniform surveillance for all patients with cirrhosis. However, studies continue to show that this broad-based approach is inefficient and poorly implemented in practice. A "personalised" approach, where the surveillance regimen is customised to the needs of the patient, is gaining growing support in the clinical community. The cornerstone of personalised surveillance is the HCC risk model - a mathematical equation predicting a patient's individualised probability of developing HCC within a specific time window. However, although numerous risk models have now been published, few are being used in routine care to inform HCC surveillance decisions. In this article, we discuss methodological issues stymieing the use of HCC risk models in routine practice - highlighting biases, evidence gaps and misconceptions that future research must address.

High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis.

Background & Aims: Progression of alcohol-associated liver disease (ALD) is driven by genetic predisposition. The rs13702 variant in the lipoprotein lipase (LPL) gene is linked to non-alcoholic fatty liver disease. We aimed at clarifying its role in ALD. Methods: Patients with alcohol-associated cirrhosis, with (n = 385) and without hepatocellular carcinoma (HCC) (n = 656), with HCC attributable to viral hepatitis C (n = 280), controls with alcohol abuse without liver damage (n = 366), and healthy controls (n = 277) were genotyped regarding the LPL rs13702 polymorphism. Furthermore, the UK Biobank cohort was analysed. LPL expression was investigated in human liver specimens and in liver cell lines. Results: Frequency of the LPL rs13702 CC genotype was lower in ALD with HCC in comparison to ALD without HCC both in the initial (3.9% vs. 9.3%) and the validation cohort (4.7% vs. 9.5%; p <0.05 each) and compared with patients with viral HCC (11.4%), alcohol misuse without cirrhosis (8.7%), or healthy controls (9.0%). This protective effect (odds ratio [OR] = 0.5) was confirmed in multivariate analysis including age (OR = 1.1/year), male sex (OR = 3.0), diabetes (OR = 1.8), and carriage of the PNPLA3 I148M risk variant (OR = 2.0). In the UK Biobank cohort, the LPL rs13702 C allele was replicated as a risk factor for HCC. Liver expression of LPL mRNA was dependent on LPL rs13702 genotype and significantly higher in patients with ALD cirrhosis compared with controls and alcohol-associated HCC. Although hepatocyte cell lines showed negligible LPL protein expression, hepatic stellate cells and liver sinusoidal endothelial cells expressed LPL. Conclusions: LPL is upregulated in the liver of patients with alcohol-associated cirrhosis. The LPL rs13702 high producer variant confers protection against HCC in ALD, which might help to stratify people for HCC risk. Impact and implications: Hepatocellular carcinoma is a severe complication of liver cirrhosis influenced by genetic predisposition. We found that a genetic variant in the gene encoding lipoprotein lipase reduces the risk for hepatocellular carcinoma in alcohol-associated cirrhosis. This genetic variation may directly affect the liver, because, unlike in healthy adult liver, lipoprotein lipase is produced from liver cells in alcohol-associated cirrhosis.

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.

Development and validation of personalised risk prediction models for early detection and diagnosis of primary liver cancer among the English primary care population using the QResearch® database: research protocol and statistical analysis plan.

BACKGROUND AND RESEARCH AIM: The incidence and mortality of liver cancer have been increasing in the UK in recent years. However, liver cancer is still under-studied. The Early Detection of Hepatocellular Liver Cancer (DeLIVER-QResearch) project aims to address the research gap and generate new knowledge to improve early detection and diagnosis of primary liver cancer from general practice and at the population level. There are three research objectives: (1) to understand the current epidemiology of primary liver cancer in England, (2) to identify and quantify the symptoms and comorbidities associated with liver cancer, and (3) to develop and validate prediction models for early detection of liver cancer suitable for implementation in clinical settings. METHODS: This population-based study uses the QResearch® database (version 46) and includes adult patients aged 25-84 years old and without a diagnosis of liver cancer at the cohort entry (study period: 1 January 2008-30 June 2021). The team conducted a literature review (with additional clinical input) to inform the inclusion of variables for data extraction from the QResearch database. A wide range of statistical techniques will be used for the three research objectives, including descriptive statistics, multiple imputation for missing data, conditional logistic regression to investigate the association between the clinical features (symptoms and comorbidities) and the outcome, fractional polynomial terms to explore the non-linear relationship between continuous variables and the outcome, and Cox/competing risk regression for the prediction model. We have a specific focus on the 1-year, 5-year, and 10-year absolute risks of developing liver cancer, as risks at different time points have different clinical implications. The internal-external cross-validation approach will be used, and the discrimination and calibration of the prediction model will be evaluated. DISCUSSION: The DeLIVER-QResearch project uses large-scale representative population-based data to address the most relevant research questions for early detection and diagnosis of primary liver cancer in England. This project has great potential to inform the national cancer strategic plan and yield substantial public and societal benefits.

Comparing Predicted Probability of Hepatocellular Carcinoma in Patients With Cirrhosis With the General Population: An Opportunity to Improve Risk Communication?

INTRODUCTION: Risk scores estimating a patient's probability of a hepatocellular carcinoma (HCC) diagnosis are abundant but are difficult to interpret in isolation. We compared the predicted HCC probability for individuals with cirrhosis and cured hepatitis C with the general population (GP). METHODS: All patients with cirrhosis achieving sustained viral response (SVR) in Scotland by April 2018 were included (N = 1,803). The predicted 3-year probability of HCC at time of SVR achievement was determined using the aMAP prognostic model. GP data on the total number of incident HCCs in Scotland, stratified by demographics, were obtained from Public Health Scotland. Predicted HCC risk of cirrhosis SVR patients was compared with GP incidence using 2 metrics: (i) incidence ratio: i.e., 3-year predicted probability for a given patient divided by the 3-year probability in GP for the equivalent demographic group and (ii) absolute risk difference: the 3-year predicted probability minus the 3-year probability in the GP. RESULTS: The mean predicted 3-year HCC probability among cirrhosis SVR patients was 3.64% (range: 0.012%-36.12%). Conversely, the 3-year HCC probability in the GP was much lower, ranging from <0.0001% to 0.25% depending on demographics. The mean incidence ratio was 410, ranging from 5 to >10,000. The mean absolute risk difference was 3.61%, ranging from 0.012% to 35.9%. An online HCC-GP comparison calculator for use by patients/clinicians is available at https://thrive-svr.shinyapps.io/RShiny/ . DISCUSSION: Comparing a patient's predicted HCC probability with the GP is feasible and may help clinicians communicate risk information and encourage screening uptake.

Evaluation of the aMAP score for hepatocellular carcinoma surveillance: a realistic opportunity to risk stratify.

BACKGROUND AND AIMS: The aMAP score is a model that predicts risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis. Its performance in a 'real world' surveillance setting has not yet been ascertained. PATIENTS AND METHODS: We had access to a cohort of 3473 individuals enrolled in a rigorously implemented and prospectively accrued surveillance programme (patients undergoing regular ultrasound and biomarker examination between 1998 and 2021). During this period 445 had HCC detected. Of these, 77.8% had early stage disease (within Milan criteria), permitting potentially curative therapy to be implemented in nearly 70% of cases. We applied the recently developed aMAP score to classify patients according to their initial aMAP score in to low, medium and high-risk groups as proposed in the original publication. The performance of the aMAP score was assessed according to the concordance-index and calibration (i.e. agreement between observed and predicted risk). Allowance was made for competing causes of death. RESULTS: The aMAP score achieved an overall C-index of 0.81 (95% CI: 0.79-0.82) consistent with the initial report and was unaffected by allowance for competing causes of death. Sub-group analysis showed that the results did not change significantly according to gender, or aetiology. However, aMAP discrimination was greater for younger individuals (versus older individuals), and also for individuals without cirrhosis. The HCC incidence rate was 0.98, 7.05 and 29.1 events per 1000 person-years in the low-, moderate- and high-risk aMAP groups, respectively. CONCLUSIONS: The results from this 'real-world' cohort demonstrate that risk stratification is a realistic prospect and that identification of a subgroup of chronic liver disease patients who have a very low risk of HCC is feasible.

Improved survival of viral hepatocellular carcinoma but not non-viral hepatocellular carcinoma from 2000 to 2020: A multi-centre cohort study of 6007 patients from high-volume academic centres in Japan.

BACKGROUND: While surveillance improves the early detection of hepatocellular carcinoma (HCC), it is unclear whether this has improved prognosis in clinical practice. AIMS: To investigate the characteristics and prognoses of patients with viral versus non-viral HCC over the previous two decades in Japan, while HCC surveillance has been active. METHODS: This multi-centre study enrolled 6007 patients initially diagnosed with HCC between 2000 and 2020 at seven high-volume academic centres. Patients were categorised based on dates of diagnosis: 2000-2006, 2007-2013 and 2014-2020. HCC characteristics and post-diagnosis survival rates were compared between periods in patients with viral and non-viral HCC. RESULTS: The percentage of patients with non-viral HCC increased during the study period. The maximal tumour size and percentage of patients with multinodular HCC decreased significantly over time in the viral HCC group but remained unchanged in the non-viral HCC group. Liver function at diagnosis improved over time in both groups, but to a greater extent in the viral HCC group. Survival rates increased significantly with time in the viral HCC group, but not in the non-viral HCC group. CONCLUSIONS: The prevalence of non-viral HCC is increasing. Although the survival of patients with viral HCC improved significantly over the past two decades, there was no improvement in patients with non-viral HCC. This was presumably due mainly to lower surveillance among patients with non-viral HCC and failure to diagnose early-stage HCC.

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.

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.

Characterizing the risk interplay between alcohol intake and body mass index on cirrhosis morbidity.

BACKGROUND AND AIMS: It is thought that alcohol intake and body mass index (BMI) interact supra-additively to modulate the risk of cirrhosis, but evidence for this phenomenon is limited. We investigated the interrelationship between alcohol and BMI on the incidence of cirrhosis morbidity for participants of the United Kingdom Biobank (UKB) study. APPROACH AND RESULTS: The primary outcome was the cumulative incidence of cirrhosis morbidity, defined as a first-time hospital admission for cirrhosis (with noncirrhosis mortality incorporated as a competing risk). All UKB participants without a previous hospital admission for cirrhosis were included in the analysis. We determined the ratio of the 10-year cumulative incidence in harmful drinkers versus safe drinkers according to BMI. We also calculated the excess cumulative incidence at 10 years for individuals with obesity and/or harmful alcohol compared to safe drinkers with a healthy BMI of 20-25.0 kg/m2 . A total of 489,285 UK Biobank participants were included, with mean of 10.7 person-years' follow-up. A total of 2070 participants developed the primary outcome, equating to a crude cumulative incidence of 0.36% at 10 years (95% CI:0.34-0.38). The 10-year cumulative incidence was 8.6 times higher for harmful (1.38%) versus safe drinkers (0.16%) if BMI was healthy. Conversely, it was only 3.6 times higher for obese participants (1.99% vs. 0.56%). Excess cumulative incidence was 1.22% (95% CI:0.89-1.55) for harmful drinkers with a healthy BMI, 0.40% (95% CI:0.34-0.46) for obese individuals drinking at safe levels, and 1.83% (95% CI:1.46-2.20) for obese harmful drinkers (all compared to safe drinkers with a healthy BMI). CONCLUSIONS: Alcohol intake and obesity are independent risk factors for cirrhosis morbidity, but they do not interact supra-additively to modulate the cumulative incidence of this outcome.

Declining incidence of hepatitis C related hepatocellular carcinoma in the era of interferon-free therapies: A population-based cohort study.

BACKGROUND & AIMS: The impact of interferon (IFN)-free therapies on the epidemiology of hepatitis C virus (HCV) related hepatocellular carcinoma (HCC) is not well understood at a population level. Our goal was to bridge this evidence gap. METHODS: This study included all patients in Scotland with chronic HCV and a diagnosis of cirrhosis during 1999-2019. Incident cases of HCC, episodes of curative HCC therapy, and HCC-related deaths were identified through linkage to nationwide registries. Three time periods were examined: 1999-2010 (pegylated interferon-ribavirin [PIR]); 2011-2013 (First-generation DAA); and 2014-2019 (IFN-free era). We used regression modelling to determine time trends for (i) number diagnosed and living with HCV cirrhosis, (ii) HCC cumulative incidence, (iii) HCC curative treatment uptake and (iv) post-HCC mortality. RESULTS: 3347 cirrhosis patients were identified of which 381 (11.4%) developed HCC. After HCC diagnosis, 140 (36.7%) received curative HCC treatment and there were 202 deaths from HCC. The average annual number of patients diagnosed and living with HCV cirrhosis was approximately seven times higher in the IFN-free versus the PIR era, whereas the number of incident HCCs was four times higher. However, the cumulative incidence of HCC was significantly lower in the IFN-free versus PIR era (sdHR: 0.65; 95%CI:0.47-0.88; P = .006). Among HCC patients, diagnosis in the IFN-free era was not associated with improved uptake of curative treatment (aOR:1.18; 95%CI:0.69-2.01; P = .54), or reduced post-HCC mortality (sdHR: 0.74; 95%CI:0.53-1.05; P = .09). CONCLUSIONS: The cumulative incidence of HCC is declining in HCV cirrhosis patients, but uptake of curative HCC therapy and post-HCC survival remains suboptimal.

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.