Liver Fibrosis Assessed Via Noninvasive Tests Is Associated With Incident Heart Failure in a General Population Cohort.

BACKGROUND & AIMS: The aim of this study was to determine whether liver fibrosis is associated with heart failure in a general population cohort, and if genetic polymorphisms (PNPLA3 rs738409; TM6SF2 rs58542926), linked to increased risk of liver fibrosis and decreased risk of coronary artery disease, modify this association. METHODS: Using UK Biobank data, we prospectively examined the relationship between noninvasive fibrosis markers (nonalcoholic fatty liver disease [NAFLD] fibrosis score [NFS], Fibrosis-4 [FIB-4] and aspartate transaminase [AST] to platelet ratio index [APRI]) and incident hospitalization/death from heart failure (n = 413,860). Cox-regression estimated hazard ratios (HRs) for incident heart failure. Effects of PNPLA3 and TM6SF2 on the association between liver fibrosis and heart failure were estimated by stratifying for genotype and testing for an interaction between genotype and liver fibrosis using a likelihood ratio test. RESULTS: A total of 12,527 incident cases of heart failure occurred over a median of 10.7 years. Liver fibrosis was associated with an increased risk of hospitalization or death from heart failure (multivariable adjusted high-risk NFS score HR, 1.59; 95% confidence interval [CI],1.47-1.76; P < .0001; FIB-4 HR, 1.69; 95% CI, 1.55-1.84; P < .0001; APRI HR, 1.85; 95% CI, 1.56-2.19; P < .0001; combined fibrosis scores HR, 1.90; 95% CI, 1.44-2.49; P < .0001). These associations persisted for people with metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD with alcohol consumption (Met-ALD), and harmful alcohol consumption. PNPLA3 rs738409 GG and TM6SF2 rs58542926 TT did not attenuate the positive association between fibrosis markers and heart failure. For PNPLA3, a statistically significant interaction was found between PNPLA3 rs738409, FIB-4, APRI score, and heart failure. CONCLUSION: In the general population, serum markers of liver fibrosis are associated with increased hospitalization/death from heart failure. Genetic polymorphisms associated with liver fibrosis were not positively associated with elevated heart failure risk.

The impact of non-alcoholic fatty liver disease and liver fibrosis on adverse clinical outcomes and mortality in patients with chronic kidney disease: a prospective cohort study using the UK Biobank.

BACKGROUND: Chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) frequently co-exist. We assess the impact of having NAFLD on adverse clinical outcomes and all-cause mortality for people with CKD. METHODS: A total of 18,073 UK Biobank participants identified to have CKD (eGFR < 60 ml/min/1.73 m2 or albuminuria > 3 mg/mmol) were prospectively followed up by electronic linkage to hospital and death records. Cox-regression estimated the hazard ratios (HR) associated with having NAFLD (elevated hepatic steatosis index or ICD-code) and NAFLD fibrosis (elevated fibrosis-4 (FIB-4) score or NAFLD fibrosis score (NFS)) on cardiovascular events (CVE), progression to end-stage renal disease (ESRD) and all-cause mortality. RESULTS: 56.2% of individuals with CKD had NAFLD at baseline, and 3.0% and 7.7% had NAFLD fibrosis according to a FIB-4 > 2.67 and NFS ≥ 0.676, respectively. The median follow-up was 13 years. In univariate analysis, NAFLD was associated with an increased risk of CVE (HR 1.49 [1.38-1.60]), all-cause mortality (HR 1.22 [1.14-1.31]) and ESRD (HR 1.26 [1.02-1.54]). Following multivariable adjustment, NAFLD remained an independent risk factor for CVE overall (HR 1.20 [1.11-1.30], p < 0.0001), but not ACM or ESRD. In univariate analysis, elevated NFS and FIB-4 scores were associated with increased risk of CVE (HR 2.42 [2.09-2.80] and 1.64 [1.30-2.08]) and all-cause mortality (HR 2.82 [2.48-3.21] and 1.82 [1.47-2.24]); the NFS score was also associated with ESRD (HR 5.15 [3.52-7.52]). Following full adjustment, the NFS remained associated with an increased incidence of CVE (HR 1.19 [1.01-1.40]) and all-cause mortality (HR 1.31 [1.13-1.52]). CONCLUSIONS: In people with CKD, NAFLD is associated with an increased risk of CVE, and the NAFLD fibrosis score is associated with an elevated risk of CVE and worse survival.

Testing to sustain hepatitis C elimination targets in people who inject drugs: A network-based model.

Little is known about the level of testing required to sustain elimination of hepatitis C (HCV), once achieved. In this study, we model the testing coverage required to maintain HCV elimination in an injecting network of people who inject drugs (PWID). We test the hypothesis that network-based strategies are a superior approach to deliver testing. We created a dynamic injecting network structure connecting 689 PWID based on empirical data. The primary outcome was the testing coverage required per month to maintain prevalence at the elimination threshold over 5 years. We compared four testing strategies. Without any testing or treatment provision, the prevalence of HCV increased from the elimination threshold (11.68%) to a mean of 25.4% (SD 2.96%) over the 5-year period. To maintain elimination with random testing, on average, 4.96% (SD 0.83%) of the injecting network needs to be tested per month. However, with a 'bring your friends' strategy, this was reduced to 3.79% (SD 0.64%) of the network (p < .001). The addition of contact tracing improved the efficiency of both strategies. In conclusion, we report that network-based approaches to testing such as 'bring a friend' initiatives and contact tracing lower the level of testing coverage required to maintain elimination.

Inequity in end-of-life care for patients with chronic liver disease in England.

BACKGROUND AND AIMS: The World Health Assembly recommends integration of palliative care into treatment of patients with any life-limiting condition, yet patients with non-malignant disease are less likely to receive specialist palliative care (SPC). This study compares SPC offered to patients with hepatocellular carcinoma (HCC) versus patients with chronic liver disease without HCC (CLD without HCC). METHODS: Patients who died from CLD or HCC over 5 years (2013-2017) in England were identified using a dataset linking national data on all hospital admissions (Hospital Episode Statistics - HES) with national mortality data from the Office for National Statistics (HES - ONS). The primary outcome was the proportion of patients who received inpatient SPC in their last year of life (LYOL). Secondary outcomes were (1) early inpatient SPC input and (2) the proportion dying in a hospice. The outcomes were compared between patients with HCC and CLD without HCC. RESULTS: 29 669 patients were identified, 8143 of whom had HCC. Patients with HCC were significantly more likely to receive inpatient SPC input-adjusted OR 3.74 (95% CI 3.52-3.97) and early inpatient SPC input-adjusted OR 7.26 (95% CI 6.38-8.25) and die in a hospice OR 8.23 (95% CI 7.33-9.24) than patients with CLD without HCC. CONCLUSIONS: These data highlight the stark inequity in access to SPC services between patients with HCC and patients with CLD without HCC in England. Addressing these inequities will improve end-of-life care for patients with CLD.

Injecting network structure determines the most efficient strategy to achieve Hepatitis C elimination in people who inject drugs.

Transmission of Hepatitis C (HCV) continues via sharing of injection equipment between people who inject drugs (PWID). Network-based modelling studies have produced conflicting results about whether random treatment is preferable to targeting treatment at PWID with multiple partners. We hypothesise that differences in the modelled injecting network structure produce this heterogeneity. The study aimed to test how changing network structure affects HCV transmission and treatment effects. We created three dynamic injecting network structures connecting 689 PWID (UK-net, AUS-net and USA-net) based on published empirical data. We modelled HCV in the networks and at 5 years compared prevalence of HCV 1) with no treatment, 2) with randomly targeted treatment and 3) with treatment targeted at PWID with the most injecting partnerships (degree-based treatment). HCV prevalence at 5 years without treatment differed significantly between the three networks (UK-net (42.8%) vs. AUS-net (38.2%), p < 0.0001 and vs. USA-net (54.0%), p < 0.0001). In the treatment scenarios UK-net and AUS-net showed a benefit of degree-based treatment with a 5-year prevalence of 1.0% vs. 9.6% p < 0.0001 and 0.15% vs. 0.44%, p < 0.0001. USA-net showed no significant difference (29.3% vs. 29.2%, p = 0.0681). Degree-based treatment was optimised with low prevalence, moderate treatment coverage conditions whereas random treatment was optimised in low treatment coverage, high prevalence conditions. In conclusion, injecting network structure determines the transmission rate of HCV and the most efficient treatment strategy. In real-world injecting network structures, the benefit of targeting HCV treatment at individuals with multiple injecting partnerships may have been underestimated.

The combined effect of alcohol and body mass index on risk of chronic liver disease: A systematic review and meta-analysis of cohort studies.

BACKGROUND & AIMS: Increasingly populations are both overweight/obese and consume alcohol. The risk of liver disease from the combination of these factors is unclear. We performed a systematic review and meta-analysis to address this important gap in evidence. Protocol registered with PROSPERO(CRD42016046508). METHODS: We performed electronic searches of Ovid Medline, Embase Classic + Embase, until 17th June 2020 for cohort studies of adults without pre-existing liver disease. Primary outcome was morbidity/mortality from chronic liver disease. Exposures were alcohol consumption categorised as within or above UK recommended limits (14 units/112 g per week) and BMI categorised as normal, overweight or obese. Non-drinkers were excluded. A Poisson regression log-linear model was used to test for statistical interaction between alcohol and BMI and to conduct a one-stage meta-analysis. RESULTS: Searches identified 3129 studies-16 were eligible. Of these, nine cohorts (1,121,514 participants) had data available and were included in the analysis. The Poisson model showed no significant statistical interaction between alcohol consumption and BMI on the risk of chronic liver disease. Compared to normal weight participants drinking alcohol within UK recommended limits, relative risk of chronic liver disease in overweight participants drinking above limits was 3.32 (95% CI 2.88 to 3.83) and relative risk in obese participants drinking above limits was 5.39 (95% CI 4.62 to 6.29). CONCLUSIONS: This meta-analysis demonstrated a significantly increased risk of chronic liver disease in participants who were both overweight/obese and consumed alcohol above UK recommended limits. This evidence should inform advice given to patients and risk stratification by healthcare professionals.

The testing of people with any risk factor for hepatitis C in community pharmacies is cost-effective.

New antiviral drugs with high efficacy mean the hepatitis C virus (HCV) can now be eliminated. To achieve this, it is necessary to identify undiagnosed cases of HCV. However, the costs of testing should be considered when judging the overall cost-effectiveness of treatment. This study describes the cost-effectiveness of a community pharmacy testing service in a population of people at risk of HCV living on the Isle of Wight (United Kingdom). Dry blood spot testing was conducted in anyone with a known risk factor for HCV in 20 community pharmacies. The outcomes and costs were entered into a Markov model. Cost and health utilities from the model were used to calculate an incremental cost-effectiveness ratio (ICER). In 24 months, 186 tests were conducted, 13 were positive for HCV RNA and six of these (46%) received treatment during the follow-up period. All achieved a sustained virological response at 3 months. The overall cost of the testing and treatment intervention was £242 183, and the ICER for the service was £3689 per quality-adjusted life year (QALY) gained. If screening had been restricted to just people with a history of injecting drug use (PWID) the ICER would have been £4865 per QALY gained. The service was effective at identifying people with HCV infection, and despite the additional cost of targeted testing, its cost-effectiveness was below the commonly accepted thresholds. In this setting, restricting targeted testing to PWID would not improve the cost-effectiveness.

Hepatitis C bio-behavioural surveys in people who inject drugs-a systematic review of sensitivity to the theoretical assumptions of respondent driven sampling.

BACKGROUND: New, more effective and better-tolerated therapies for hepatitis C (HCV) have made the elimination of HCV a feasible objective. However, for this to be achieved, it is necessary to have a detailed understanding of HCV epidemiology in people who inject drugs (PWID). Respondent-driven sampling (RDS) can provide prevalence estimates in hidden populations such as PWID. The aims of this systematic review are to identify published studies that use RDS in PWID to measure the prevalence of HCV, and compare each study against the STROBE-RDS checklist to assess their sensitivity to the theoretical assumptions underlying RDS. METHOD: Searches were undertaken in accordance with PRISMA systematic review guidelines. Included studies were English language publications in peer-reviewed journals, which reported the use of RDS to recruit PWID to an HCV bio-behavioural survey. Data was extracted under three headings: (1) survey overview, (2) survey outcomes, and (3) reporting against selected STROBE-RDS criteria. RESULTS: Thirty-one studies met the inclusion criteria. They varied in scale (range 1-15 survey sites) and the sample sizes achieved (range 81-1000 per survey site) but were consistent in describing the use of standard RDS methods including: seeds, coupons and recruitment incentives. Twenty-seven studies (87%) either calculated or reported the intention to calculate population prevalence estimates for HCV and two used RDS data to calculate the total population size of PWID. Detailed operational and analytical procedures and reporting against selected criteria from the STROBE-RDS checklist varied between studies. There were widespread indications that sampling did not meet the assumptions underlying RDS, which led to two studies being unable to report an estimated HCV population prevalence in at least one survey location. CONCLUSION: RDS can be used to estimate a population prevalence of HCV in PWID and estimate the PWID population size. Accordingly, as a single instrument, it is a useful tool for guiding HCV elimination. However, future studies should report the operational conduct of each survey in accordance with the STROBE-RDS checklist to indicate sensitivity to the theoretical assumptions underlying the method. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019245.

Barriers and facilitators experienced in delivering alcohol screening and brief interventions in community pharmacy: a qualitative evidence synthesis.

BACKGROUND: Following increases in deaths due to alcohol during the COVID-19 pandemic, there have been renewed calls to increase resources in alcohol screening and brief intervention (SBI). Research has shown that community pharmacy could be a promising setting for SBI. This review aimed to investigate the barriers and facilitators to SBI delivery in community pharmacy to inform its further development. METHODS: A systematic search of four databases (MEDLINE, EMBASE, CINAHL, and PsycINFO) was conducted in October 2021 to identify relevant published qualitative or mixed-method studies. Relevant qualitative data were extracted from the included studies and a framework synthesis was performed using the Capability-Opportunity-Motivation-Behaviour (COM-B) model. RESULTS: Two thousand two hundred and ten articles were screened and nine studies were included in the review (seven in the United Kingdom and two in Australia). Identified barriers and facilitators to delivering SBI corresponded to all components of the COM-B model. Facilitators included non-confrontational communication skills, aligning SBI with existing pharmacy services and pharmacist role legitimacy. Barriers included multiple demands on staff time, a lack of staff experience with screening tools, and staff concerns of causing offence. Using the Behaviour Change Wheel (BCW), we propose five elements of a pharmacy SBI to address identified barriers. CONCLUSIONS: Research into SBI in community pharmacy is limited in comparison to other healthcare settings and this review provides an understanding of the barriers and facilitators to the delivery of SBI in community pharmacy from a behavioural perspective. Through the use of COM-B and BCW, our findings could inform the development of future pharmacy-based SBI.

Noninvasive serum biomarkers for liver fibrosis in NAFLD: current and future.

In the last 20 years, noninvasive serum biomarkers to identify liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) have been developed, validated against liver biopsy (the gold standard for determining the presence of liver fibrosis) and made available for clinicians to use to identify ≥F3 liver fibrosis. The aim of this review is firstly to focus on the current use of widely available biomarkers and their performance for identifying ≥F3. Secondly, we discuss whether noninvasive biomarkers have a role in identifying F2, a stage of fibrosis that is now known to be a risk factor for cirrhosis and overall mortality. We also consider whether machine learning algorithms offer a better alternative for identifying individuals with ≥F2 fibrosis. Thirdly, we summarise the utility of noninvasive serum biomarkers for predicting liver related outcomes (e.g., ascites and hepatocellular carcinoma) and non-liver related outcomes (e.g., cardiovascular-related mortality and extra hepatic cancers). Finally, we examine whether serial measurement of biomarkers can be used to monitor liver disease, and whether the use of noninvasive biomarkers in drug trials for non-alcoholic steatohepatitis can accurately, compared to liver histology, monitor liver fibrosis progression/regression. We conclude by offering our perspective on the future of serum biomarkers for the detection and monitoring of liver fibrosis in NAFLD.

The role of natural experiments in hepatology research: filling the gap between clinical trials and service evaluations.

Research developing and testing interventions that address the social determinants of liver disease are urgently needed; however, this cannot be achieved using conventional clinical research designs. A different approach is needed to conduct widely applicable, inclusive, and community-based research that addresses upstream factors driving liver morbidity. Natural experimental studies encompass a well-established field of research methodology that is less familiar to clinical hepatologists than conventional research methods such as the randomized control trial. The key strength of natural experiments is that, when robustly designed, they can be used to imply causality from routinely collected data. As such, they are well placed to test the impact of community interventions that aim to address social determinants of liver disease that cannot feasibly be assessed in a randomized control trial. In this review, we define natural experiments and their potential utility. We then work through examples of where they have already been used in clinical hepatology to highlight a range of research designs, analytical approaches, and best practices regarding their conduct and reporting. In doing so, we hope to equip clinical hepatologists with another tool to ensure the hepatology community can meet the global liver disease epidemic with evidence-based interventions.

Performance of the Enhanced Liver Fibrosis Score, Comparison with Vibration-controlled Transient Elastography Data, and Development of a Simple Algorithm to Predict Significant Liver Fibrosis in a Community-based Liver Service: A Retrospective Evaluation.

Background and Aims: Liver fibrosis is a key risk factor for cirrhosis, hepatocellular carcinoma and end stage liver failure. The National Institute for Health and Care Excellence guidelines for assessment for advanced (≥F3) liver fibrosis in people with nonalcoholic fatty liver disease recommend the use of enhanced liver fibrosis (ELF) test, followed by vibration-controlled transient elastography (VCTE). Performance of ELF at predicting significant (≥F2) fibrosis in real-world practice is uncertain. To assess the accuracy of ELF using VCTE; investigate the optimum ELF cutoff value to identify ≥F2 and ≥F3; and develop a simple algorithm, with and without ELF score, for detecting ≥F2. Methods: Retrospective evaluation of patients referred to a Community Liver Service for VCTE, Jan-Dec 2020. Assessment included: body mass index (BMI), diabetes status, alanine aminotransferase (ALT) levels, ELF score and biopsy-validated fibrosis stages according to VCTE. Results: Data from 273 patients were available. n=110 patients had diabetes. ELF showed fair performance for ≥F2 and ≥F3, area under the curve (AUC) = 0.70, 95% confidence interval (CI) 0.64-0.76 and AUC=0.72, 95% CI: 0.65-0.79 respectively. For ≥F2 Youden's index for ELF=9.85 and for ≥F3, ELF=9.95. Combining ALT, BMI, and HbA1c (ALBA algorithm) to predict ≥F2 showed good performance (AUC=0.80, 95% CI: 0.69-0.92), adding ALBA to ELF improved performance (AUC=0.82, 95% CI: 0.77-0.88). Results were independently validated. Conclusions: Optimal ELF cutoff for ≥F2 is 9.85 and 9.95 for ≥F3. ALT, BMI, and HbA1c (ALBA algorithm) can stratify patients at risk of ≥F2. ELF performance is improved by adding ALBA.

Quality standards for the management of alcohol-related liver disease: consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology ARLD special interest group.

OBJECTIVE: Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care. DESIGN: A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology ALD Special Interest Group developed the quality standards, with input from the British Liver Trust and patient representatives. RESULTS: The standards cover three broad themes: the recognition and diagnosis of people with ALD in primary care and the liver outpatient clinic; the management of acutely decompensated ALD including acute alcohol-related hepatitis and the posthospital care of people with advanced liver disease due to ALD. Draft quality standards were initially developed by smaller working groups and then an anonymous modified Delphi voting process was conducted by the entire group to assess the level of agreement with each statement. Statements were included when agreement was 85% or greater. Twenty-four quality standards were produced from this process which support best practice. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice and an audit tool provided. CONCLUSION: It is hoped that services will review their practice against these recommendations and key performance indicators and institute service development where needed to improve the care of patients with ALD.

Alcohol use disorder and the liver.

Alcohol use disorders (AUD) cause a range of physical harms, but the major cause of alcohol-related mortality is alcohol-related liver disease (ALD), in some countries accounting for almost 90% of alcohol-related deaths. The risk of ALD has an exponential relationship with increasing alcohol consumption, but is also associated with genetic factors, other life-style factors and social deprivation. ALD includes a spectrum of progressive pathology, from liver steatosis to fibrosis and liver cirrhosis. There are no specific treatments for liver cirrhosis, but abstinence from alcohol is key to limit progression of the disease. Over time, cirrhosis can progress (often silently) to decompensated cirrhosis and hepatocellular carcinoma (HCC). Liver transplantation may be suitable for patients with decompensated liver cirrhosis and may also be used as a curative intervention for HCC, but only for a few selected patients, and complete abstinence is a prerequisite. Patients with AUD are also at risk of developing alcoholic hepatitis, which has a high mortality and limited evidence for effective therapies. There is a strong evidence base for the effectiveness of psychosocial and pharmacological interventions for AUD, but very few of these have been trialled in patients with comorbid ALD. Integrated specialist alcohol and hepatology collaborations are required to develop interventions and pathways for patients with ALD and ongoing AUD.