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The rising incidence of chronic liver disease continues to be an increasing health burden. The morbidity and mortality associated with chronic liver disease typically occur in patients with advanced fibrosis. Hence, early identification of those at-risk is of vital importance to ensure appropriate ongoing management. Currently, tools for appropriate risk stratification remain limited. Increasing awareness of the limitations of liver biopsy has driven research into alternative non-invasive methods of fibrosis assessment including serological markers assessing functional changes. One such biomarker, the Enhanced Liver Fibrosis test, was initially validated in a cohort of 1021 patients with mixed aetiology chronic liver disease and shown to perform well. Since this pathfinder study, it has been independently validated in cohorts of hepatitis C, non-alcoholic fatty liver disease, alcoholic liver disease, primary biliary cirrhosis and primary sclerosing cholangitis. In addition to performing well as a diagnostic tool, the Enhanced Liver Fibrosis test has been shown to outperform liver biopsy in prognostic studies and is the only non-invasive marker to do so. However, questions remain regarding the use of this test, particularly regarding the possible effect age and alcohol may have on test scores. This review examines the current literature published in relation to the Enhanced Liver Fibrosis test and its clinical utility and highlights areas requiring further study.

ObjectivesTwenty per cent of people with alcohol use disorders develop advanced fibrosis and warrant referral to secondary care. Improving outcomes in alcohol-related liver disease (ArLD) relies on its earlier detection in primary care with non-invasive tests (NIT). We aimed to determine the proportion of alcohol-related referrals who were diagnosed with advanced fibrosis in secondary care, the prevalence of both alcohol and fatty liver disease (‘BAFLD’) and the potential impact of NIT on referral stratification.Design/settingRetrospective analysis of all general practitioner-referrals with suspected ArLD/non-alcoholic fatty liver disease (NAFLD) to a UK hepatology-centre between January 2015 and January 2018.ParticipantsOf 2944 new referrals, 762 (mean age 55.5±13.53 years) met inclusion criteria: 531 NAFLD and 231 ArLD, of which 147 (64%) could be reclassified as ‘BAFLD’.Primary outcome measureProportion of referrals with suspected ArLD/NAFLD with advanced fibrosis as assessed by tertiary centre hepatologists using combinations of FibroScan, imaging, examination and blood tests and liver histology, where indicated.Secondary outcome measuresIncluded impact of body mass index/alcohol consumption on the odds of a diagnosis of advanced fibrosis, and performance of NIT in predicting advanced fibrosis in planned post-hoc analysis of referrals.ResultsAmong ArLD referrals 147/229 (64.2%) had no evidence of advanced fibrosis and were judged ‘unnecessary’. Advanced fibrosis was observed in men drinking ≥50 units per week (U/w) (OR 2.74, 95% CI 1.51 to 5, p=0.001) and ≥35 U/w in women (OR 5.11, 95% CI 1.31 to 20.03, p=0.019). Drinking >14 U/w doubled the likelihood of advanced fibrosis in overweight/obesity (OR 2.11; 95% CI 1.44 to 3.09; p<0.001). Use of fibrosis 4 score could halve unnecessary referrals (OR 0.50; 95% CI 0.32 to 0.79, p=0.003) with false-negative rate of 22%, but was rarely used.ConclusionsThe majority of referrals with suspected ArLD were deemed unnecessary. NIT could improve identification of liver damage in ArLD, BAFLD and NAFLD in primary care. Anecdotal thresholds for harmful drinking (35 U/w in women and 50 U/w in men) were validated. The impact of alcohol on NAFLD highlights the importance of multi-causality in chronic liver disease.

mortality. 4,5 NAFLD is the most rapidly increasing aetiology on the liver transplant waiting list; a retrospective study in the USA found that the incidence of NAFLD on the liver transplant list had increased by 170% between 2004 and 2013. 6 Over the past 5 years, NAFLD accounted for between 10-15% of patients listed annually for orthotopic liver transplants (OLTs) in the UK. 7 An index presentation with hepatocellular cancer or a decompensating event, such as ascites, hepatic encephalopathy or variceal haemorrhage, has a profound impact on morbidity and mortality and has a significant negative impact on the patient's quality of life. 8 Earlier detection of NAFLD provides opportunities to instigate interventions such as lifestyle modifications with the aim of sustained weight loss resulting in fibrosis regression, potentially averting or reducing the likelihood of the serious lifethreatening complications of portal hypertension. 9-14 Furthermore, earlier detection of hepatocellular cancers creates possibilities for interventions with curative potential such as resection and radiofrequency ablation rather than transplantation or palliation that are often the only option with late diagnosis. Despite the rising incidence and burden of NAFLD and its associated comorbidities, there remains a poor awareness regarding its recognition and management. Concerningly, the Veterans Administration primary care centre study highlighted that patients at highest risk of NAFLD were not being evaluated for this condition. 15 Only 21.5% of patients who were identified by study investigations had a confirmed diagnosis of NAFLD in primary care, 14.7% were counselled regarding diet and exercise and 10.4% were referred to a specialist. We hypothesise that many patients reaching liver transplant listing are only diagnosed with NAFLD at a point where liver disease has resulted in irreversible complications. We have conducted a retrospective analysis of patients with NAFLD cirrhosis referred for OLT assessment, aiming to determine their disease status at their first presentation to healthcare, and their subsequent clinical outcomes. Methods This was a cross-sectional analysis of all patients who underwent OLT assessment for a sole indication of NAFLD at the Royal Free London NHS Foundation Trust between January 2003 and December 2017. NAFLD was defined by the sonographic demonstration of hepatic steatosis in the presence of metabolic risk factors and the exclusion of significant alcoholic consumption

Background Alcohol is the main cause of chronic liver disease. The Enhanced Liver Fibrosis (ELF) test is a serological biomarker for fibrosis staging in chronic liver disease, however its utility in alcohol-related liver disease warrants further validation. We assessed the diagnostic and prognostic performance of ELF in alcohol-related liver disease. Methods Observational cohort study assessing paired ELF and histology from 786 tertiary care patients with chronic liver disease due to alcohol (n = 81) and non-alcohol aetiologies (n = 705). Prognostic data were available for 64 alcohol patients for a median of 6.4 years. Multiple ELF cut-offs were assessed to determine diagnostic utility in moderate fibrosis and cirrhosis. Survival data were assessed to determine the ability of ELF to predict liver related events and all-cause mortality. Results ELF identified cirrhosis and moderate fibrosis in alcohol-related liver disease independently of aminotransferase levels with areas under receiver operating characteristic curves of 0.895 (95% CI 0.823–0.968) and 0.923 (95% CI 0.866–0.981) respectively, which were non-inferior to non-alcohol aetiologies. The overall performance of ELF was assessed using the Obuchowski method: in alcohol = 0.934 (95% CI 0.908–0.960); non-alcohol = 0.907 (95% CI 0.895–0.919). Using ELF < 9.8 to exclude and ≧ 10.5 to diagnose cirrhosis, 87.7% of alcohol cases could have avoided biopsy, with sensitivity of 91% and specificity of 85%. A one-unit increase in ELF was associated with a 2.6 (95% CI 1.55–4.31, p < 0.001) fold greater odds of cirrhosis at baseline and 2.0-fold greater risk of a liver related event within 6 years (95% CI 1.39–2.99, p < 0.001). Conclusions ELF accurately stages liver fibrosis independently of transaminase elevations as a marker of inflammation and has superior prognostic performance to biopsy in alcohol-related liver disease.

Background Alcohol is the main cause of chronic liver disease. The Enhanced Liver Fibrosis (ELF) test is a serological biomarker for fibrosis staging in chronic liver disease, however its utility in alcohol-related liver disease warrants further validation. We assessed the diagnostic and prognostic performance of ELF in alcohol-related liver disease. Methods Observational cohort study assessing paired ELF and histology from 786 tertiary care patients with alcohol-related liver disease due to alcohol (n = 81) and non-alcohol aetiologies (n = 705). Prognostic data were available for 64 alcohol patients for a median of 6.4 years. Multiple ELF cut-offs were assessed to determine diagnostic utility in moderate fibrosis and cirrhosis. Survival data were assessed to determine the ability of ELF to predict liver related events and all-cause mortality. Results ELF identified cirrhosis and moderate fibrosis in alcohol-related liver disease independently of aminotransferase levels with areas under receiver operating characteristic curves of 0.895 (95% CI:0.823–0.968) and 0.923 (95% CI:0.866–0.981) respectively, which were non-inferior to non-alcohol aetiologies. The overall performance of ELF was assessed using the Obuchowski method: in alcohol = 0.934 (95% CI:0.908–0.960); non-alcohol = 0.907 (95% CI:0.895–0.919). Using ELF < 9.8 to exclude and ≧ 10.5 to diagnose cirrhosis, 87.7% of alcohol cases could have avoided biopsy, with sensitivity of 91% and specificity of 85%. A one-unit increase in ELF was associated with a 2.6 (95% CI:1.55–4.31, p < 0.001) fold greater odds of cirrhosis at baseline and 2.0-fold greater risk of a liver related event within 6 years (95% CI:1.39–2.99, p < 0.001). Conclusions ELF accurately stages liver fibrosis independently of transaminase elevations as a marker of inflammation and has superior prognostic performance to biopsy in alcohol-related liver disease.

Background and aims Alcohol use disorders (AUD) cause 7.2% of UK hospital admissions/year. Most are not managed by hepatologists and liver disease may be missed. We used the Enhanced Liver Fibrosis (ELF) test to investigate prevalence and associations of occult advanced liver fibrosis in AUD patients not known to have liver fibrosis. Methods Liver fibrosis was assessed using ELF in prospective patients referred to the Royal Free Hospital Alcohol Specialist Nurse (November 2018–December 2019). Known cases of liver disease were excluded. Patient demographics, blood tests, imaging data and alcohol histories recorded. Advanced fibrosis was categorised as ELF ≥ 10.5. Results The study included 99 patients (69% male, mean age 53.1 ± 14.4) with median alcohol intake 140 units/week (IQR 80.9–280), and a mean duration of harmful drinking of 15 years (IQR 10–27.5). The commonest reason for admission was symptomatic alcohol withdrawal (36%). The median ELF score was 9.62, range 6.87–13.78. An ELF score ≥ 10.5 was recorded in 28/99 (29%) patients, of whom 28.6% had normal liver tests. Within previous 5-years, 76% had attended A&E without assessment of liver disease. The ELF score was not associated with recent alcohol intake (p = 0.081), or inflammation (p = 0.574). Conclusion Over a quarter of patients with AUD had previously undetected advanced liver fibrosis assessed by ELF testing. ELF was not associated with liver inflammation or recent alcohol intake. The majority had recent missed opportunities for investigating liver disease. We recommend clinicians use non-invasive tests to assess liver fibrosis in patients admitted to hospital with AUD.

Background and Aim Mortality of alcohol‐related liver disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non‐invasive tests (NITs) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease, and in particular in ArLD, is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (Fibrosis 4 test [FIB4], Enhanced Liver Fibrosis [ELF] test, FibroScan, and FibroTest) in ArLD. Methods Applying systematic review methodology, we searched four databases from inception to May 2020. Inclusion/exclusion criteria were applied to search using Medical Subject Heading terms and keywords. The first and second reviewers independently screened results, extracted data, and performed risk‐of‐bias assessment using Quality in Prognosis Studies tool. Results Searches produced 25 088 articles. After initial screening, 1020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4 + FibroScan, and one on FibroTest + FIB4. Area under the receiver operating characteristic curves for outcome prediction ranged from 0.65 to 0.76 for FibroScan, 0.64 to 0.83 for FIB4, 0.69 to 0.79 for FibroTest, and 0.72 to 0.85 for ELF. Studies scored low–moderate risk of bias for most domains but high risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. Conclusions This systematic review returned 11 papers, six of which were conference abstracts and one unpublished manuscript. While the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (area under the receiver operating characteristic curves >0.7 in each NIT category) and may add value to prognostication in clinical practice.