David J. Harman

Direct targeting of risk factors significantly increases the detection of liver cirrhosis in primary care: a cross-sectional diagnostic study utilising transient elastography

Objectives To assess the feasibility of a novel diagnostic algorithm targeting patients with risk factors for chronic liver disease in a community setting. Design Prospective cross-sectional study. Setting Two primary care practices (adult patient population 10 479) in Nottingham, UK. Participants Adult patients (aged 18 years or over) fulfilling one or more selected risk factors for developing chronic liver disease: (1) hazardous alcohol use, (2) type 2 diabetes or (3) persistently elevated alanine aminotransferase (ALT) liver function enzyme with negative serology. Interventions A serial biomarker algorithm, using a simple blood-based marker (aspartate aminotransferase:ALT ratio for hazardous alcohol users, BARD score for other risk groups) and subsequently liver stiffness measurement using transient elastography (TE). Main outcome measures Diagnosis of clinically significant liver disease (defined as liver stiffness ≥8 kPa); definitive diagnosis of liver cirrhosis. Results We identified 920 patients with the defined risk factors of whom 504 patients agreed to undergo investigation. A normal blood biomarker was found in 62 patients (12.3%) who required no further investigation. Subsequently, 378 patients agreed to undergo TE, of whom 98 (26.8% of valid scans) had elevated liver stiffness. Importantly, 71/98 (72.4%) patients with elevated liver stiffness had normal liver enzymes and would be missed by traditional investigation algorithms. We identified 11 new patients with definite cirrhosis, representing a 140% increase in the number of diagnosed cases in this population. Conclusions A non-invasive liver investigation algorithm based in a community setting is feasible to implement. Targeting risk factors using a non-invasive biomarker approach identified a substantial number of patients with previously undetected cirrhosis. Trial registration number The diagnostic algorithm utilised for this study can be found on clinicaltrials.gov (NCT02037867), and is part of a continuing longitudinal cohort study.

Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review

As of 2016, there is no evidence-based pathway to stratify the risk of chronic liver disease in a general population setting. Non-invasive tests of liver fibrosis might provide a mechanism for earlier diagnosis. These tests have been extensively validated in the hospital setting but their performance in a general population setting is unclear. We did a systematic review of non-invasive tests used to stratify patients at risk of clinically significant liver disease in a general population setting and report the prevalence of chronic liver disease as defined by these tests. We systematically searched Embase, MEDLINE, Web of Science, reference lists from the original studies identified, and recent conference proceedings. All study designs were considered. 19 studies were identified, in which 11 non-invasive tests were used. Only transient elastography and FibroTest were compared with histological endpoints. The prevalence of liver fibrosis varied between 0·7% and 25·7%. More focused stratification for advanced liver fibrosis (0·9-2·0%) or cirrhosis (0·1-1·7%) narrowed the estimates of prevalence. Investigators from studies targeting patients with risk factors of liver disease, such as non-alcoholic fatty liver disease, hazardous alcohol use, or type 2 diabetes, reported higher prevalence of advanced liver fibrosis (0-27·9%) and cirrhosis (2·4-4·0%) than those in the general population. Validated non-invasive tests for liver fibrosis consistently detected otherwise unrecognised liver disease in the general population. Reliance on abnormal liver function tests will miss most patients with significant liver injury. New pathways to stratify chronic liver disease, with the use of non-invasive markers of liver fibrosis, are needed in the general population setting.

Economic modelling of early transjugular intrahepatic portosystemic shunt insertion for acute variceal haemorrhage.

Introduction Early insertion of transjugular intrahepatic portosystemic shunt (TIPS) in high-risk patients with acute variceal haemorrhage reduces rebleeding and mortality. However, the economic benefit of utilizing this approach remains unclear. We evaluated the economic implications of introducing early TIPS into routine algorithms for the management of variceal bleeding. Methods Consecutive patients admitted in 2009 with variceal haemorrhage to two liver units and eligible for early TIPS insertion were identified retrospectively. The costs of a 12-month follow-up from index bleeding admission were calculated – the actual cost of follow-up and rebleeding in this cohort was compared with the theoretical 12-month follow-up costs of instead inserting an early TIPS at index admission. Our findings were subjected to a sensitivity analysis to assess the cost effectiveness of early TIPS insertion compared with standard care. Results In 2009, 78 patients were admitted to our units with variceal haemorrhage; 27 patients (35%) were eligible for early TIPS insertion. The actual cost of a 12-month follow-up was £138 473.50. Early TIPS insertion, assuming a 3.2% rebleeding rate, would save £534.70 per patient per year (P<0.0001). On sensitivity analysis, early TIPS dominated standard care up to an early TIPS rebleeding rate of 6% and remained cost-effective up to a rebleeding rate of 12%. Conclusion Early TIPS insertion for high-risk patients with acute variceal bleeding is a cost-efficient intervention. This has important implications for the introduction of early TIPS as standard care and the organization of interventional radiology services.

Prevalence and natural history of histologically proven chronic liver disease in a longitudinal cohort of patients with type 1 diabetes

Although a higher prevalence of raised liver enzymes and altered echotexture on ultrasound have been reported in patients with type 1 diabetes mellitus (T1DM), the histological spectrum and natural history of chronic liver disease (CLD) in T1DM is unknown. We investigated the prevalence and outcome of histologically proven CLD in a longitudinal cohort of patients with T1DM. We identified patients who have had liver biopsy from a computerized database (DIAMOND; Hicom Technology, Brookwood, UK) containing longitudinal data for over 95% of type 1 diabetes patients from an overall catchment population of 700,000 people. Gender‐matched patients with oral hypoglycemic‐treated (T2OH) and insulin‐treated type 2 diabetes (T2IN) who had liver biopsy formed two comparative cohorts. We collated clinical and histological data, as well as long‐term outcomes of all three groups, and compared T1DM cirrhosis incidence to UK general population data. Of 4,644 patients with T1DM, 57 (1.2%) underwent liver biopsy. Of these, 53.1% of patients had steatosis, 20.4% had nonalcoholic steatohepatitis, and 73.5% had fibrosis on index liver biopsy. Cirrhosis was diagnosed in 14 patients (24.6%) during follow‐up. T1DM with age under 55 years had an odds ratio of 1.875 (95% confidence interval: 0.936‐3.757) for cirrhosis incidence, compared to the general population. Longitudinal liver‐related outcomes were similar comparing the T1DM cohort and respective type 2 diabetes cohorts—when adjusted for important confounders, diabetic cohort type did not predict altered risk of incident cirrhosis or portal hypertension. Conclusion: Type 1 diabetes is associated with a previously unrecognized burden of CLD and its complications. (Hepatology 2014;60:158–168)

Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography

Rising cirrhosis incidence and mortality in the United Kingdom has been attributed predominantly to excess alcohol consumption. However, metabolic risk factors such as Type 2 diabetes and obesity may also be important.

Economic evaluation of a community-based diagnostic pathway to stratify adults for non-alcoholic fatty liver disease: a Markov model informed by a feasibility study

Objectives To assess the long-term cost-effectiveness of a risk stratification pathway, compared with standard care, for detecting non-alcoholic fatty liver disease (NAFLD) in primary care. Setting Primary care general practices in England. Participants Adults who have been identified in primary care to have a risk factor for developing NAFLD, that is, type 2 diabetes without a history of excessive alcohol use. Intervention A community-based pathway, which uses transient elastography and hepatologists to stratify patients at risk of NAFLD, has been implemented and demonstrated to be feasible (NCT02037867). Earlier identification could mean earlier treatments, referral to specialist and enrolment into surveillance programmes. Design The impact of earlier detection and treatment with the risk stratification pathway on progression to later stages of liver disease was examined using decision modelling with Markov chains to estimate lifetime health and economic effects of the two comparators. Data sources Data from a prospective cross-sectional feasibility study indicating risk stratification pathway and standard care diagnostic accuracies were combined with a Markov model that comprised the following states: no/mild liver disease, significant liver disease, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplant and death. The model data were chosen from up-to-date UK sources, published literature and an expert panel. Outcome measure An incremental cost-effectiveness ratio (ICER) indicating cost per quality-adjusted life year (QALY) of the risk stratification pathway compared with standard care was estimated. Results The risk stratification pathway was more effective than standard care and costs £2138 per QALY gained. The ICER was most sensitive to estimates of the rate of fibrosis progression and the effect of treatment on reducing this, and ranged from −£1895 to £7032/QALY. The risk stratification pathway demonstrated an 85% probability of cost-effectiveness at the UK willingness-to-pay threshold of £20 000/QALY. Conclusions Implementation of a community-based risk stratification pathway is likely to be cost-effective. Trial registration number NCT02037867, ClinicalTrials.gov.

Non-invasive tests for the detection of oesophageal varices in compensated cirrhosis: systematic review and meta-analysis:

Introduction Conclusive data on the accuracy and clinical applicability of non-invasive screening tests for oesophageal varices (OV) in patients with compensated cirrhosis remain lacking. We conducted this study to identify currently available tests, estimate their diagnostic performance and then exemplify how these could be utilized in clinical practice. Materials and methods A systematic literature search was performed to identify all primary studies that reported accuracy using oesophagogastroduodenoscopy (OGD) as the gold standard. Sources searched included Ovid MEDLINE, Ovid EMBASE and The Cochrane Library databases. Results Twenty-one studies with a total of 2471 patients were identified. Several tests were evaluated in more than three studies. Platelet count/spleen diameter ratio (PSR) had the highest summary area under the curve for detection of any size OV of 0.85 (95% confidence interval 0.78–0.92). At a cut-off of 909 (n = 4 studies) and prevalence rates of 10, 20, 30, 40 and 50% for OV, PSR screening correctly avoided the need for OGD in 70, 62, 55, 47 and 39% of patients, respectively. Conclusions PSR appears to be the most accurate and validated non-invasive screening test for OV in patients with compensated cirrhosis. At a cut-off of 909, PSR could be clinically useful to avoid OGDs in a significant proportion of patients.

OC-018 Obesity and type 2 diabetes are predominant risk factors underlying previously undetected cirrhosis in the general population

Introduction Epidemiological studies have attributed the rising cirrhosis incidence and mortality in the UK predominantly to excess alcohol consumption. However, obesity acts synergistically with alcohol to increase the risk of cirrhosis. In addition, asymptomatic liver disease goes undetected; as a result nearly 50% of cirrhotics are diagnosed when presenting with hepatic decompensation. We utilised Transient Elastography (TE) to screen at-risk individuals in the general population, aiming to establish the prevalence of undetected liver cirrhosis and the risk factors underlying these cases. Method The study was undertaken in 4 general practices in Nottingham between February 2012 and September 2014. The total adult patient population was 20,868. Patients with pre-defined risk factors for chronic liver disease (hazardous alcohol use as identified by general practitioner (GP), type 2 diabetes and/or persistent ALT rise with negative serology) were identified from the GP electronic records and invited for TE even if liver enzymes were normal. TE was performed by trained nurses at the general practice sites. Liver stiffness of ≥8 kilopascals prompted review by a Consultant Hepatologist and liver cirrhosis was confirmed by established histological, radiological and biochemical methods. Results Of 2,022 patients eligible, 919 attended TE; 899 (97.8%) had valid liver stiffness measurements. Elevated liver stiffness was detected in 230 patients (25.6%) and cirrhosis in 26 (2.9%). Liver enzymes were normal in 16/26 (61.5%) of cirrhosis cases. Prior to the study, 23 patients with cirrhosis (aetiologies: alcohol (14), viral hepatitis (5), Non-alcoholic steatohepatitis (1), other (3)) had been identified; a diagnosed cirrhosis prevalence which was not significantly different compared to general population estimates of 76.3 cases per 100,000. Following the study, the prevalence of cirrhosis diagnosis was 49/20,868 (234.8 cases per 100,000 (95% CI 201.3–268.3)) was 3 fold higher than the previous general population estimate. Risk factors for new cirrhosis diagnoses were obesity and/or type 2 diabetes in 16 patients (61.5%), alcohol alone in 3 (11.5%) and both alcohol and obesity and/or diabetes in 7 (26.9%). Conclusion Investigating defined risk factors for liver disease using TE in a community setting detects a significant amount of previously unidentified cirrhosis. Cirrhosis prevalence in the general population is at least 3 times recent UK estimates. Obesity and type 2 diabetes are the predominant risk factors underlying previously undetected cirrhosis cases. Disclosure of interest None Declared.

PTU-026 Prevalence of liver histological abnormalities in type 1 diabetes and the long term consequences

Introduction Patients with type 1 diabetes have a higher prevalence of raised liver enzymes than the general population. Ultrasound diagnosis of non-alcoholic fatty liver disease has been reported to be common in type 1 diabetes despite associated insulin deficiency rather than insulin resistance. However, the histological spectrum of liver disease in type 1 diabetes and the natural history of chronic liver disease in this cohort is unknown. We describe the histological findings of patients with type 1 diabetes who had liver biopsy in a tertiary referral centre, and their long-term clinical outcome. Methods The DIAMOND database, which contains longitudinal data for over 95% of type 1 diabetes patients from an overall catchment population of 750 000 in Nottingham, was crossmatched with the clinical pathology database to identify those who had undergone liver biopsy. Case notes were reviewed to obtain follow-up data, and identify liver and non-liver related outcomes. Results Out of 2800 patients with Type 1 Diabetes, 57 patients underwent a total of 82 liver biopsies. Common indications for biopsy were abnormal liver enzymes (28 patients), malignancy (8), Hepatitis C staging (7) and clinical evidence of cirrhosis (3). On index biopsy, 86% had significant histological abnormalities (Abstract PTU-026 figure 1) and 10 patients (17.5%) had cirrhosis. During a total follow-up of 336.4 patient years (median 5.6 years), a further four patients developed cirrhosis, giving a cirrhosis prevalence of at least 500 per 100 000 population—this compares with an estimated UK cirrhosis prevalence of 76.3 per 100 000 population.1 Portal hypertensive sequelae occurred in 11 patients (78.6%) with cirrhosis and hepatocellular carcinoma in three patients. 22 patients (38.6%) died during follow-up. Crude death rate was 6539 per 100 000 person years, compared with national Type 1 Diabetes data2 of 1878 per 100 000 person years.Abstract PTU-026 Figure 1 Index liver biopsy diagnoses. Conclusion Type 1 Diabetes is associated with significant liver histology abnormalities and a higher than expected occurrence of cirrhosis, portal hypertension and mortality. These findings have implications for long-term management of patients with Type 1 Diabetes. Competing interests None declared. References 1. Fleming KM, Aithal GP, Solaymani-Dodaran M, et al. Incidence and prevalence of cirrhosis in the United Kingdom, 1992-2001: a general population-based study. J Hepatol 2008;49:732–8. 2. NHS IC. National Diabetes Audit Mortality Analysis 2007-2008. NHS IC, 2011.

P39 An analysis of rebleeding rates for variceal haemorrhage at a regional centre: what is the applicability and potential cost for early TIPS?

Introduction A recent randomised controlled trial demonstrated that the early use of TIPS in patients with Child-Pugh class B and C cirrhosis presenting with acute variceal haemorrhage was associated with a significant reduction in rebleeding and mortality.1 However, it remains unclear whether an additional economic benefit exists with their approach compared to the current standard of care utilising pharmacological and endoscopic therapies, and rescue TIPS. Aim We aimed to ascertain how many patients would benefit from early TIPS and the economic implications of introducing this into practice, by observing retrospective data from our tertiary care liver unit. Method Consecutive patients admitted in 2009 with oesophageal variceal haemorrhage to a tertiary care liver unit at Nottingham University Hospitals (NUH) NHS Trust were identified retrospectively using a dedicated endoscopy database and cross-checking with the emergency medicine database. Patients with non-cirrhotic portal hypertension or isolated gastric varices were not included in our study. Standard management protocols including endoscopic therapy within 24 h, glypressin and prophylactic antibiotics were used. Data were collected on demography, aetiology, rebleeding related hospital admissions and mortality at 12 months. Costs of rebleeding were analysed for all patients meeting inclusion criteria for the original study1 and included subsequent inpatient care costs and endoscopic/radiological intervention (figures were supplied by the NUH finance and procurement department and based on established national tariffs). The actual cost of rebleeding in our Child Pugh score 7–13 patients was compared to the theoretical cost of introducing early TIPS in this group. Results 51 cirrhotic patients were admitted to our unit with oesophageal variceal bleeding. 20% of this cohort had Childs A, 40% Childs B and 40% Childs C cirrhosis. The rebleeding rate was 15% at 28 days and 34% at 1-year follow-up. The survival rates were 82% at 28 days and 40% at 1 year. 35 patients (70% of the cohort) had a Child Pugh score of 7–13. Within this subgroup there was a 31% rebleeding rate requiring hospital admission over 12 months and 8% required a TIPS procedure within 12 months. The actual cost of rebleeding episodes for the selected subgroup was 138 446, (3955 per patient). The theoretical cost of early TIPS in this group was calculated as 117 670, (3362 per patient). Assuming a rebleeding rate of 3% with early TIPS1, this strategy has a potential cost reduction of 7% per patient outcome year compared with current standard management. Conclusion The proportion of variceal bleed patients benefitting from early TIPS could approach 70% in regional centres. This has implications for the provision and organisation of interventional radiology services. Our retrospective analysis suggests marginal cost benefit, complementing the previously observed reduction in rebleeding and mortality; however prospective studies are needed to confirm this.