Validation of a Model for Identification of Patients With Compensated Cirrhosis at High Risk of Decompensation.

BACKGROUND & AIMS: It is important to rapidly identify patients with advanced liver disease. Routine tests to assess liver function and fibrosis provide data that can be used to determine patients' prognoses. We tested the validated the ability of combined data from the ALBI and FIB-4 scoring systems to identify patients with compensated cirrhosis at highest risk for decompensation. METHODS: We collected data from 145 patients with compensated cirrhosis (91% Child A cirrhosis and median MELD scores below 8) from a cohort in Nottingham, United Kingdom, followed for a median 4.59 years (development cohort). We collected baseline clinical features and recorded decompensation events. We used these data to develop a model based on liver function (assessed by the ALBI score) and extent of fibrosis (assessed by the FIB-4 index) to determine risk of decompensation. We validated the model in 2 independent external cohorts (1 in Dublin, Ireland and 1 in Menoufia, Egypt) comprising 234 patients. RESULTS: In the development cohort, 19.3% of the patients developed decompensated cirrhosis. Using a combination of ALBI and FIB-4 scores, we developed a model that identified patients at low vs high risk of decompensation (hazard ratio [HR] for decompensation in patients with high risk score was 7.10). When we tested the scoring system in the validation cohorts, the HR for decompensation in patients with a high-risk score was 12.54 in the Ireland cohort and 5.10 in the Egypt cohort. CONCLUSION: We developed scoring system, based on a combination of ALBI and FIB-4 scores, that identifies patients at risk for liver decompensation. We validated the scoring system in 2 independent international cohorts (Europe and the Middle East), so it appears to apply to diverse populations.

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

UNLABELLED: 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.

Transient Elastography in Community Alcohol Services: Can It Detect Significant Liver Disease and Impact Drinking Behaviour?

Introduction: Alcohol is the leading cause of cirrhosis in Western populations. The early identification of high-risk drinkers followed by intervention is an effective way to reduce harm. We aim to assess the feasibility of integrating transient elastography (TE) into community alcohol services, and to determine its impact on modifying drinking behaviours. Method: A prospective cohort study was conducted at a community alcohol clinic in Nottingham, UK (April 2012 to March 2014). Patients (>18 years) with a primary alcohol problem were recruited. Those known to liver services or those known to have chronic liver disease were excluded. Significant liver fibrosis was defined by a liver stiffness of >8 kilopascal (kPa). Follow-up was for a minimum of six months. Data were descriptively analysed for significant differences between patients with a normal liver stiffness versus raised liver stiffness. Results: 156 patients were invited; n = 87 attended and n = 86 underwent successful TE. The majority were male (n = 53, 70.0%), and the mean age was 46.3 years (SD ± 9.8). Median liver stiffness was 6.9 kPa (range 3.1-75.0kPa). Clinically significant liver fibrosis was identified in n = 33 (38.4%), of which n = 6 were in the cirrhotic range (≥15 kPa). The baseline median self-reported alcohol intake for normal stiffness was 126 units per week (range 24-378) and in raised stiffness was 149.0 units per week (range 39.0-420.0); this difference was nonsignificant (p = 0.338). The median reduction in self-reported alcohol intake in the whole cohort was 65.0 units per week (range 27.0-88.0, p < 0.001); in the normal liver stiffness group it was 25.0 units per week (range 18.0-75.0, p = 0.154), and in the raised liver stiffness group it was 78.5 units per week (range 36.0-126.0, p < 0.001). Conclusion: The study demonstrated that transient elastography is a feasible tool to stratify clinically significant liver disease in community alcohol services. It can stimulate a change in high-risk drinking behaviour and a normal liver stiffness result does not provide false reassurance to participants.

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 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.

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.

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.