Feasibility and acceptability of a primary care liver fibrosis testing pathway centred on the diabetes annual review: PRELUDE1 prospective cohort study protocol.

INTRODUCTION: Non-alcoholic fatty liver disease is the most common chronic liver disease worldwide affecting 20%-25% in the USA and Europe with a 60%-80% lifetime prevalence for people with type 2 diabetes (T2D). Fibrosis has repeatedly been demonstrated to be the major determinant of liver disease morbidity and mortality and there is currently no routine screening for liver fibrosis in at-risk T2D population. METHODS AND ANALYSIS: This 12-month prospective cohort study of automated fibrosis testing uses the fibrosis-4 score (FIB-4) in patients with T2D linked to the investigation of hospital-based versus community-based second-tier transient elastography (TE) testing. We plan to include >5000 participants across 10 General Practitioner (GP) practices in East London and Bristol. This will determine the rate of undiagnosed significant liver fibrosis in a T2D population, the feasibility of two-tier liver fibrosis screening using FIB-4 at the diabetes annual review and subsequent TE delivered either in the community or secondary care settings. This will include an intention-to-treat analysis for all those invited to attend for diabetes annual review. A qualitative substudy regarding the acceptability of the fibrosis screening pathway will comprise semistructured interviews/focus groups with primary care staff (GPs and practice nurses), and patients taking part in the wider study. ETHICS AND DISSEMINATION: This study received a favourable opinion from the Cambridge East research ethics committee. The results of this study will be disseminated in peer-reviewed scientific journals, conference presentations and local diabetes lay panel meetings. TRIAL REGISTRATION NUMBER: ISRCTN14585543.

Single-cell phenotypes of peripheral blood immune cells in early and late stages of non-alcoholic fatty liver disease.

BACKGROUND/AIMS: Immune and inflammatory cells respond to multiple pathological hits in the development of nonalcoholic steatohepatitis (NASH) and fibrosis. Relatively little is known about how their type and function change through the non-alcoholic fatty liver disease (NAFLD) spectrum. Here we used multi-dimensional mass cytometry and a tailored bioinformatic approach to study circulating immune cells sampled from healthy individuals and people with NAFLD. METHODS: Cytometry by time of flight using 36 metal-conjugated antibodies was applied to peripheral blood mononuclear cells (PBMCs) from biopsy-proven NASH fibrosis (late disease), steatosis (early disease), and healthy patients. Supervised and unsupervised analyses were used, findings confirmed, and mechanisms assessed using independent healthy and disease PBMC samples. RESULTS: Of 36 PBMC clusters, 21 changed between controls and disease samples. Significant differences were observed between diseases stages with changes in T cells and myeloid cells throughout disease and B cell changes in late stages. Semi-supervised gating and re-clustering showed that disease stages were associated with fewer monocytes with active signalling and more inactive NK cells; B and T cells bearing activation markers were reduced in late stages, while B cells bearing co-stimulatory molecules were increased. Functionally, disease states were associated with fewer activated mucosal-associated invariant T cells and reduced toll-like receptor-mediated cytokine production in late disease. CONCLUSION: A range of innate and adaptive immune changes begin early in NAFLD, and disease stages are associated with a functionally less active phenotype compared to controls. Further study of the immune response in NAFLD spectrum may give insight into mechanisms of disease with potential clinical application.

What's new in non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, with an estimated prevalence of 25% in the Western World. NAFLD is a broad spectrum of disease states and while most people with NAFLD do not have progressive disease, 10-20% of patients develop histological features of inflammation (non-alcoholic steatohepatitis), fibrosis, cirrhosis and its complications. Despite this large disease burden of significant clinical impact, most people living with NAFLD are undiagnosed, disease course prediction is imprecise and there are no treatments licensed for this condition. In this review, we discuss some of the recent developments in NAFLD, focusing on disease definition and diagnosis, risk stratification and treatments.

The contribution of daytime sleepiness to impaired quality of life in NAFLD in an ethnically diverse population.

Health-related quality of life (HRQoL) is lower in people with NAFLD compared to the general population. Sleep disturbance resulting in daytime sleepiness is common in patients with NAFLD, but the effect of daytime sleepiness on HRQoL in NAFLD is unclear. The prevalence and natural history of NAFLD vary in different ethnic groups, but there has been limited ethnic diversity in HrQoL studies to date. We aimed to assess whether daytime sleepiness is independently associated with reduced HRQoL in an ethnically diverse UK population. We conducted HRQoL assessments using SF-36 version 2 and Epworth Sleepiness Scale (ESS) questionnaires in 192 people with NAFLD. Multivariate linear regression was used to identify factors independently affecting HRQoL scales. People with NAFLD reported significantly reduced physical health-related SF-36 scores compared to the general UK population. South Asian NAFLD patients reported impairment in physical health, but not mental health, approximately a decade before White NAFLD patients. In multivariate linear regression, daytime sleepiness (ESS score > 10), was the most significant independent predictor of reduced physical health. Age, BMI and liver stiffness score were also significantly associated. HRQoL is impaired earlier in patients of South Asian ethnicity. ESS score > 10, indicative of excessive daytime sleepiness, is an independent predictor of reduced HRQoL in people with NAFLD regardless of ethnicity. Daytime sleepiness should be considered as a contributing factor to reduced HRQoL in clinical practice and when evaluating patient-related outcomes in clinical trials.