The utility of biomarkers for non-alcoholic fatty liver disease in adolescents

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

The liver is the largest glandular organ in the body and is involved in a large number of the body?s normal functions. It produces the chemicals needed to breakdown fat in the circulation and produces cholesterol. It converts glucose (sugar) from the circulation to a form that can be stored and is responsible for maintaining a proper level of glucose in the circulation. It also makes a number of amino acids (the basic building blocks of proteins), stores key vitamins and minerals and filters harmful substances, such as alcohol, from the body. Until recently high levels of alcohol intake were seen as the major cause of liver disease in developed population. However, because of the recent obesity epidemic the most common cause of liver disease in the developed world now is caused by deposits of fat in the liver, so called non-alcoholic fatty liver disease (NALFD). Studies from America suggest that NAFLD starts to occur in adolescence with up to 15% of healthy adolescents in the US having NAFLD. In adults NAFLD can progress to cirrhosis and is also associated with increased risk of diabetes and cardiovascular disease. However, its causes and consequences in adolescents have not been extensively studied because of the difficulties of safely and accurately diagnosing this condition. The most accurate way to diagnose NAFLD is to take a sample (biopsy) from the liver and examine it under a microscope. However, this method is potentially dangerous and very costly and is not practical for large-scale research studies. A number of scanning methods, including ultrasound scan, are also useful for accurate diagnosis but these are too expensive and time consuming for large-scale studies. In this study we aim to develop a way of diagnosing NAFLD in adolescents that would be suitable for large studies of generally healthy young people. We will test a number of blood test results and measurements of total fat and abdominal fat in relation to NAFLD diagnosed by ultrasound scan in 3500 UK individuals aged 17 years. Once we have developed a safe diagnostic tool we will then test it again in an independent group of 17 year olds from Australia, in order to make sure it really is valid. This project brings together an international team of experts in research methods, liver medicine, clinical pathology and liver scanning. Our results will enable the much needed research in this area to progress.

Technical Summary

Our aim is to develop and evaluate a non-invasive, safe and accurate biomarker tool for diagnosing non-alcoholic fatty liver disease (NAFLD) in adolescents. This work is needed because: (i) NAFLD is common in adolescents in Western populations and its prevalence is increasing; (ii) amongst adults the longer the duration of NAFLD the greater the likelihood of progression to severe liver disease (fibrosis and cirrhosis), meaning that if NAFLD commences in adolescence and progresses into adulthood population levels of liver cirrhosis could increase markedly as a consequence; (iii) in adults NAFLD is associated with increased risk of diabetes and cardiovascular disease and in adolescents with early markers, fasting glucose, insulin and lipids, for these conditions. Despite evidence that NALFD is common in adolescence and that it could result in marked increases in severe liver disease, type 2 diabetes and cardiovascular disease, there has been little epidemiological research or trials in healthy adolescent populations. A key reason for the bottleneck in research in this area is the lack of suitable safe and accurate diagnostic biomarkers. It would be unethical and impractical to use the gold standard diagnostic tool (liver biopsy) in such studies and also impractical and too expensive to use scanning modalities that have also been shown to accurately diagnose NAFLD.
There is biological plausibility that a number of biochemical and anthropometric measurements could provide valid biomarkers for the diagnosis of NAFLD in adolescents. We will develop a diagnostic predictive model based on plausible biomarkers (ALT, AST, GGT, total bilirubin, fasting glucose, total cholesterol, HDLc, LDLc, triglycerides, BMI, waist circumference) using ultrasound scan diagnosed NAFLD as the gold standard in a general population sample of 3500 UK adolescents (mean age 17 years; 50% female). We will further test whether diagnostic accuracy of this model is increased by the addition of more expensive (but also feasible and biologically plausible) biomarkers (apolipoprotein A1 (ApoA1), fasting insulin, alpha 2 macroglobin, haptoglobin). If the addition of these more expensive markers increases accuracy to an important extent, we will compare costs of the cheaper and more expensive diagnostic models. Finally, we will validate our diagnostic predictive model(s) in an independent study sample of 17 year olds from Australia. This project brings together an international team of experts in research methods, liver medicine, clinical pathology and liver scanning, as well as collaboration with industry. Our results will enable the much needed research in this area to progress

Publications

10 25 50
 
Description Active For Life Year 5: A cluster randomised controlled trial of a primary school-based intervention to increase levels of physical activity, decrease sedentary behaviour and improve diet
Amount £1,464,457 (GBP)
Funding ID 09/3005/04 
Organisation Public Health Research Consortium 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 03/2015
 
Description British Heart Foundation Project Grant
Amount £130,493 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Excessive drinking and alcohol related harms in Adulthood - MRC
Amount £1,736,826 (GBP)
Funding ID MR/L022206/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description Fatty Liver: Inhibition of Progression (FLIP) programme (6m euros across 17 participants)
Amount £2,000,000 (GBP)
Funding ID 241762 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start  
 
Description Modifiable early life determinants of adolescent NAFLD and its association with metabolic and vascular traits
Amount £130,493 (GBP)
Funding ID PG/11/33/28794 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2012 
End 03/2015
 
Title Development of Triangulation method for causal inference 
Description Study design and analytical method for improving causal inference Paper published in IJE and work presented at (a) Causal inference workshop in Harvard Boston USA November 2016 and (b) at the London School of Hygiene & Tropical Medicine to MSc, PhD students and staff March 2017 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2016 
Provided To Others? Yes  
Impact To date too early to tell 
 
Description CHICOS 
Organisation CHICOS: Developing a Child Cohort Research Strategy for Europe
Country European Union (EU) 
Sector Academic/University 
PI Contribution Overall aim is to improve child health across Europe by developing an integrated strategy for mother-child cohort research in Europe. Methodologically we are working on ways of harmonising data and comparing results between and, where appropriate, pooling data from all European mother-child cohorts. I lead the work on child obesity and cardiometabolic health. I contribute data and/or analyses results for reserach that other partners lead in other research areas.
Collaborator Contribution Partners contribute data or results from analyses for research that I lead on child obesity and cariometabolic health.
Impact Publications currently being drafted
Start Year 2010
 
Description EAGLE 
Organisation Center for Research in Environmental Epidemiology
Country Spain 
Sector Academic/University 
PI Contribution Early Genetics and Lifecourse Epidemiology Consortium (EAGLE) is a large collaboration of cohorts interested in genetic and early life determinants of childhood phenotypes. I make key contributions using data from ALSPAC and BiB in relation to determinants of cardiometabolic phenotypes and in relation to pregnancy phenotypes.
Collaborator Contribution For projects that I lead partners to the collaborations follow analyses plans if they are contributing to discovery analyses and, where appropriate, help by obtaining new data (e.g. SNP data) and completing analyses for replication.
Impact Formed in 2010 and ALSPAC has been a key contributing discovery cohort (unique in being the only cohort with GWAS in mothers and offspring) from the start. Large number of publications (see EAGLE website)
Start Year 2010
 
Description EAGLE 
Organisation Erasmus University Rotterdam
Country Netherlands 
Sector Academic/University 
PI Contribution Early Genetics and Lifecourse Epidemiology Consortium (EAGLE) is a large collaboration of cohorts interested in genetic and early life determinants of childhood phenotypes. I make key contributions using data from ALSPAC and BiB in relation to determinants of cardiometabolic phenotypes and in relation to pregnancy phenotypes.
Collaborator Contribution For projects that I lead partners to the collaborations follow analyses plans if they are contributing to discovery analyses and, where appropriate, help by obtaining new data (e.g. SNP data) and completing analyses for replication.
Impact Formed in 2010 and ALSPAC has been a key contributing discovery cohort (unique in being the only cohort with GWAS in mothers and offspring) from the start. Large number of publications (see EAGLE website)
Start Year 2010
 
Description EAGLE 
Organisation Harvard University
Department Harvard T.H. Chan School of Public Health
Country United States 
Sector Academic/University 
PI Contribution Early Genetics and Lifecourse Epidemiology Consortium (EAGLE) is a large collaboration of cohorts interested in genetic and early life determinants of childhood phenotypes. I make key contributions using data from ALSPAC and BiB in relation to determinants of cardiometabolic phenotypes and in relation to pregnancy phenotypes.
Collaborator Contribution For projects that I lead partners to the collaborations follow analyses plans if they are contributing to discovery analyses and, where appropriate, help by obtaining new data (e.g. SNP data) and completing analyses for replication.
Impact Formed in 2010 and ALSPAC has been a key contributing discovery cohort (unique in being the only cohort with GWAS in mothers and offspring) from the start. Large number of publications (see EAGLE website)
Start Year 2010
 
Description EAGLE 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Early Genetics and Lifecourse Epidemiology Consortium (EAGLE) is a large collaboration of cohorts interested in genetic and early life determinants of childhood phenotypes. I make key contributions using data from ALSPAC and BiB in relation to determinants of cardiometabolic phenotypes and in relation to pregnancy phenotypes.
Collaborator Contribution For projects that I lead partners to the collaborations follow analyses plans if they are contributing to discovery analyses and, where appropriate, help by obtaining new data (e.g. SNP data) and completing analyses for replication.
Impact Formed in 2010 and ALSPAC has been a key contributing discovery cohort (unique in being the only cohort with GWAS in mothers and offspring) from the start. Large number of publications (see EAGLE website)
Start Year 2010
 
Description EAGLE 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Early Genetics and Lifecourse Epidemiology Consortium (EAGLE) is a large collaboration of cohorts interested in genetic and early life determinants of childhood phenotypes. I make key contributions using data from ALSPAC and BiB in relation to determinants of cardiometabolic phenotypes and in relation to pregnancy phenotypes.
Collaborator Contribution For projects that I lead partners to the collaborations follow analyses plans if they are contributing to discovery analyses and, where appropriate, help by obtaining new data (e.g. SNP data) and completing analyses for replication.
Impact Formed in 2010 and ALSPAC has been a key contributing discovery cohort (unique in being the only cohort with GWAS in mothers and offspring) from the start. Large number of publications (see EAGLE website)
Start Year 2010
 
Description EAGLE 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution Early Genetics and Lifecourse Epidemiology Consortium (EAGLE) is a large collaboration of cohorts interested in genetic and early life determinants of childhood phenotypes. I make key contributions using data from ALSPAC and BiB in relation to determinants of cardiometabolic phenotypes and in relation to pregnancy phenotypes.
Collaborator Contribution For projects that I lead partners to the collaborations follow analyses plans if they are contributing to discovery analyses and, where appropriate, help by obtaining new data (e.g. SNP data) and completing analyses for replication.
Impact Formed in 2010 and ALSPAC has been a key contributing discovery cohort (unique in being the only cohort with GWAS in mothers and offspring) from the start. Large number of publications (see EAGLE website)
Start Year 2010
 
Description EAGLE 
Organisation University of Western Australia
Country Australia 
Sector Academic/University 
PI Contribution Early Genetics and Lifecourse Epidemiology Consortium (EAGLE) is a large collaboration of cohorts interested in genetic and early life determinants of childhood phenotypes. I make key contributions using data from ALSPAC and BiB in relation to determinants of cardiometabolic phenotypes and in relation to pregnancy phenotypes.
Collaborator Contribution For projects that I lead partners to the collaborations follow analyses plans if they are contributing to discovery analyses and, where appropriate, help by obtaining new data (e.g. SNP data) and completing analyses for replication.
Impact Formed in 2010 and ALSPAC has been a key contributing discovery cohort (unique in being the only cohort with GWAS in mothers and offspring) from the start. Large number of publications (see EAGLE website)
Start Year 2010
 
Description Fatty Liver: Inhibition of Progression (FLIP) 
Organisation University Hospitals in Paris
Department Department of Hepatology
Country France 
Sector Hospitals 
PI Contribution We will contribute to understanding of the developmental and genetic causes of NAFLD in adolescence
Collaborator Contribution This collaboration has successfully obtained a large EU FP7 grant. I lead one work-package on the epidemiology of non-alcoholic fatty liver disease in adolescents, with the grant providing funds for a statistician to complete analyses in this area. Together my input and that of all other partners will provide a step change in understanding by determining the causes and consequences of NAFLD across the lifecourse from childhood through to old age.
Impact Successful EU FP7 grant
Start Year 2010
 
Description Radio 4 Inside Science 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Participated in Inside Science radio 4 programme - discussing the value of population cohort studies for understanding causes of disease and how to prevent these
Year(s) Of Engagement Activity 2016
 
Description You-tube video describing the Avon Longitudinal Study of Parents and Children - Generation 2 cohort and its contribution to research 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I produced a you-tube video with ALSPAC study participants and staff who collect data in ALSPAC, to inform a wide range of people about the value of the multi-generational ALSPAC study and the research it has contributed to. We also promoted the importance of population health studies such as ALSPAC in general.
The video can be found here
https://www.youtube.com/watch?v=sQtnmCNgmXI
Year(s) Of Engagement Activity 2019
URL https://www.youtube.com/watch?v=sQtnmCNgmXI