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

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.

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