Professor Anil Dhawan
2012 - BSPGHAN/Guts UK Award
Title: Body composition and metabolic profile of children with end stage liver disease before and after liver transplant; relations with outcome and cell energy controlling metabolic pathways
Project Start Date: 14 February 2013
Completion Date: 31 January 2017
Children who have end stage liver disease sometimes suffer from a form of wasting known as cachexia. These children can lose weight in the form of both fat and muscle mass. Cachexia is not just the result of poor appetite and malabsorption of nutrients caused by the disease: it is also caused by changes to the way the children’s cells process energy from food (metabolism), resulting in an excess energy use by the cells and ensuing higher energy requirements in these children. The growth and development of these children can be compromised.
Children with cachexia tend to have more complications after their liver transplant. However we are not sure how changes to the body composition and to the energy requirements of children with liver disease affect their clinical outcomes. We are also not sure what changes take place in the cells of those children to cause the excess energy use and resulting fat and muscle loss.
Professor Dhawan and his team received funding from Guts UK and BSPGHAN to investigate these changes in children with end stage liver disease scheduled to receive a liver transplant. The team assessed how the body composition and energy requirements of children with end stage liver disease change before and after liver transplantation. They also compared how these factors differ from those of healthy children.
The team used a number of techniques to calculate the body composition of the children. These techniques (basic anthropometry, stable isotopes, bioelectrical impedance, DXA scan and air displacement plethysmography) can give an estimate of the percentage of fat mass, muscle mass and water content in the children’s bodies. The amount of energy used by these children was assessed by another technique, known as indirect calorimetry. Finally, to understand what changes were taking place within the cells that causes changes in energy requirements, the team took biopsy samples of the liver, the muscle and the fat tissue of the children and examined the cells obtained from these samples.
The body composition, growth and energy requirements of children enlisted in the study were assessed before and at 6 months after their liver transplant. Those children who still had high energy requirements at 6 months were assessed again 1 year after their transplant. Additionally, these factors were compared between children with liver disease and healthy children, who acted as controls in the study.
The researchers also examined the liver, muscle and fat tissue obtained from the children at the time of their liver transplant. They measured the level of activity of genes involved in how cells process energy. In particular they were interested in genes involved in obtaining energy from nutrients such as fats and sugars, as well as genes involved in how muscle and fat tissue build up.
The analyses the researchers found that children awaiting liver transplantation show loss of muscle mass, as well as higher levels of water retention. However, their fat mass was relatively normal. This is important as the researchers also showed that children with more fat mass had a shorter stay in hospital after their transplant.
When the researchers examined the tissue samples from the liver, fat and muscle biopsies, they noted that a small group of children displayed changes in the activity of genes associated with the development of insulin resistance. Insulin resistance is a metabolic disturbance that can lead to diabetes and is linked to the preservation of fat mass. The researchers propose that in these children insulin resistance might be responsible for the maintenance of their fat stores and, arguably, could be a defence mechanism in children with liver disease. Their work shows the importance of ensuring children with end stage liver disease are adequately nourished before they receive their transplant.
This was a pilot study and the researchers plan to examine the tissue samples in more detail, to shed more light on the genetic and molecular mechanisms involved in the changes in body composition of these children. This might allow them to, in the future, manipulate these mechanisms in a way that is beneficial to the children.