Current Research Projects



1. Association of stool microbial profile with short-term outcome in infants with biliary atresia after Kasai Portoenterostomy

Dr Vandana Jain at King’s College Hospital, London

What is this study looking at?

Biliary atresia (BA) is a disease in children where inflammation within the bile ducts lead to jaundice and liver inflammation. An operation called a “Kasai-Portoenterostomy” (Kasai) can be performed in the first two months of life to “re-plumb” the liver to the gut to restore bile flow between the liver and the gut.

It is thought that microorganisms (such as bacteria, viruses, and fungi) within the gut may have an impact on how serious liver disease in children with BA becomes. The research team will look at the microorganisms inside the guts of children who have had the Kasai at different ages.

The team will then compare which microorganisms are present in the guts of children who have BA but are healthy after the Kasai procedure, those with BA who have the procedure but need a liver transplant afterwards and healthy children without biliary atresia.

Why is this research important?

The impact of microorganisms in the gut has been studied in adults with liver disease and is believed to play a role in adult liver disease. Until now there has been little research into its potential role in biliary atresia. This research will further our knowledge and understanding of whether microorganisms have a role in paediatric liver disease.

What about the future?

It is hoped that we will be able to find out if microorganisms inside the gut play a role in making liver disease worse in biliary atresia, and if so, which ones.

If microorganisms are identified the next step is to find out how to target these bacteria so we can reduce the number of harmful bacteria in the guts of biliary atresia patients. Potential treatments may include antibiotics, diet or probiotics.

 

2. Optimising drug regimens in paediatric liver disease using experimentally-derived simulation tools

Professor Amin Rostami and Dr Jill Barber at the University of Manchester

What is this study looking at?

This research is exploring how medications act in children’s livers including those which a liver disease. Livers vary from person to person and these differences can affect how much of a drug a child should be given. Size of liver is one important variation and another is the level of different enzymes in the liver. The enzymes help different reactions take place in the liver including the breakdown of medications. The research team have developed a way to measure the level of enzymes in livers. They will be looking at livers from children with and without liver disease and comparing the levels of a number of different enzymes.

Why is this research important?

At the moment it is very difficult for doctors to know exactly how much of a drug a child should be given. This means they have to try and estimate dosages based on adult amounts.

What about the future?

The results of this study will feed into a model which will help doctors prescribing medicines to children with liver disease to prescribe the most suitable dose.

 

3. Bilibaby: an ongoing project to develop a screening test to be able to detect bilirubin in stool to screen for childhood liver diseases

Professor Alastair Sutcliffe at King’s College London

What is this study looking at?

This study is looking into ways to identify biliary atresia (BA) in newborns by looking at the stool (poo) of babies born with BA. The researchers have produced a testing stick which can test stool for neonatal cholestasis. The stick changes colour from colourless to pink when no problem is detected with the stool but remains colourless when there is a problem with bile flow.

This funding has been awarded to enable further testing of the stick. Nurses at King’s College London will collect stool samples from all babies with BA over a 6 month period, as well as from other babies to test the accuracy of the stick.

Why is this research important?

At the moment healthcare professionals use their judgement to tell whether or not a stool is a healthy colour or whether it is pale, which could be a warning sign of liver disease. Sometimes this can be difficult as it is a very subjective process. The stick would allow midwives to test all babies’ stool and would tell midwives whether or not the baby may have a problem with their liver due to a reduced bile flow.

What about the future?

If the study is successful the research team will look to develop and produce the testing stick which will help healthcare professionals to identify diseases such as BA in newborns at an early stage in order to improve the outcome for patients with BA.

 

4. New non-invasive serological and virological markers of hepatitis b virus (HBV) – can they help determine future chronic hepatitis b outcomes in children with perinatally acquired HBV infection?

Dr Ivana Carey at King’s College Hospital

What is this study looking at?

Although the recently introduced general HBV vaccination in infancy, efficient screening during pregnancy and adequate management of pregnant HBV positive parents reduces the risk of transmission to the child there still remains a large cohort of paediatric patients contracting this persistent disease. This study is focusing on the impact of HBV infection on liver disease progression and looking into its management to reduce progression to prevent further transmission.

This study is investigating the new markers of HBV proteins (antigens) to monitor paediatric patients with chronic hepatitis b and whether this can predict the progression of liver disease in adolescence or young adulthood. Translating genetic information of the virus into HBV proteins (antigens) were recently discovered and represent very useful non-invasive tool to monitor activity of HBV in blood without needing the liver sample.

The study aims to explore whether any of these markers of viral activity at diagnosis alone or in combination help to predict liver disease progression through enabling more precise diagnostics and whether this can assist in early intervention.

Why is this research important?

Chronic hepatitis b accounts for 1 million deaths yearly and it is a persistent disease contracted in childhood. Despite vaccination, passive immunisation and HBV treatment in pregnancy, 10% of infants of mothers with high viral load still get infected. Understanding the pathways involved in the viral control in children is important to prevent the progression of the disease and reduce the risk of having highly active disease during childbearing age.

What about the future?

If this study is successful it will lead to considering the setup of a national multicentre study focusing on this cohort of patients and their long-term management. This will have a further impact on reducing the risk of transmission and disease burden overall.

 

5.Using Nuclear Magnetic Resonance (NMR) Spectroscopy to understand hepatic lipid metabolism in paediatric NAFLD

Dr Emer Fitzpatrick at King’s College Hospital

What is this study looking at?

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in children and young people (CYP). NAFLD is an overweight/obesity-related condition, but a high body mass index is only one of the factors that determine disease. Certain people are more susceptible to the condition. This is partially determined by genetics, but other influences are likely to also be important. Studying liver tissue (biopsy) is one such way to examine the processes involved in development of disease. However, it is unpleasant and invasive. Given the risks, inconvenience and limitations of studying liver tissue itself, modern imaging techniques can be utilised to look at processes going on in the cells. Once these processes are understood treatments can be targeted to modify them.

This project will look at tiny frozen sections of liver to further evaluate and develop imaging protocols using a technique called nuclear magnetic resonance (NMR) spectroscopy. The study will look specifically at the pattern and the ‘metabolism’ (i.e. uptake, processing and release) of lipids (fats) within the liver cells of a CYP with NAFLD, comparing this with the pattern in their blood and also with liver cells from CYP without NAFLD.

Why is this research important?

NAFLD is estimated to occur in up to 10% of CYP with 3% having evidence of progressive disease. Separating out those who will develop significant liver injury (progressive fibrosis) from those who will not, is not currently possible.

This study will be of value for phenotyping (observing biochemical characteristics) of CYP with NAFLD to decide which groups of patients are most suitable for therapeutic intervention. The data will assist the development of biopsy-free evaluation of liver disease and used to inform studies of novel therapies for NAFLD in CYP.

What about the future?

The hope is that this study will lead to the ability to use NMR to evaluate the patterns of lipids in liver cells of patients with NAFLD in a non-invasive and safe way. This project may also yield results which can be used to develop a planned trial of novel treatment in children and young people with NAFLD. This treatment will be aimed at changing the lipid profile and metabolism of the liver to reduce progression of NAFLD.

 

6. Role of Sarcopenia in Paediatric Non-Alcoholic Fatty Liver Disease

 Dr Eirini (Serena) Kyrana at Leeds Children’s Hospital, Leeds Teaching Hospitals NHS Trust

What is this study looking at?

Muscle wasting, also known as sarcopenia, has for many years been associated with chronic disease including chronic liver disease. It is now clear that sarcopenia can often exist undetected in the presence of obesity and still exert its harmful effects. The prevalence of sarcopenia in paediatric NAFLD and its associated risks are unknown.

This study will assess the body composition of children with non-alcoholic fatty liver disease. This will be done by established, simple, painless methods that require minimal cooperation. The study will aim to identify the relationship between sarcopenia and degree of steatosis, fibrosis and inflammation on liver biopsy and any associations with molecules associated with muscle growth, insulin resistance and liver fibrosis.

Why is this research important?

NAFLD has become the most common paediatric chronic liver disease in industrialised countries and in the United States (in adults) the second leading cause for liver transplantation. NAFLD in children provides a pure model of the disease as children have significantly less additional conditions like heart disease and cancer. Children are also more likely to have a significant benefit from the development of effective interventions. In addition, the benefits for society from treating children, who are carrying this condition into adulthood is also greater. There has been no previous paediatric study, to our knowledge, exploring the association of sarcopenia with increased fibrosis and/or inflammation in the context of NAFLD. No study in children with NAFLD has investigated the various myokines (products released by muscle cells) and adipokines (protein secreted by body fat) in relation to muscle mass. This study would help to generate data that would provide the basis for developing larger multicentre studies looking at the effect of interventions like exercise and even interventions like GDF15 stimulators or myostatin inhibitors when they come into practice.

What about the future?

The long-term goal for this study is to gain insight that will provide the basis of successful interventions and potential treatment strategies in the near future. Successful interventions in childhood would have exponential benefits both for the child and for our society, as NAFLD is a condition carrying significant morbidity and mortality into the future.

 

7. The role of vascular adhesion protein-1 in the pathogenesis of chronic graft hepatitis and fibrosis after paediatric liver transplantation

Dr Steffen Hartleif at Graft Injury Group, Birmingham Children’s Hospital in collaboration with University Hospital Tuebingen

What is this study looking at?

Patient and graft survival after paediatric liver transplantation (pLT) has improved significantly. However, chronic graft hepatitis and fibrosis are common and account for long-term graft injury and graft loss after pLT. Currently, mechanisms of chronic graft hepatitis and fibrosis are incompletely understood and there is no specific treatment. In other liver diseases associated with inflammation and fibrosis, the vascular adhesion protein-1 (VAP-1) plays an important role in immune responses that mediate liver injury. This study looks into whether VAP-1 also drives inflammation in chronic graft hepatitis.

Why is this research important?

As survival after paediatric LT has improved, chronic allograft hepatopathy is likely to play an increasingly important role for late morbidity and potentially also for long-term survival. However, the mechanisms of chronic allograft hepatitis and fibrosis after paediatric LT remain largely unclear. This study will contribute to assess a new pathway of alloimmune response after organ transplantation. If we can confirm an important role for VAP-1 signalling pathways in graft hepatitis and fibrosis, soluble VAP-1 could serve as a novel biomarker. There is great medical need for biomarkers in order to monitor unapparent chronic graft hepatitis and to prevent severe graft fibrosis in children after LT.

What about the future?

If VAP-1 mediated pathways prove to be important in the pathogenesis of late graft inflammation and fibrosis, there may be recommendations and interest in designing a multicentre study to investigate the possibility of implementing therapeutic strategies in children with progressive fibrosis after pLT.

 

For details of all research projects we have previously funded Click Here