Sara Mancell of King’s College London and King’s College Hospital NHS Foundation Trust discusses her research and what it means for the nutritional management of children with biliary atresia.

Background:

Biliary atresia (BA) is a rare liver disease of the bile ducts. As bile from the bile ducts is needed to digest fat, babies with BA may not absorb enough fat and can become malnourished. To help prevent malnutrition and help babies to grow, medium-chain fat is given as an energy source. Medium-chain fat is a special fat that can be absorbed even when there is no bile available. It is incorporated into specialist formula milks and can also be added separately to formula milk or to expressed breast milk as an oil.

Even though medium-chain fats are used widely in the NHS there is no agreement on how much to give. Babies are given anywhere from 30% to 75% of their total fat intake as medium-chain fat with the remainder being regular fat.

This study involves giving babies with biliary atresia either low or high amounts of medium-chain fat for six weeks in the period after kasai portoenterostomy surgery. This will be done by adding a small amount of either regular fat (from safflower oil) or medium-chain fat (from coconut oil) to specialist formula milk. We will monitor weight, intake of formula milk and feeding tolerance during the study.

Why is this research important?

There has been little research on medium-chain fat supplementation in children with liver disease. This research will increase our understanding of medium-chain fat supplementation and provide the basis for developing a larger multicentre study.

What about the future?

Our aim is to carry out a future trial comparing growth and outcomes in babies receiving different amounts of medium-chain fats. This could improve the nutritional management and outcomes not just for children with biliary atresia but for all children with liver disease given medium-chain fat supplementation.

The post Medium-chain fat supplementation and growth in infants with biliary atresia appeared first on Childrens Liver Disease Foundation.

Joint CLDF and BSPGHAN Project Grant

Dr Vandana Jain of King’s College London shared updates on her research project with CLDF and what it means for the future of treating biliary atresia.

Background

Biliary Atresia is a liver disease that presents in babies, involving the blockage of bile ducts, associated with life-long complications. A surgical procedure, called the Kasai, is needed to try and unblock these ducts. However, a large proportion of patients still have complications and require a liver transplant. Despite plenty of ongoing research into this condition, no treatment/medication has managed to reduce the rate of complications or the number of liver transplants.

Over the last few decades research has shown that the bacteria in the gut can affect your health and has been associated with childhood diseases such as inflammatory bowel disease and asthma. Importantly, the bacteria in the gut have been shown to affect certain adult liver diseases, which show similarities to biliary atresia.

Encouraging results regarding gut-bacteria related treatments in adult liver disease have been demonstrated.

In view of these findings, this study aims to explore the gut bacteria in biliary atresia, with the intention to find gut bacteria-related treatments, which could improve the outlook for these patients.

Findings

Our initial results have shown that there is a difference in the overall composition of the gut bacteria in babies with biliary atresia compared to healthy babies. One bacteria called ‘bifidobacterium’ is much lower in those with biliary atresia.

This difference is seen before the Kasai operation, but also at several timepoints after the operation.

This questions whether we could investigate ways to change the gut bacteria in biliary atresia babies so that it matches that of healthy babies. For example, by increasing the ‘bifidobacterium’ content and see what effect this has on disease.

Potential next steps

Potential next steps could include a trial involving Bifidobacterium supplementation after the Kasai operation to see if this improves the outlook for these children by potentially reducing complications such as portal hypertension and cirrhosis (scarring) and with it time to transplant.

This area of research is still in the early stages but we hope to hear more about the link between Bifidobacterium and biliary atresia and the impact this may have on future treatments.

The post Biliary Atresia Research Update appeared first on Childrens Liver Disease Foundation.

As part of the process of approving new treatments available on the NHS, further insight is needed into the experiences of partial external biliary diversion (PEBD). This is the drain that some children need to prevent a build-up of bile acids.

CLDF are calling on any families who have a child or teenager with a PEBD (or who has had a PEBD in the past) and also have a diagnosis of PFIC to see if they would be willing to take part in a 30 minute interview with a researcher from Acaster Lloyd Consulting Ltd – a research consultancy. During the interview you would be asked questions about how your child is able to cope with their PEBD and any problems that they experience. After that you will be asked to rate some descriptions of patients with liver disease. None of the questions would be intrusive and if there were any questions you didn’t want to answer then that’s fine. Parents will be offered a small payment as a thank you for your time.

We are aware that the process involved in being part of the earlier Burden of PFIC study was somewhat problematic. We can assure you that this will be easier to take part in.

The process is very simple if you would like to take part:

1. Email Harpreet Brrang (Information and Research Hub Manager) at irhm@childliverdisease.org
2. We will send your email and your first name on to the contact at Acaster Lloyd Consulting
3. The company will be in touch via email to book a time for the discussion and answer any initial questions
4. They will also send you further information about what they hope to discuss as well as a copy of the questions if requested

If you have any queries please don’t hesitate to get in touch via Harpreet’s email above. There is a short turnaround for this so please get in touch as soon as possible.

We hope you choose to take part as it will allow us and others in this field to provide greater evidence when sharing your voice with stakeholders such as the NHS and The National Institute for Health and Care Excellence (NICE) .

The post Calling parents of children who have undergone a PEBD appeared first on Childrens Liver Disease Foundation.

Institution – University of Manchester

Background

In proteomics research, we quantify all the proteins, including the proteins that metabolise (change into a form that can used by your body) and transport drugs in a tissue of interest.

We can use this information to build computer-based avatars (also known as virtual twins) representing patients or groups of patients. Virtual clinical trials can be conducted on these avatars in circumstances where it would be unethical or impractical to perform trials on patients. These trials normally relate to dose-adjustment, and might include, for example, determining the best dose of pain medication for children with biliary atresia.

In this project, we set out to understand how the proteins that metabolise and transport drugs in the livers of biliary atresia patients differ from those of healthy children.

It is impossible to obtain liver tissue from very young healthy children, but we can obtain it from children who have died from factors other than liver disease. Children with biliary atresia typically undergo a surgical procedure (the Kasai procedure) at a very young age which yields small amounts of liver tissue that can be used for research. Thus, we have been able to compare the protein profiles of 25 patients with biliary atresia to 22 children with no liver disease.

Findings

The analysis has shown that, in general terms, biliary atresia results in a child’s liver failing to develop a mature enzyme profile. This means that many drugs cannot be metabolised normally and the implications will vary from drug to drug.

We have shown that the enzyme responsible for paracetamol toxicity (cause of side effects when taking large doses) is much reduced in biliary atresia which may allow larger doses of this drug to be given safely than in healthy infants. However, there are also several drugs transporters which are present at relatively high concentrations in biliary atresia. The significance of this finding is not yet clear; it may reflect the body attempting to compensate for the disease.

There have been five scientific articles resulting from this research so far.

Possible next steps

Next steps include building virtual twins of biliary atresia patients, and conducting virtual clinical trials, particularly of the effect of paracetamol on biliary atresia patients. Potential patient benefits are in dose adjustment. We would expect some drugs to require lower doses in biliary atresia patients, but paracetamol may be tolerated at higher doses, allowing more effective pain medication. This needs to be tested. It is also possible to quantify other proteins of interest using the data collected, and to determine whether other metabolic pathways are affected by biliary atresia. The data has been deposited in a public repository, where it is available for future research.

The post Research Update – Optimising drug regimens in paediatric liver disease using experimentally derived simulation tools appeared first on Childrens Liver Disease Foundation.

We’re calling on our wonderful parents and young people to support us in sharing patient experience during a paediatric cholestasis workshop to be held virtually on 12th May.

If you are a parent or a young person affected by a Biliary Atresia, PFIC, Alpha 1 Antitrypsin Deficiency and Alagille Syndrome diagnosis, keep reading to find out what this entails and how you can participate.

We would like parents/young people to record a 3-4 minute video about the following:

1. Parent of a toddler (aged 2-3) who is currently experiencing pruritus – to discuss how this impacts you, your child and your family.
2. Parent of a child who has previously been impacted by pruritus and has been part of a clinical trial – to discuss how this impacted you, your child and family as well as your experience of clinical trials (e.g. what made you decide to take part and the importance, positives, negatives, what you would say to other parents in that situation, and any improvements you would suggest for trials).
3. A young person (16-25) who has previously been impacted by pruritus and can talk about the effect it had on them.

We would like one representative to attend the session live so that you can engage with the audience alongside Alison Taylor, our Chief Executive. This session will take place between 15.15 – 15.30 on 12th May 2021.

The meeting is organised by British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) and European Reference Networks (ERN). The virtual meeting will bring together colleagues and professionals from around the globe.

If you would be interested in providing your experience, please contact Harpreet (Information and Research Hub Manager) by emailing irhm@childliverdisease.org or calling 0121 212 6029. When contacting, please share which category (1,2 or 3 as indicated above) you would like to be a representative for.

The post Call for parent and patient voices and experiences appeared first on Childrens Liver Disease Foundation.

Establishment – University of Cambridge

Dr Jake Mann provides an update on his research study and what it means for the future of testing for paediatric fatty liver disease.

Background:

Fatty liver (also known as NAFLD) is the most common cause of abnormal liver blood tests in children in the UK. The majority of children do not have severe fatty liver but a small proportion might get liver inflammation or scarring (fibrosis) due to the build-up of fat. Currently the main way to test if there is scarring in children with fatty liver would be by doing a liver biopsy. However, this is quite a big procedure so we would like to find more simple tests that can avoid needing a biopsy.
In this research we aimed to use several different blood tests to see if they could give us the same information as a biopsy. We used two specialist research tests: ‘lipidomics’, which measures hundreds of different fats in the blood; and the ‘ELF test’, which tests three specific chemicals in the blood. We also used several genetic tests that have been said to be important in adults with fatty liver.

Findings:

We used blood samples from over 300 children, some of whom had fatty liver and some whom didn’t have liver disease and ran the lipidomics tests. We found that some patterns of fats did seem to be linked to more severe liver disease. This is an important finding as it gives hope that a test like this could be used instead of performing biopsies.

Whereas the ELF test did not seem to work so well in showing who had fibrosis and who didn’t, from the samples we had.

We also found that the majority of the genetic changes that are linked to severe fatty liver in adults are also linked to more severe fatty liver in children. This is really important for our general understanding of fatty liver in children.

Two scientific papers have been published as a result of this study with two further papers currently under review.

Next Steps:

The next step will be to check that the same results can be found in a separate group of children with fatty liver, ideally by a separate group of researchers. This ‘validation’ is really important to make sure the results are accurate. We hope to set up a big study across Europe to help us do this.

The post Identification of biomarkers in paediatric fatty liver disease appeared first on Childrens Liver Disease Foundation.

Children’s Liver Tumour European Research Network is an international research project with the aim to cure more children with liver cancer. It is linked to one of the largest clinical (PHITT) trial, with partners in Europe and with associate partners in USA (Cancer Oncology Group) and Japan (Japan Children Cancer Group).

The aim of the ChiLTERN’s Public Advisory Group is to reach out and share lived experiences with parents, carers and families of children and youth with liver cancer. Since its inception in 2018, the activities that ChiLTERN’s Public Advisory Group has undertaken has grown from strength to strength. In the current health crisis, we continue to meet virtually to promote active involvement, participation and involvement with other parents to share valuable knowledge and expertise based on their own experiences. What started as a small group of parents and patients based in the United Kingdom, we now have parents/patients in the Netherlands, Spain and the USA. It is our hope that the work we do will help parents in similar situations.

ChiLTERN has circulated a survey to gain a better understanding of how parents and carers felt about their child’s treatment and where applicable about their child being treated on a clinical trial. Whilst we are aware that liver cancer in the paediatric population is rare, we are hopeful that a sizeable response of at least 30 participants is achievable.

As part of co-producing in research, ChiLTERN Public Advisory Group has produced three short mini videos, each for nursery, primary and secondary schools to increase awareness of high frequency hearing loss due to cisplatin. These videos can used by schools, especially by Special Education Needs teachers, on how they can effectively support a child in the classroom to better integrate and participate fully once the child has completed their treatment.

These videos are not specified to just liver cancer. It can used as a support for any child/youth who has a hearing loss from cancer treatment. It is our hope that these videos will create a wider impact as they can also be used by children who have had osteosarcoma, neuroblastoma, medulloblastoma or malignant germ cell tumour who also received cisplatin and have acquired hearing loss. More importantly, other children watching these videos would also be able to relate and understand a little bit more about the children who have high frequency hearing loss. These videos are made possible by the kind contribution of Fennec Pharmaceuticals.

Additionally, we have also produced patients’ stories on ChiLTERN’s website. We are very keen to hear from other parents as well – either in the UK or beyond. Our latest efforts involve working with parents/carers groups in the USA (Jack’s Angels Foundation and Momcology) which has a well-established network of parents from all over USA, Europe and beyond. It is our hope that these efforts will lend itself to further contribution from parents and patients into research and helping parents and patients with liver cancer or any other cancer.

Read Olaf’s story

To find out more and get involved, please contact Mrs Norihan Mohd-Taib via email n.mohdtaib@bham.ac.uk.

Video Resources

The post Children’s Liver Tumour European Research Network (ChiLTERN) appeared first on Childrens Liver Disease Foundation.

Are you the caregiver of a child with PFIC and live in US, UK, France or Germany?

If yes, the PICTURE study would love to hear from you!

Together with leading specialists and member organisations the PICTURE study aims to understand the disease burden upon patients, their caregivers and from a socio-economic perspective. This is hoped to be achieved by providing the very individuals living with and caring for those with PFIC 1 or 2, the opportunity to have their direct input into the study.

This study hopes to:

• provide evidence of patient need to support development of future treatments.
• back up calls for support and awareness for how those with rare childhood liver conditions are impacted on a daily basis.

REGISTER HERE 

In recognition of this invaluable input £30 remuneration will be provided to you or a member organisation of your choice. At the end of the survey you will be redirected to a page to submit your preference for payment.

The process:

• Follow the link above to be directed to the study registration page.
• You will then be sent a separate invite for the specific survey via email (please check your junk email). Alternatively, you can also log into your M3 profile and find the study on your dashboard. Please note there may be a delay in receiving the invite (both via email and on your dashboard) if details are submitted outside of normal working hours.

For any general queries contact research-hub@childliverdisease.org. For technical queries regarding the survey contact MAfonso@m3global.com.

The post The PICTURE Study Calls on PFIC Parents appeared first on Childrens Liver Disease Foundation.

Naomi Richardson and Professor David Wraith provided an update on their study funded by a CLDF PhD fellowship grant:

Background:

Antigen-specific immunotherapy (ASI) can re-instate immune tolerance by ‘re-educating’ the immune system. ASI is now an established treatment approach for a number of allergies, including peanut, insect sting, grass pollen and cat allergies. ASI has also been translated to autoimmune disease clinical trials in multiple sclerosis and Graves’ disease, which have shown disease-modifying effects of treatment. Professor David Wraith, the primary supervisor on this PhD project has been a pioneer in this area of research for over 30 years.

This project is the first application of ASI to Autoimmune Hepatitis (Type 2) in the hope that this will lead to a potential new treatment option. Patients diagnosed with AIH-2 have a severe and progressive form of liver disease driven by the immune system targeting the body’s own liver tissue. AIH-2 is more commonly diagnosed in children or young adults and is less likely to be sufficiently controlled using immunosuppressive drugs. AIH-2 patients possess immune responses against a key liver protein, CYP2D6, which contributes to chronic and persistent liver damage.

Findings:

To develop a new treatment approach to specifically ‘switch off’ cells targeting liver protein CYP2D6, we investigated the interaction between CYP2D6 and T cells (an essential part of the immune system).

By measuring how much T cells are activated from different individuals, we have learned which specific parts of the protein (peptides) are responsible for stimulating the immune system. It is likely that these play a significant role in AIH-2 disease.

We compared T cell activation patterns between three patient groups: AIH-2 paediatric, AIH-2 adult, AIH-1 adult and healthy blood donors. This revealed two key peptide regions of CYP2D6 which were significantly more potent activators of T cells from the AIH-2 groups. Interestingly, our work also discovered a previously unidentified activatory CYP2D6 peptide region from AIH-1 patients.

We have then further refined these regions to their smallest possible components, T cell epitopes. Previous work from members of the Wraith lab group have determined that when T cell epitope peptides are delivered to T cells in a tolerance-inducing setting, these disease-driving immune cells in fact become deactivated and are no longer able to generate autoimmune disease.

We hope to provide further updates as we learn more. 

The post T cell epitopes for the development of biomarkers and novel therapeutics in autoimmune hepatitis type 2 (AIH-2) appeared first on Childrens Liver Disease Foundation.

Establishment – University of Oxford

Dr Deborah Gill provides an update on her research study and what it means for the future of treating childhood liver disease.

Background:

We aim to treat paediatric liver diseases caused by genetic mutations (such as alpha-1 antitrypsin deficiency or Wilson’s disease) using gene therapy. Traditional gene therapy approaches deliver a new, functional copy of the gene to liver cells.

This approach is problematic for paediatric liver disease because as the liver grows, and the treated liver cells divide, the new gene is eventually lost. Instead, we proposed to use genome editing to facilitate the precise insertion of a functional copy of the gene into the DNA of a patient’s liver cells. This approach has the potential for that gene to function for the lifetime of the patient.

Findings:

The main outcome of this work was the successful establishment of the liver organoid model in our lab for the investigation of liver gene editing and gene therapy approaches to liver disease.

We have demonstrated that our genome editing approach can work in human liver cell lines. We also hope to reproduce this work in small artificial livers (known as liver organoids) and in mouse disease models. This work is important because there is currently no definitive cure for AAT deficiency and many other liver diseases.

Two scientific articles have been published as a result of this study so far.

Next steps:

Funding was also used to breed and characterise two mouse models so that we can combine our genome editing strategy with our viral delivery method. This is ongoing. Ultimately, we aim to assess the efficacy, safety and therapeutic applicability of our genome editing platform for the treatment of paediatric genetic liver diseases.

The post Genome editing of liver organoids for treatment of alpha-1 antitrypsin deficiency. appeared first on Childrens Liver Disease Foundation.