How does chronic liver disease in infancy and childhood alter brain maturation?

The impact of lifelong physical conditions is rarely restricted to one organ. The effect on brain development - and subsequent education, employment, and mental health outcomes - has largely been neglected. To make a difference, we need to understand the difficulties our patients experience during the course of their life.
Children's liver diseases are a growing health problem with over 1000 children a year being diagnosed. Whereas the survival of children with chronic liver disease has improved over time, in part due to the success of liver transplantation, our patients are likely to have a delay in their development with 30% requiring special support at school. Adolescence is a challenging period and adolescents more like to have mental health problems, struggle with taking their medications and finding it difficult to develop the skills to manage their condition independently as adults. This is impacting on their outcomes, which we know are worse compared to younger and older age groups. The Lancet commission declared this health inequality 'unacceptable' and patients and parents want us to pay more attention to mental and social well being. The Children's Liver Disease Foundation is a full partner in this project.
The mechanisms causing developmental and mental health problems in children with chronic liver disease are not well understood. The liver is vital; it regulates hormones, metabolism and blood clotting amongst others. It also helps with clearing toxins from the blood. We know that any disruption in this process will lead to problems with brain functions such as concentration and alertness. In certain liver conditions an inflammatory process, driven by the immune system, can worsen the liver disease. Interestingly, inflammatory processes have also been associated with a risk to develop lifelong neuro-developmental-psychiatric difficulties, such as Attention-Deficit-Hyperactivity Disorder (ADHD), autism, anxiety and mood disorders. It is therefore possible that the immune system plays a role both in causing ongoing liver damage in childhood liver diseases as well as neuro-developmental difficulties. We are keen to look into this in more detail. Finally, hormones, responsible for pubertal development also regulate structural and functional brain changes occurring during adolescence. We now know that this process continues up to 25 years of age.
This project will try to untangle the multiple mechanisms influencing brain development in children and young people with chronic liver disease and by doing so trying to find opportunities to improve outcome for our patients. We are planning to invite 72 adolescents with liver disease aged 11-24 years to take part. We will carry out an MRI scan to look at the brain structure, function and chemical reactions in the brain. With the experience of our collaborators, Professor McAlonan and her team, we will be able to compare the brain maturation in the children and adolescents with liver disease with children and adolescents with/without other health conditions. We will also investigate how the findings on the MRI scan relate to their development and mental health by doing a series of developmental assessments. Finally, we are keen to explore how the severity of the liver disease impacts on brain maturation by looking at markers of the liver disease, inflammation and pubertal development with blood and urine tests, and ultrasound scan.
We believe that routine screening and timely detection of problems related to overall development as well as a better understanding of factors that might interact with this (e.g. liver toxins, hormones and immune mechanisms), will help to identify new treatment targets and intervention approaches. This could bring about a change in the quality of life of children and adolescents with childhood liver disease and optimising their long-term outcomes with regard to education, employment and mental health.

Design: exploratory study with recruitment of 72 adolescents from our clinical service to acquire a brain MRI and characterise their cognitive and behavioural phenotype.
Methods
i) MRI overview: Because different measures are sensitive to distinct neurodevelopmental processes, with specific spatial and temporal patterns of development over childhood and adolescence, structural [volumetric and microstructure (DTI)], functional MRI and Magnetic Resonance Spectroscopy (MRS) for brain chemistry will be acquired. First-pass analyses will examine the extent to which there are volumetric and microstructural differences between adolescents with chronic liver disease and the normative data obtained from the reference cohort; because these indices have already been shown to predict cognitive and adaptive outcomes.
ii) Cognitive and behavioural measures: These will include the Vineland Adaptive Behaviour Scales and the Wechsler Intelligence Scale for Children (WISC) as primary measures for first pass analyses. Standardized and validated categorical diagnostic outcomes (e.g. ADHD, ASD, Anxiety and Mood disorders), clinical and continuous outcome measures (neurodevelopmental and psychiatric traits) including socio-emotional, intellectual and executive skills (age-appropriate) will also be recorded to support secondary analyses. We will examine whether individual deviations in brain maturation are correlated with IQ and adaptive outcomes measures initially, before moving to investigate finer-grained outcomes.
iii) Mechanistic variables: including liver function indices, markers of pubertal development and inflammatory status. Our first pass analyses will examine whether individual deviations in brain maturation are correlated with validated indices of liver disease and/or pro-inflammatory cytokines. For secondary analysis, detailed indices of liver function (biochemistry, haematological, hormonal), ultrasound scan and fibroscan will be accessed for analysis.