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

终身身体状况的影响很少局限于一个器官。对大脑发育以及随后的教育、就业和心理健康结果的影响在很大程度上被忽视了。为了有所作为，我们需要了解我们的患者在他们的生活过程中所经历的困难。儿童肝病是一个日益严重的健康问题，每年有1000多名儿童被确诊。虽然慢性肝病儿童的存活率随着时间的推移而有所改善，部分原因是肝移植的成功，但我们的患者可能会延迟他们的发育，30%的患者需要在学校得到特别支持。青春期是一个充满挑战的时期，青少年更喜欢有心理健康问题，难以服药，成年后很难培养独立管理自己状况的技能。这对他们的结果产生了影响，我们知道，与年轻和老年群体相比，他们的结果更糟糕。柳叶刀委员会宣布这种健康不平等是不可接受的，患者和父母希望我们更多地关注精神和社会健康。儿童肝病基金会是该项目的完全合作伙伴。导致慢性肝病儿童发育和心理健康问题的机制尚不清楚。肝脏是至关重要的；它调节荷尔蒙、新陈代谢和血液凝固等。它还有助于清除血液中的毒素。我们知道，这一过程中的任何干扰都会导致注意力和警觉性等大脑功能出现问题。在某些肝脏疾病中，由免疫系统驱动的炎症过程可能会加重肝脏疾病。有趣的是，炎症过程还与患上终生神经发育精神障碍的风险有关，如注意力缺陷多动障碍(ADHD)、自闭症、焦虑和情绪障碍。因此，免疫系统可能在导致儿童肝病和神经发育障碍的持续肝损伤中发挥作用。我们热衷于更详细地研究这一点。最后，负责青春期发育的荷尔蒙也调节青春期大脑结构和功能的变化。我们现在知道，这个过程将持续到25岁。这个项目将试图理清影响慢性肝病儿童和年轻人大脑发育的多种机制，并试图通过这样做来为我们的患者找到改善结果的机会。我们计划邀请72名11-24岁的肝病青少年参加。我们将进行核磁共振扫描，以观察大脑的结构、功能和大脑中的化学反应。凭借我们的合作者McAlonan教授和她的团队的经验，我们将能够比较患有肝病的儿童和青少年与有/没有其他健康状况的儿童和青少年的大脑成熟情况。我们还将通过进行一系列的发育评估来调查MRI扫描的结果与他们的发育和心理健康的关系。最后，我们热衷于通过观察肝病、炎症和青春期发育的标志物、血液和尿液测试以及超声波扫描，来探索肝病的严重程度对大脑成熟的影响。我们认为，常规筛查和及时发现与整体发育相关的问题，以及更好地了解可能与此相互作用的因素(如肝毒素、激素和免疫机制)，将有助于确定新的治疗目标和干预方法。这可能会改变患有儿童期肝病的儿童和青少年的生活质量，并优化他们在教育、就业和心理健康方面的长期结果。

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.