Hepatic Fibrogenesis in Paediatric Cholestatic Liver Disease.

儿童肝脏疾病对寿命和生活质量造成重大影响。儿童肝病最常见的原因是胆汁淤积，或与胆汁流出肝脏受阻有关的疾病。在我们刚刚开始了解的方式中，胆汁流动的阻塞刺激肝脏瘢痕形成，如果不治疗，会导致正常肝脏组织的替代，最终导致肝脏衰竭。在婴儿中，最常见和最严重的胆汁淤积性肝病是胆道闭锁。它在出生时或出生后不久发展，伴随着负责将胆汁从肝脏中运输出来的胆管的进行性破坏。如果没有早期诊断和手术，这些婴儿会发展为进行性肝瘢痕形成，导致肝功能衰竭和死亡或在1-2年内进行肝移植。这是西方世界儿童肝移植的最常见原因（55-60%）。即使手术成功，大多数（如果不是所有）患者也会在随后的25年内接受肝移植，因为疤痕形成持续但较慢。在年龄较大的儿童中，囊性纤维化等疾病会导致胆管阻塞，导致进展缓慢且不可预测的肝脏瘢痕形成，导致高达20%的患者健康状况不佳，5%的患者死于终末期肝病或肝移植。使用来自患有这两种疾病的儿童的肝脏组织，我们已经能够识别控制肝脏瘢痕过程的关键细胞，即肝星状细胞。我们现在需要研究胆汁成分在这两种疾病的瘢痕形成过程中的作用。我们将利用一个充分表征的动物模型来研究胆汁成分对从该模型中分离的细胞的影响，并将这些发现应用于患者样本，以确定它们在儿科胆汁淤积性肝病中的作用。这将有助于我们更好地了解疾病过程，更重要的是，开发更有效和更早的治疗方法。

Liver disease in children causes a significant impact on lifespan and quality of life. The commonest causes of liver disease in children are cholestatic, or diseases related to obstruction of bile flow out of the liver. In ways we are only beginning to understand, obstruction of bile flow stimulates liver scar formation which, if untreated, leads to replacement of normal liver tissue and ultimately to failure of the liver. In infants, the most common and serious cholestatic liver disease is biliary atresia. It develops at, or shortly after birth with progressive destruction of the bile ducts, responsible for transporting bile out of the liver. Without early diagnosis and surgery these infants develop progressive liver scarring leading to liver failure and death or liver transplantation within 1-2 years. It is the commonest reason for liver transplantation in children (55-60%) in the Western world. Even with successful surgery, most, if not all patients will come to liver transplantation over the subsequent 25 years because of ongoing, but slower, scar formation. In older children, diseases like cystic fibrosis cause bile duct blockages leading to progressive liver scarring that is slower and unpredictable, contributing to ill health in up to 20% of patients and death from end stage liver disease or liver transplantation in 5%. Using liver tissue from children with these two disorders we have been able to identify the key cells that control the liver scar process, the Hepatic Stellate Cell. We now need to investigate the role of bile constituents on the scar-forming process in these two diseases. We will utilise a well characterised animal model to investigate the influence of bile constituents on cells isolated from this model and apply these findings back to patient samples to determine their role in paediatric cholestatic liver disease. This will help us to better understand the disease process and importantly, develop more effective and earlier treatment.