Clinical-Res-Project3

项目3 -摘要/摘要 导致肝衰竭的肝细胞损伤、肝纤维化和肝硬化已在文献中描述 尿素循环障碍（UCD）患者亚组。此外，还有肝功能异常的报告 在几种疾病的高氨血症急性发作期间，包括鸟氨酸转氨甲酰酶 缺乏症（OTCD），UCD中有肝细胞癌的单一病例报告。共同 UCD患者肝脏的组织病理学表现包括肝细胞增大， 糖原沉积和脂肪变性。然而，没有长期监测的建议， 慢性肝脏并发症虽然使用血清转氨酶和合成功能的标记物 为了监测肝病，这种检测肝病进展的测定法的灵敏度很低。 最近，肝纤维化的几种非侵入性生物标志物，包括血清生物标志物组和 各种形式的弹性成像已被证实可用于预测患有各种疾病的患者的纤维化程度 慢性肝病的症状在这个项目中，我们建议使用这些非侵入性工具来评估范围， 肝病患病率在一个大型队列的个人与UCD。来自UCD纵向研究的数据， 尿素循环障碍联盟（UCDC）项目1显示，慢性肝细胞损伤的风险是 远端UCD较高（例如，瓜氨酸琥珀酸裂解酶缺乏症- ASLD、瓜氨酸血症-ASS 1D和瓜氨酸酶 缺乏-ARG 1D）与OTCD（一种近端UCD）相比。我们假设，肝纤维化，如测量 非侵入性生物标志物，也是远端UCD的重要和被低估的并发症， 脂肪变性和糖原积累是肝病的病因。为了验证这个假设，我们 将比较ASS 1D、ASLD和ARG 1D与OTCD个体的纤维化血清生物标志物， 将测试纤维化血清生物标志物的升高是否与肝硬度相关， 磁共振弹性成像（MRE）。最后，我们将组织病理学评分纤维化阶段和脂肪变性 对两例UCDC肝移植的肝组织和肝活检组织中的糖原含量进行分级和定量 中心，以确定这些并发症在UCD的患病率。总的来说，这将是最大的， 在UCD肝病的综合研究。这项研究将使我们了解自然历史， UCD中的肝脏疾病，为开发新的生物标志物评估肝脏疾病提供基础， UCD，并验证未来可用于评估干预措施有效性的终点。 预防和/或治疗UCD中的肝脏疾病。

PROJECT 3 - SUMMARY/ABSTRACT Hepatocellular injury, hepatic fibrosis, and cirrhosis leading to liver failure have been described in a subset of patients with urea cycle disorders (UCD). In addition, there are reports of abnormal liver function during acute episodes of hyperammonemia in several disorders, including ornithine transcarbamylase deficiency (OTCD), and there are single case reports of hepatocellular carcinoma in UCD. Common histopathologic findings in the liver of individuals with UCD include hepatocyte enlargement, increased glycogen deposition, and steatosis. However, there are no recommendations for long-term surveillance for chronic hepatic complications. Although serum aminotransferases and markers of synthetic function are used to monitor hepatic disease, the sensitivity of such assays to detect progression of liver disease is low. Recently, several non-invasive biomarkers for liver fibrosis including serum biomarker panels and various forms of elastography have been validated for predicting the degree of fibrosis in patients with a variety of chronic liver diseases. In this project, we propose to use these non-invasive tools to assess the extent and prevalence of liver disease in a large cohort of individuals with UCD. Data from the Longitudinal Study of UCD, Urea Cycle Disorders Consortium (UCDC) Project 1, show that the risk for chronic hepatocellular injury is higher in distal UCD (e.g., argininosuccinate lyase deficiency – ASLD, citrullinemia – ASS1D, and arginase deficiency - ARG1D) compared to OTCD, a proximal UCD. We hypothesize that liver fibrosis, as measured by non-invasive biomarkers, is also a significant and underestimated complication of distal UCD and that both steatosis and glycogen accumulation contribute to the etiology of the liver disease. To test this hypothesis, we will compare serum biomarkers for fibrosis in individuals with ASS1D, ASLD, and ARG1D vs. OTCD, and we will test whether elevation in serum biomarkers for fibrosis correlate with liver stiffness as measured by magnetic resonance elastography (MRE). Lastly, we will histopathologically score fibrosis stage and steatosis grade, and quantify the glycogen content in hepatic explants and biopsies from two UCDC liver transplant centers in order to determine the prevalence of these complications in UCD. Overall, this will be the largest, comprehensive study of liver disease in UCD. This study will inform our understanding of the natural history of liver disease in UCD, provide the basis for the development of new biomarkers for assessing liver disease in UCD, and validate endpoints that could be used in the future to assess efficacy of interventions for the prevention and/or therapy of liver disease in UCD.