Clinical-Res-Project3

项目3--摘要/摘要 肝细胞损伤、肝纤维化和导致肝功能衰竭的肝硬变已在一项 尿素循环障碍(UCD)患者的亚组。此外，还有肝功能异常的报道。 在包括鸟氨酸转氨酶在内的几种疾病的高氨血症急性发作期间 缺乏症(OTCD)，在UCD有肝细胞癌的单一病例报告。普普通通 UCD患者肝脏的组织病理学表现为肝细胞增大、增多 糖原沉积和脂肪变性。然而，没有关于长期监测的建议 慢性肝脏并发症。尽管使用了血清转氨酶和合成功能标记物 为了监测肝病，这种检测方法检测肝病进展的灵敏度很低。 最近，几种非侵入性肝纤维化生物标志物，包括血清生物标志物面板和 各种形式的弹性成像已经被证实可以预测不同类型的患者的纤维化程度。 慢性肝病。在这个项目中，我们建议使用这些非侵入性工具来评估 肝病在一大群UCD患者中的患病率。来自UCD纵向研究的数据， 尿素循环紊乱联盟(UCDC)项目1表明，慢性肝细胞损伤的风险是 远端UCD较高(例如精氨酸琥珀酸裂解酶缺乏症-ASLD、瓜氨酸血症-ASS1D和精氨酸酶 缺乏-ARG1D)与OTCD相比，OTCD是一种近端UCD。我们假设肝纤维化，通过 非侵入性生物标志物，也是远端UCD的一个重要且被低估的并发症，而且两者 脂肪变性和糖原积聚是肝病的病因。为了检验这一假设，我们 将比较ASS1D、ASLD和ARG1D患者与OTCD患者的血清纤维化生物标志物，我们 将测试血清纤维化生物标记物的升高是否与肝脏硬度相关，通过 磁共振弹性成像(MRE)。最后，我们将对纤维化分期和脂肪变性进行组织病理学评分。 分级，并量化两个UCDC肝移植肝组织和活检组织中的糖原含量 以确定这些并发症在UCD中的患病率。总体而言，这将是最大的， UCD中肝脏疾病的综合研究。这项研究将有助于我们理解地球的自然历史 UCD中的肝病，为开发新的生物标志物评估UCD中的肝病提供了基础 UCD，并验证未来可用于评估干预措施有效性的端点 UCD中肝病的预防和/或治疗。

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.