Gender and hormonal influences on liver fibrosis after transplant for hepatitis C

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染是美国肝移植的主要适应症。不幸的是，同种异体移植物的再次感染是普遍的。尽管丙型肝炎复发的病程各不相同，但肝纤维化的速度是加快的。由于肝纤维化发生的速度很快，复发的丙型肝炎病毒是肝移植后发病率和死亡率的主要原因。最近的数据表明，在丙型肝炎患者肝移植后结局的设定上存在性别差异。重要的是，女性性行为现在被认为是同种异体移植不良和患者存活不良的一个新的和重要的风险因素。这种差异背后的机制还没有得到很好的理解。然而，有动物数据支持雌激素对肝纤维化过程的保护作用。这些数据还表明，雌激素耗竭状态，如更年期或卵巢切除术，可能会增强肝纤维化。这项建议将广泛研究性别和激素对丙型肝炎肝移植后肝纤维化的影响。其具体目的是确定在慢性丙型肝炎病毒感染的肝移植后，女性是否比男性有更快的肝纤维化发生率，在按受体Se分层后，确定临床因素是否与肝纤维化进展有关，并确定在接受丙型肝炎病毒移植的女性中，雌二醇耗竭状态是否是加速纤维化进展的风险因素。使用混合效应模型，将分析上述暴露的METAVIR阶段的肝纤维化进展率。调整后的混合效应模型将被用于控制重要的混杂变量。 公共卫生相关性：因丙型肝炎接受过肝移植的女性比因同样的适应症而接受肝移植的男性的预后更差。这可能是因为绝经后女性缺乏雌激素等女性荷尔蒙，从而影响了不同的结果。如果发现情况属实，则此关键信息将 帮助指导新疗法的测试，并改变女性移植后丙型肝炎病毒治疗的方法。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the US. Unfortunately, re-infection of the allograft is universal. Though the course of recurrent HCV is variable, the rate of hepatic fibrosis is accelerated. Because of the rapidity with which hepatic fibrosis occurs, recurrent HCV is a major cause of morbidity and mortality after liver transplant. Recent data suggest that a gender disparity exists in the setting of post liver transplant outcomes for HCV patients. Importantly, female sex is now appreciated as a new and significant risk factor for poor allograft and patient survival. The mechanisms underlying this disparity are not well understood. However, there are animal data that support a protective effect of estrogen on the process of hepatic fibrosis. These data also suggest that estrogen deplete states, such as that seen with menopause or oophorectomy, may enhance hepatic fibrosis. This proposal will broadly examine the effect of gender and hormonal Influences on hepatic fibrosis after liver transplantation for HCV. The specific aims are to determine whether women have more rapid rates of hepatic fibrosis than men after liver transplantation for chronic HCV infection, to determine whether clinical factors are associated with hepatic fibrosis progression after stratifying by recipient se and to determine if an estradiol-deplete state is a risk factor for accelerated fibrosis progressio in women transplanted for HCV. Using mixed effects models, hepatic fibrosis progression rates, in METAVIR stages, will be analyzed for the above exposures. Adjusted mixed effects models will be utilized to control for important confounding variables. PUBLIC HEALTH RELEVANCE: Women who have had a liver transplant for hepatitis C have poorer outcomes than men who have been transplanted for the same indication. It may be that the absence of female sex hormones like estrogen, as is seen in postmenopausal women, influences the disparate outcomes. If this is found to be the case, this critical information will help to guide the testing of new therapies and alter the approach to HCV therapy in women after transplant.