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

描述（由申请方提供）：丙型肝炎病毒（HCV）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感染是普遍的。 尽管HCV复发的过程是可变的，但肝纤维化的速度加快。 由于肝纤维化发生的迅速性，HCV复发是肝移植后发病和死亡的主要原因。 最近的数据表明，在HCV患者肝移植后结局的设定中存在性别差异。 重要的是，女性现在被认为是同种异体移植物和患者生存不良的一个新的重要风险因素。 造成这种差异的机制尚不清楚。 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，如绝经或卵巢切除术，可能会增强肝纤维化。这项提案将广泛研究性别和激素对HCV肝移植后肝纤维化的影响。 具体目的是确定女性慢性HCV感染肝移植后肝纤维化发生率是否比男性更快，确定临床因素是否与受者性别分层后的肝纤维化进展相关，并确定雌二醇耗竭状态是否是HCV移植女性加速纤维化进展的危险因素。 将使用混合效应模型，分析上述暴露量在METAVIR分期的肝纤维化进展率。 将使用调整后的混合效应模型控制重要的混杂变量。 公共卫生相关性：患有丙型肝炎肝移植的女性比因相同适应症接受移植的男性结果更差。 这可能是因为绝经后妇女缺乏雌激素等女性性激素，影响了不同的结果。 如果情况属实，这一关键信息将 有助于指导新疗法的测试，并改变移植后妇女的HCV治疗方法。

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.