Unraveling Racial Disparities in Portal Hypertension: A Clinical, Spectroscopic and SNP Approach

门脉高压是肝硬变的主要后果，可导致灾难性的并发症，如 大量潜在的食道和胃底静脉曲张大出血。流行病学研究 表明非裔美国人(AA)门脉高压并发症的死亡率高于白人 但造成差异的机制，即是生物差异还是社会经济差异，目前仍不清楚。门静脉高压症 以肠粘膜血流量增加(胃病、结肠病)为特征，在一些研究中发现 显示与门脉压力相关，从而与肝病的严重程度相关。我们已经开发出一种强大的 光谱技术--可精确测量肠道粘膜的偏振门控光谱技术 血液流动。我们已经广泛地使用PGS来检测大肠肿瘤，通过检测血流增加 结肠组织外观正常，但不适用于门静脉高压症。我们的结直肠数据 在AAS和白人中显示了不同的微血管模式。我们有更多的初步数据 强大的下一代偏振门控光谱(NG-PGS)显示显著增强 肝硬变的十二指肠微循环。此外，种族差异的生物学基础也得到了种族的支持 系统性高血压等其他循环系统疾病与单核苷酸多态的差异 与门静脉高压症相关的基因有关。R21的目标是阐明生物学上的差异 在AA和白人之间通过利用一种新的、侵入性较小的方法导致门静脉高压症差异的研究 光谱微血管十二指肠粘膜生物标记物，可作为门脉压力的潜在替代物。 我们将利用波士顿大学医疗中心的非凡资源，这是一家提供安全保障的医院 肝脏就诊次数高的多元化人群(40%AA)。我们将进行一项前瞻性病例对照研究， 对肝硬变患者进行分级，并根据临床上有意义的门脉高压症的临床标志物进行分层。 (CSPH)即静脉曲张的存在和大小，并与种族相关。我们将检查深度选择性NG-PGS 术中评估十二指肠微循环(总血红蛋白、氧合状态和血管半径) 诊断精索静脉曲张的高位内窥镜检查标准将与静脉曲张的存在/大小相关 并在AAS和白人中有明显的种族特征(目标1)。然后，我们将测试优化后的 在AIM 1中开发的十二指肠微血管生物标记物，作为检测门静脉变化的伴随生物标记物 奥曲肽试验(AIM)治疗十二指肠微循环改变引起的压力 2)。使用这些新颖而严谨的方法，我们将首次对差异的机制进行研究 门静脉高压症。在临床上，这些研究将为门静脉高压症的治疗开辟新的前景。 未来R01的应用可能侧重于将NG-PG作为标准(β-阻滞剂)或新型的伴生生物标志物 抗门脉高压药物试验，并作为与内窥镜检查脱钩的潜在护理点测试(直接 插入胃或直肠黏膜)，以改善获得护理问题。

Portal hypertension is the major consequence of cirrhosis which can lead to catastrophic complications such as massive, potentially exsanguinating hemorrhage from esophageal and gastric varices. Epidemiological studies indicate that African Americans (AAs) have higher mortality from portal hypertensive complications than Whites but the mechanism of disparity i.e. whether it is biologic or socio-economic remains unclear. Portal hypertension is characterized by increase in gut mucosal blood flow (gastropathy, colopathy) that in some studies has been shown to correlate with portal pressure and thus, severity of liver disease. We have developed a powerful spectroscopic technique- polarization gating spectroscopy (PGS) which can accurately measure gut mucosal blood flow. We have used PGS extensively to detect colorectal neoplasia by detecting increased blood flow in normal appearing colonic tissue but have not applied to issues in portal hypertension. Our colorectal data demonstrated distinct microvascular patterns in AAs and Whites. We have preliminary data with the more powerful next generation polarization gated spectroscopy (NG-PGS) that shows marked augmentation of duodenal microcirculation in cirrhosis. In addition, the biological basis of racial disparity is supported by racial differences in other circulatory disorders like systemic hypertension and in single nucleotide polymorphisms involved in genes involved in portal hypertension. The goal of this R21 is to elucidate the biological differences between AAs and Whites that lead to disparities in portal hypertension by utilizing a novel, less-intrusive spectroscopic microvascular duodenal mucosal biomarker that can be a potential surrogate for portal pressure. We will leverage the extraordinary resources at Boston University Medical Center, a safety net hospital serving a diverse population (40% AAs) with high number of liver visits. We will perform a prospective case control study, in with cirrhotics and stratify them by well-established clinical markers of clinically significant portal hypertension (CSPH) i.e. presence and size of varices and correlate it with race. We will examine if depth-selective NG-PGS assessment of duodenal microcirculation (total hemoglobin, oxygenation status and blood vessel radius) during standard of care diagnostic upper endoscopy for variceal detection will correlate with presence/size of varices and have distinct racial signatures in AAs and Whites (aim 1). We will then test the utility of the optimized duodenal microvasculature biomarker developed in aim 1, as a companion biomarker to detect changes in portal pressure by changes in duodenal microcirculation with a well-established therapeutic agent, octreotide test (aim 2). Using these novel and rigorous approaches, ours will the first study to provide into mechanisms of disparities in portal hypertension. Clinically, these studies will open new vistas in the management of portal hypertension. Future R01 applications may focus on NG-PGS as a companion biomarker to standard (β-blockers) or novel anti-portal hypertensive agent trial and as a potential point-of care test decoupled from endoscopy (direct insertion in stomach or rectal mucosa) to ameliorate access to care issues.