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

门静脉高压症是肝硬化的主要后果，可导致灾难性的并发症， 食管和胃静脉曲张引起的大量潜在失血性出血。流行病学研究 表明非裔美国人（AAs）门静脉高压并发症的死亡率高于白人 但造成差异的机制，即差异是生物差异还是社会经济差异，仍不清楚。门静脉高压 特征在于肠粘膜血流量增加（胃病、结肠病），在一些研究中， 显示与门静脉压力相关，因此与肝病的严重程度相关。我们开发了一个强大的 光谱技术-偏振门控光谱（PGS），可以准确地测量肠道粘膜 血流我们已经广泛使用PGS检测大肠肿瘤，通过检测血流量的增加， 结肠组织外观正常，但不适用于门静脉高压问题。我们的结直肠数据 在AA和白人中表现出不同的微血管模式。我们有初步的数据， 强大的下一代偏振门控光谱（NG-PGS），显示出显着增强 肝硬化十二指肠微循环此外，种族差异的生物学基础是由种族歧视支持的。 其他循环系统疾病如系统性高血压和单核苷酸多态性的差异 与门脉高压相关的基因。本R21的目标是阐明生物学差异 通过使用一种新的、侵入性较低的 光谱微血管十二指肠粘膜生物标志物可以作为门静脉压力的潜在替代物。 我们将利用波士顿大学医学中心的非凡资源，这是一家安全网医院， 多样化人群（40% AA），肝脏访视次数高。我们将进行前瞻性病例对照研究， 并通过临床显著门静脉高压症的成熟临床标志物对其进行分层 （CSPH）即静脉曲张的存在和大小，并将其与种族相关联。我们将研究深度选择性NG-PGS 评估十二指肠微循环（总血红蛋白、氧合状态和血管半径）， 用于静脉曲张检测的标准诊断性上消化道内窥镜检查将与静脉曲张的存在/大小相关 在AA和白人中有不同的种族特征（目标1）。然后，我们将测试优化的 在目标1中开发的十二指肠微血管生物标志物，作为检测门脉变化的伴随生物标志物 通过十二指肠微循环的变化与公认的治疗剂奥曲肽试验（目的 2）。使用这些新颖而严谨的方法，我们将首次研究差异的机制 门静脉高压症这些研究将为门静脉高压症的临床治疗开辟新的前景。 未来的R 01应用可能集中在NG-PGS作为标准（β-阻滞剂）或新的伴随生物标志物 抗门脉高压药物试验，并作为与内窥镜检查分离的潜在床旁检测（直接 插入胃或直肠粘膜中）以改善护理问题。

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.