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 (?-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.
The mechanism behind disproportionate toll of African Americans with portal hypertensive complications in cirrhosis is unclear. This proposal will elucidate the mechanisms that lead to this disparity by stratifying the risk of clinically significant portal hypertension (varices) and response to portal hypertensive therapy by race and by determining racial signatures in spectroscopic duodenal microcirculation.
