Raufman Jean-Pierre, Metry Melissa, Felton Jessica, Cheng Kunrong, Xu Su, Polli James
Division of Gastroenterology and Hepatology, Department of Medicine, and Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, and the VA Maryland Healthcare System, Baltimore, MD, 21201, USA.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.
MAGMA. 2019 Feb;32(1):163-171. doi: 10.1007/s10334-018-0713-9. Epub 2018 Nov 1.
In up to 50% of people diagnosed with a common ailment, diarrhea-predominant irritable bowel syndrome, diarrhea results from excess spillage of bile acids into the colon-data emerging over the past decade identified deficient release of a gut hormone, fibroblast growth factor 19 (FGF19), and a consequent lack of feedback suppression of bile acid synthesis as the most common cause. Selenium homotaurocholic acid (SeHCAT) testing, considered the most sensitive and specific means of identifying individuals with bile acid diarrhea, is unavailable in many countries, including the United States. Other than SeHCAT, tests to diagnose bile acid diarrhea are cumbersome, non-specific, or insufficiently validated; clinicians commonly rely on a therapeutic trial of bile acid binders. Here, we review bile acid synthesis and transport, the pathogenesis of bile acid diarrhea, the reasons clinicians frequently overlook this disorder, including the limitations of currently available tests, and our efforts to develop a novel F magnetic resonance imaging (MRI)-based diagnostic approach. We created F-labeled bile acid analogues whose in vitro and in vivo transport mimics that of naturally occurring bile acids. Using dual H/F MRI of the gallbladders of live mice fed F-labeled bile acid analogues, we were able to differentiate wild-type mice from strains deficient in intestinal expression of a key bile acid transporter, the apical sodium-dependent bile acid transporter (ASBT), or FGF15, the mouse homologue of FGF19. In addition to reviewing our development of F-labeled bile acid analogue-MRI to diagnose bile acid diarrhea, we discuss challenges to its clinical implementation. A major limitation is the paucity of clinical MRI facilities equipped with the appropriate coil and software needed to detect F signals.
在高达50%被诊断患有常见疾病——腹泻型肠易激综合征的患者中，腹泻是由于胆汁酸过量溢入结肠所致。过去十年出现的数据表明，肠道激素成纤维细胞生长因子19（FGF19）释放不足以及随之而来的胆汁酸合成缺乏反馈抑制是最常见的原因。硒同型牛磺胆酸（SeHCAT）检测被认为是识别胆汁酸腹泻患者最敏感和特异的方法，但在包括美国在内的许多国家都无法进行。除了SeHCAT检测外，诊断胆汁酸腹泻的检测方法繁琐、非特异性或验证不足；临床医生通常依靠胆汁酸结合剂的治疗性试验。在这里，我们回顾胆汁酸的合成与运输、胆汁酸腹泻的发病机制、临床医生经常忽视这种疾病的原因，包括现有检测方法的局限性，以及我们开发基于新型氟磁共振成像（MRI）诊断方法的努力。我们创建了氟标记的胆汁酸类似物，其体外和体内运输模拟天然存在的胆汁酸。通过对喂食氟标记胆汁酸类似物的活小鼠胆囊进行双氢/氟MRI，我们能够区分野生型小鼠与肠道关键胆汁酸转运体——顶端钠依赖性胆汁酸转运体（ASBT）或FGF19的小鼠同源物FGF15表达缺陷的品系。除了回顾我们开发用于诊断胆汁酸腹泻的氟标记胆汁酸类似物MRI外，我们还讨论了其临床应用面临的挑战。一个主要限制是配备检测氟信号所需的适当线圈和软件的临床MRI设备匮乏。
