Pathophysiology of Anorectal Disorders

描述(申请人提供)：排便障碍(DD)，通常导致慢性便秘，通过临床特征和异常的肛门直肠测试来诊断，应该通过盆底生物反馈治疗而不是泻药来治疗。DD是由于排便时盆底收缩“不适应”所致。这种模式忽略了内脏紊乱的影响(例如，肛门静息压升高或肛门高血压)。生物反馈疗法并不广泛可用，目前还没有治疗DD的药理学方法。肛门直肠测试并不广泛，而且一项关键的诊断测试，即模拟排便过程中的直肠肛门负倾斜(直肠和肛门压力)的准确性值得怀疑，因为许多无症状的受试者也有负倾斜。我们已经确定了三种不同的表型(即“高位肛门”、“低位直肠”和“混合型”)，它们由排便过程中直肠压力和肛门松弛的大小来定义。因此，“高肛门”模式的定义是正常的直肠压力(推进力)，但在排便过程中肛门松弛受损。高肛门表型还以高肛门静息压(肛门高压)为特征。基于初步研究，我们的假设是：(1)在DD患者中，肛门高压与肛门扩张性降低、肛门内括约肌僵硬增加和排空障碍有关。分别用肛门气囊扩张和磁共振弹性成像(MRE)评估肛门的扩张性和僵硬性，用动态盆腔MRI评估60例健康人和60例DD患者的直肠排空功能。(2)α-1肾上腺素能激素参与了DD的肛门高压。我们将评估α1-肾上腺素能拮抗剂对36名健康受试者和36名DD患者的肛门压力的影响，以及对36名DD患者的症状的影响。(3)直肠压力更高，直肠肛门压力测量比左侧坐位(3a)和直肠肛门压力测量(3b)更准确地识别坐位DD，并且直肠肛门压力可以通过便携式测压准确测量(3b)。我们将比较60名健康受试者和60名DD患者坐位和左侧位高分辨率和便携式测压测量的压力；盆底运动和直肠排空将通过动态MRI进行评估。一个多学科的协作团队将应用创新的方法，以高度精炼的方式解决这些假设。每项研究都旨在改善人类对患者的护理。

DESCRIPTION (provided by applicant): Defecatory disorders (DD), which commonly cause chronic constipation, are diagnosed by clinical features supplemented by abnormal anorectal tests, and should be managed by pelvic floor retraining by biofeedback therapy rather than by laxatives. DD are attributed to "maladaptive" pelvic floor contraction during defecation. This paradigm overlooks the contribution of visceral disturbances (e.g., increased anal resting pressure or anal hypertension). Biofeedback therapy is not widely available and there are no pharmacological approaches to manage DD currently. Anorectal tests are not widely available, and the accuracy of a key diagnostic test, i.e. a negative rectoanal gradient (rectal < anal pressure), during simulated evacuation is questionable because many asymptomatic subjects also have a negative gradient. We have identified 3 distinct phenotypes (i.e. "high anal", "low rectal" and "hybrid") which are defined by the magnitude of rectal pressure and anal relaxation during evacuation. Thus, the "high anal" pattern is defined by normal rectal pressure (propulsive force) but impaired anal relaxation during evacuation. The high anal phenotype is also characterized by high anal resting pressure (anal hypertension). Based on preliminary studies, our hypotheses are that: (1) Anal hypertension is associated with reduced anal distensibility, increased internal anal sphincter stiffness, and impaired evacuation in DD. Anal distensibility and stiffness will be evaluated by anal balloon distention and magnetic resonance elastography (MRE) respectively and rectal evacuation will be assessed by dynamic pelvic MRI in 60 healthy subjects and 60 patients with DD. (2) α1- adrenergic tone contributes to anal hypertension in DD. We will evaluate the effects of an α1-adrenergic antagonist on anal pressures in 36 healthy subjects and 36 patients with DD, and on symptoms in 36 patients with DD, and (3) Rectal pressure is higher and rectoanal pressure measurements are more accurate for identifying DD in the seated than the left lateral position (3a) and rectoanal pressures can be accurately measured by portable manometry (3b). We will compare pressures measured by high resolution and portable manometry in the seated and left lateral positions in 60 healthy subjects and 60 patients with DD; pelvic floor motion and rectal evacuation will be evaluated by dynamic MRI. A multi-disciplinary collaborative team will apply innovative approaches to address these hypotheses in a highly refined manner. Each study is designed to improve patient care in humans.