Pathophysiology of Anorectal Disorders

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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.