The causes of constipation. Reclassifying constipation using MRI and high resolution manometry to define mechanism of disease and target treatment.

便秘是一个常见的问题，影响到七分之一的人口，但超过一半的患者治疗不满意。其中一个原因可能是，目前的分类系统决定了医生的治疗选择是基于症状而不是根本原因。这是因为目前很难确定病因，包括大肠内的异常收缩，因为这只能通过排空结肠并用肠道内的小探针（一种称为测压法的技术）测量收缩压力来完成。这是耗时的，技术上困难的，需要高度专业的工作人员来执行。此外，它需要一个相机测试（结肠镜检查），以实际将探针放置在正确的位置。这对病人来说既昂贵又不愉快。传统的便秘理论是由于结肠活动不足，即减少或没有收缩。我们最近开发了一种新的磁共振成像（MRI）技术，它是非侵入性的（不涉及将任何东西放入肠道），为患者所接受，并且可能更广泛地使用，因为它可以使用标准的MRI扫描仪进行。我们已经将这种MRI方法应用于一组便秘患者。令人惊讶的是，一些患者在小肠内容物进入结肠的右半部分，肠收缩（运动）次数正常或增加。我们在大约一半的病人身上发现了这种情况，尽管他们在整个结肠中发现了缓慢的运动（称为缓慢运输）。最近，使用测压法直接测量压力的进展表明，便秘型肠易激综合征患者的结肠收缩可能不协调，或者实际上可能推动液体向后（逆行收缩），而不是像人们通常期望的那样向前。这种收缩的增加会阻碍通过肠道的运动（延长运输时间），并且通过分离液体和固体使大便更硬。这是一种全新的、完全不同的关于便秘原因的观点。在诺丁汉和伦敦的三所一流大学医院，我们计划研究80名便秘患者和40名健康志愿者，使用MRI和测压仪来确定我们的新MRI方法是否可以像测压仪一样用于检测异常收缩。我们的首要目标是证实我们最初的发现。我们还将用核磁共振成像来比较左右结肠的活动性，看看两侧的活动性是否相似。我们还将使用一种新的高度敏感的测压技术来评估左结肠的运动，看看用这种方法对患者进行分类是否能识别出与MRI测试相同的患者。然后，我们将邀请接受结肠收缩评估的受试者参加两种截然不同的随机治疗的试验，一种是增加收缩（称为促动力），另一种是减少收缩（肌肉松弛剂）。在试验期间，受试者和研究者都不知道采用了哪种治疗方法。我们想知道我们新的运动测试是否能预测哪种治疗方法能减轻症状（便秘和疼痛）。我们假设给正常或增强收缩的患者服用促动力药会加重症状，但对收缩不活跃的患者则会改善症状。相反，给予肌肉松弛剂来减少收缩会改善那些收缩增加或异常的人，但对那些正常或不活跃的收缩没有帮助。如果成功，我们希望未来治疗对简单措施无反应的便秘将基于使用新的MRI测试的客观评估，而不是目前不满意的基于症状的方法。这将大大增加对治疗满意的患者比例，从而减少医生就诊、检查和休假时间。

Constipation is a common problem affecting up to 1 in 7 of the population but treatment is unsatisfactory for over half the patients treated. One reason may be that the current system of classification which determines doctors' choice of treatment is based on symptoms rather than underlying causes. This is because defining the causes, which include abnormal contractions within the large bowel, is difficult at present as this can only be done by emptying the colon and measuring contraction pressure with small probes (a technique called manometry) within the bowel. This is time consuming, technically difficult and requires highly specialist staff to perform. Also, it requires a camera test (colonoscopy) to actually put the probe in the right place. This is expensive and unpleasant for patients. The traditional theory of constipation is that it is due to underactivity of the colon i.e. reduced or absent contractions. We have recently developed a new magnetic resonance imaging (MRI) technique, which is non-invasive (does not involve putting anything up the bowel), acceptable to patients and potentially more widely available as it can be performed using standard MRI scanners. We have applied this MRI method to a group of patients with constipation. Surprisingly some patients have normal or increased numbers of bowel contractions (motility) in the right half of the colon where the small intestinal contents enter the colon. We see this in around half our patients despite finding slow movement throughout the colon (called slow transit). Recently advances in directly measuring pressure using manometry have shown that colonic contractions in patients with constipation-type irritable bowel syndrome may be uncoordinated or may actually serve to propel fluid backwards (retrograde contractions) rather than forwards as one would normally expect. An increase in such contractions would impede movement through the bowel (prolonging transit time) and by separating fluid from solid make the stool harder. This is a new and radically different view of the cause of constipation.At 3 leading University Hospitals in Nottingham and London we propose to study up to 80 patients with constipation and 40 healthy volunteers, using MRI and manometry to determine if our new MRI methods can be used to detect abnormal contractions as well as manometry can. Our first aim is to confirm our original findings. We will also compare motility in both the right and left side of the colon using MRI to see if activity is similar on the two sides. We will also assess the motility of the left colon using a new highly sensitive manometry technique to see if classifying patients in this way identifies the same patients as the MRI test. We will then invite subjects who have had their colonic contractions assessed to take part in a trial of two very different treatments given in random order, one which increases contractions (called a prokinetic) and one which reduces contractions (muscle relaxant). During the trial neither the subject nor investigator will know which treatment has been given. We want to know if our new motility test will predict which treatment works to reduce symptoms (constipation and pain). We hypothesise that giving a prokinetic to patients with normal or increased contractions will aggravate symptoms but improve symptoms in those with underactive contractions. Conversely giving a muscle relaxant to reduce contractions will improve those with increased or abnormal contractions but not help those with normal or underactive contractions. If successful we hope that future treatment of constipation unresponsive to simple measures will be based on objective assessment using the new MRI test rather than the current unsatisfactory symptom-based methods. This should substantially increase the proportion of patients who are satisfied with their treatment, thereby reducing doctor visits, investigations and time off work.