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，影响多达七分之一的人口，但治疗是不满意的一半以上的患者治疗。原因之一可能是目前的分类系统决定了医生选择的治疗方法是基于症状而不是根本原因。这是因为目前很难确定原因，包括大肠内的异常收缩，因为这只能通过排空结肠并用小探针测量肠道内的收缩压力（一种称为测压的技术）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），实际上把探头在正确的位置。这对患者来说是昂贵和不愉快的。便秘的传统理论是，它是由于结肠活动不足，即减少或缺乏收缩。我们最近开发了一种新的磁共振成像（MRI）技术，该技术是非侵入性的（不涉及将任何东西放入肠道），患者可以接受，并且可能更广泛地使用，因为它可以使用标准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结肠中具有正常或增加的肠收缩（能动性）次数。我们在大约一半的患者中看到这种情况，尽管发现整个结肠的运动缓慢（称为慢传输）。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是不协调的，或者实际上可能是向后推动液体（逆行收缩），而不是像人们通常预期的那样向前。这种收缩的增加会阻碍通过肠道的运动（延长通过时间），并通过将液体与固体分离使粪便变硬。在诺丁汉和伦敦的三所领先的大学医院，我们计划研究多达80名便秘患者和40名健康志愿者，使用MRI和测压来确定我们的新MRI方法是否可以像测压一样用于检测异常收缩。我们的首要目标是确认我们最初的发现。我们还将使用MRI比较结肠右侧和左侧的运动性，以查看两侧的活动是否相似。我们还将使用一种新的高灵敏度测压技术来评估左结肠的能动性，以确定以这种方式对患者进行分类是否可以识别出与MRI检查相同的患者。然后，我们将邀请已经评估过结肠收缩的受试者参加一项试验，试验中随机给予两种非常不同的治疗方法，一种是增加收缩（称为促动力剂），另一种是减少收缩（肌肉松弛剂）。试验期间，受试者和研究者均不知道接受了哪种治疗。我们想知道我们的新动力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，给予正常或增加收缩的患者促动力剂会加重症状，但改善收缩不活跃的患者的症状。相反，给予肌肉松弛剂以减少收缩会改善那些收缩增加或异常的人，但对那些收缩正常或不活跃的人没有帮助。如果成功的话，我们希望未来对简单措施无反应的便秘的治疗将基于使用新的MRI测试的客观评估，而不是目前不令人满意的基于MRI的方法。这将大大增加对治疗感到满意的病人比例，从而减少看医生、调查和休假的时间。

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.