Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation

BACKGROUND: Interstitial cells of Cajal (ICC) are required for normal intestinal motility. ICC are found throughout the human colon and are decreased in the sigmoid colon of patients with slow transit constipation. AIMS: The aims of this study were to determine the normal distribution of ICC within the human colon and to determine if ICC are decreased throughout the colon in slow transit constipation. PATIENTS: The caecum, ascending, transverse, and sigmoid colons from six patients with slow transit constipation and colonic tissue from patients with resected colon cancer were used for this study. METHODS: ICC cells were identified with a polyclonal antibody to c-Kit, serial 0.5 microm sections were obtained by confocal microscopy, and three dimensional software was employed to reconstruct the entire thickness of the colonic muscularis propria and submucosa. RESULTS: ICC were located within both the longitudinal and circular muscle layers. Two networks of ICC were identified, one in the myenteric plexus region and another, less defined network, in the submucosal border. Caecum, ascending colon, transverse colon, and sigmoid colon displayed similar ICC volumes. ICC volume was significantly lower in the slow transit constipation patients across all colonic regions. CONCLUSIONS: The data suggest that ICC distribution is relatively uniform throughout the human colon and that decreased ICC volume is pan-colonic in idiopathic slow transit constipation.     

Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon

BACKGROUND: The pathophysiology of constipation is not clearly identified as yet, and the interstital cells of Cajal (ICC), known to generate the slow wave activity and to be involved in intestinal neurotransmission and the enteric nervous system (ENS), are suspected to play an important role. The aims of the present study were to assess the distribution of ICC and neuronal cells of ENS in patients with slow-transit constipation and acquired megacolon. METHODS: Sigmoid colon specimens were obtained from patients who underwent colectomy due to slow-transit constipation (n = 10), acquired megacolon (n = 9) and non-obstructive colon cancer (n = 10) as a control group. The ICC were visualized by c-Kit immunohistochemistry and neuronal cells of the ENS were demonstrated by protein gene product (PGP) 9.5. Density of cells stained by c-Kit and PGP 9.5 was calculated as percent area (area stained/area of X-Y plane) x 100, when images were collected at a magnification of x40 objective, with maximum area examined in the horizontal X-Y plane of 400 microm x 400 microm using an image analyzer. RESULTS: The densities of ICC and PGP 9.5 reactive neuronal structures were significantly decreased in all layers of sigmoid colon specimens in patients with slow-transit constipation and acquired megacolon, compared with that of the control group. However, there was no statistically significant difference in either the density of ICC or that of neuronal structures between the patients with slow-transit constipation and acquired megacolon. CONCLUSIONS: Slow-transit constipation and acquired megacolon were associated with alteration of ICC and neuronal cells of ENS in the sigmoid colon.     

Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon

BACKGROUND & AIMS: A variety of gastrointestinal motility disorders have been attributed to alterations of interstitial cells of Cajal and malformations of the enteric nervous system. This study evaluates both the distribution of interstitial cells of Cajal and the pathohistology of the enteric nervous system in 2 severe human colorectal motility disorders. METHODS: Colonic specimens obtained from patients with slow-transit constipation (n = 11), patients with megacolon (n = 6), and a control group (n = 13, nonobstructing neoplasia) were stained with antibodies against c-kit (marker for interstitial cells of Cajal) and protein gene product 9.5 (neuronal marker). The morphometric analysis of interstitial cells of Cajal included the separate registration of the number and process length within the different regions of the muscularis propria. The structural architecture of the enteric nervous system was assessed on microdissected whole-mount preparations. RESULTS: In patients with slow-transit constipation, the number of interstitial cells of Cajal was significantly decreased in all layers except the outer longitudinal muscle layer. The myenteric plexus showed a reduced ganglionic density and size (moderate hypoganglionosis) compared with the control group. Patients with megacolon were characterized by a substantial decrease in both the number and the process length of interstitial cells of Cajal. The myenteric plexus exhibited either complete aganglionosis or severe hypoganglionosis. CONCLUSIONS: The enteric nervous system and interstitial cells of Cajal are altered concomitantly in slow-transit constipation and megacolon and may play a crucial role in the pathophysiology of colorectal motility disorders.     

Decreased interstitial cells of Cajal in the sigmoid colon of patients with slow transit constipation

Background and aims Slow transit constipation (STC) is a colonic motor disorder that is characterized by measurably delayed movement of materials through the colon. Although abnormalities in the neuronal networks of the colon have been demonstrated in patients with STC, the etiology of STC remains unclear. Interstitial cells of Cajal (ICC) have been shown to be the pacemaker cells of the intestine and have been implied in the pathogenesis of a number of gastrointestinal motility dysfunctions, including idiopathic STC. This study aimed to determine the normal distribution of ICC within the colon of the Chinese and also to determine if ICC are decreased in Chinese STC patients.Patients and methods Twelve patients with STC and eight age-matched normal controls were studied. Specimens of sigmoid colon were obtained immediately after resection. ICC were identified with a monoclonal antibody to c-kit by an indirect immunofluorescence method. Immunostained tissues were examined with a laser scanning confocal microscope and the area occupied by ICC was calculated with an image analysis system.Results ICC were located in the external muscle layers including myenteric plexus (MP) and submucosal border (SMB). Two types of Kit-positive ICC were observed: bipolar cells characterized by one or two long processes and multipolar cells characterized by long stellate processes extending in various directions. A higher percentage of ICC was present in the MP regions and circular muscle (CM) layers compared with the SMB and longitudinal muscle (LM) layers. Tissues from STC patients showed a considerable decrease in the number of ICC located in the four regions (ICC-LM, ICC-MP, ICC-CM, ICC-SMB), especially the ICC-SMB, in which ICC almost completely disappeared.Conclusions Similar distribution of ICC was observed in the normal sigmoid colon of the Chinese. Decreased area of c-kit+ ICC may play an important role in the pathophysiology of STC. It remains to be determined whether the loss of ICC is primary or secondary to another lesion.     

Abnormal colonic endocrine cells in patients with chronic idiopathic slow-transit constipation

BACKGROUND: The aim of the present study was to investigate the colonic endocrine cells in patients with slow-transit constipation, to ascertain the presence of a possible abnormality. METHODS: Ten patients with chronic slow-transit constipation were investigated. As controls, macroscopically and histologically normal tissues from the colon of 12 patients were examined. These patients had polyps, prolapsis, chronic diverticulitis, volvulus, and haemorrhoids. The endocrine cells were stained by immunocytochemistry and quantified by computerized image analysis. RESULTS: There were significantly fewer enteroglucagon- and serotonin-immunoreactive cells in patients with chronic slow-transit constipation. There was no statistically significant difference between patients and controls with regard to the number of peptide YY (PYY)-, pancreatic polypeptide (PP)-, and somatostatin-immunoreactive cells. The cell secretory indexes (CSI) of enteroglucagon- and somatostatin-immunoreactive cells were significantly decreased. There was no statistically significant difference in the CSI between the patients and controls with regard to PYY-, PP-, and serotonin-immunoreactive cells. CONCLUSION: The changes in colonic endocrine cells in patients with slow-transit constipation may be one cause of the decreased motility in the colon and consequent development of constipation.     

慢性特发性便秘发病机制探讨

目的通过结肠、肛门直肠动力学的变化及心理学基础初步探讨慢性特发性便秘(CIC)可能的发病机制.方法用肛门直肠测压法检测21例CIC患者肛门直肠动力学的变化,同时进行心理测试.20名健康者作对照.CIC组中11例行远端结肠测压,9例非CIC组作对照.结果CIC患者年龄偏大(P＜0.05);肛门括约肌静息压、最大缩榨压降低(P＜0.025,P＜0.005);肛管高压带长度增加(P＜0.005);引起直肠肛门抑制反射的最小松弛容量(MVR)增加(P＜0.005),肛门括约肌松弛率下降(P＜0.025);直肠内部容量刺激的排便阈值和最大耐受量均明显增加(P＜0.005,P＜0.005);11例CIC组患者远端结肠测压结果表明收缩时间百分比、动力指数较非CIC组均明显降低(P＜0.005);CIC患者焦虑、抑郁精神心理异常倾向的出现明显高于对照组(P＜0.05,P＜0.01).结论CIC发病机制是复杂的,结肠、肛门直肠动力学及精神心理因素均参与发病.     

Phenotypic alteration of interstitial cells of Cajal in idiopathic sigmoid megacolon

BACKGROUND: Interstitial cells of Cajal (ICCs) are detected as a pacemaker of gastrointestinal movement and express c-kit and CD34. Recently, ICCs have implicated pathogenesis in several human diseases presenting gastrointestinal motor dysfunction. This study was performed to clarify the role of ICCs in idiopathic sigmoid megacolon using histological and immunohistochemical examinations. METHODS: Four adult patients with idiopathic sigmoid megacolon and 11 controls were studied. Histology and immunocytochemistry using NSE, S100, c-kit, and CD34 were performed in conjunction with quantitative analysis using the public domain NIH image program. RESULTS: Little histological change in neuromuscular structures in megacolon was observed. Immunohistochemistry demonstrated remarkable decrease of c-kit expressing ICCs without reduction of CD34 expression in the similar interstitial cell population. This observation was further supported by quantitative assessment using public domain NIH image program. CONCLUSIONS: A specific downregulation of c-kit in ICCs may be a cause of idiopathic sigmoid megacolon in adults.     

Loss of interstitial cells of Cajal network in severe idiopathic gastroparesis

INTRODUCTION Gastroparesis syndrome is a clinical entity characterized by chronic nausea, epigastric discomfort and recurrent vomiting, in the absence of mechanical obstruction[1]. Gastroparesis may be either primary (idiopathic) or secondary, i.e. associ…     

慢性特发性便秘患者肛门直肠的动力改变

目的　测定慢性特发性便秘患者肛门直肠压力 ,探讨肛门直肠动力障碍在便秘发病机制中的作用。方法　采用美国Sandhill公司生产的BioLAB动力学参数监测系统及固态压力传感器导管 ,对 40例CIC患者进行肛门直肠压力测定 ,并与 40例正常人进行对比。结果　便秘组肛管静息压、最大缩榨压、最大缩榨间期及缩榨指数均明显低于对照组 (P <0 0 5 ,P <0 0 5 ,P <0 0l,P<0 0 1) ;模拟排便动作时肛管剩余压明显高于对照组 (P <0 0 0 1) ,肛管松弛率、排便指数均低于对照组 ,统计学处理具有显著性差异 ;初始感阈值容量大于对照组 (P <0 0 0 1) ,排便感阈值大于对照组 (P <0 0 5 ) ,最大耐受量明显低于对照组 (P <0 0 1)。结论　慢性特发性便秘病人存在肛管直肠的动力学异常及直肠敏感性降低     

The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine

BACKGROUND & AIMS: It has been generally assumed that interstitial cells of Cajal (ICC) in the human gastrointestinal tract have similar functions to those in rodents, but no direct experimental evidence exists to date for this assumption. This is an important question because pathologists have noted decreased numbers of ICC in patients with a variety of motility disorders, and some have speculated that loss of ICC could be responsible for motor dysfunction. Our aims were to determine whether myenteric ICC (ICC-MY) in human jejunum are pacemaker cells and whether these cells actively propagate pacemaker activity. METHODS: The mucosa and submucosa were removed, and strips of longitudinal muscle were peeled away to reveal the ICC-MY network. ICC networks were loaded with the Ca(2+) indicator fluo-4, and pacemaker activity was recorded via high-speed video imaging at 36.5 degrees C +/- 0.5 degrees C. RESULTS: Rhythmic, biphasic Ca(2+) transients (6.03 +/- 0.33 cycles/min) occurred in Kit-positive ICC-MY. These consisted of a rapidly propagating upstroke phase that initiated a sustained plateau phase, which was associated with Ca(2+) spikes in neighboring smooth muscle. Pacemaker activity was dependent on inositol 1,4,5-triphosphate receptor-operated stores and mitochondrial function. The upstroke phase of Ca(2+) transients in ICC-MY appeared to result from Ca(2+) influx through dihydropyridine-resistant Ca(2+) channels, whereas the plateau phase was attributed to Ca(2+) release from inositol 1,4,5-triphosphate receptor-operated Ca(2+) stores. CONCLUSIONS: Each ICC-MY in human jejunum generates spontaneous pacemaker activity that actively propagates through the ICC network. Loss of these cells could severely disrupt the normal function of the human small intestine.     

老年慢性特发性便秘患者结肠动力学变化

目的：探讨老年慢性特发性便秘（ＣＩＣ）患者结肠运行功能变化及其与心理因素的关系,方法：应用不透Ｘ线标记物法及Ｚung抑郁自评量表（ＳＤＳ）及焦虎自评量表（ＳＡＳ）对５９例老年ＣＩＣ患者及３６例老年对照者进行结肠通过时间检查及心理状况分析,结果：（１）老年ＣＩＣ组全结肠及分段结肠通过时间较老年对照组明显延长（Ｐ＜０．０５）,（２）长期服用泻药组的老年ＣＩＣ患者其全结肠及分段结肠通过时间较间断服药和不服药者明显延长（Ｐ＜０．０５）,（３）老年ＣＩＣ患者ＳＤＳ,ＳＡＳ标准总分均明显高于对照组（Ｐ＜０．０５,（４）老年ＣＩＣ患者中结肠通过时间延长组ＳＤＳ标准通过时间延长组（Ｐ＜０．０５）,结论：老年ＣＩＣ患者存在结肠动力学异常,抑郁情绪和焦虑情绪与老年ＣＩＣ患者结肠运行功能异常有关。     

老年特发性便秘直肠肛门压力测试59例分析

目的　探讨老年慢性特发性便秘 (CIC)患者直肠肛门运动功能变化 ,　 方法 　采用瑞典Medtronic公司生产的 8通道水灌注式消化道压力检测系统对 5 9例老年CIC患者及 36例老年对照者进行直肠肛门压力测定。　 结果 　老年CIC患者最大缩榨压、模拟排便时肛管压力变化低于老年对照组 (P <0 0 5 ) ,直肠初始感觉阈值、排便阈值和最大耐受容量均高于老年对照组 (P <0 0 5 ) ,2 8例 (47 5 % )老年CIC患者模拟排便时出现肛管压力异常升高。　 结论 　老年CIC与直肠低敏感、高耐受及排便时直肠肛管运动不协调有关     

Morphology and rheology of the rectum in patients with chronic idiopathic constipation

To evaluate whether there is a relationship between the viscoelastic properties of the rectum and its surface, barium enema and rectal accommodation studies were performed under standard conditions in 46 subjects (25 adults, 21 children) with chronic idiopathic constipation. In adults, a significant correlation was found between rectal surface at barium enema and the minimum radius of rectal distention with a balloon necessary to higher wall tension changes (r=0.68;P<0.01). In both adults (r=0.48;P<0.05) and children (r=0.57;P<0.01), negative correlations were found between the surface of the rectum and its elasticity. It is concluded that rectal accommodation studies produce data comparable to those of radiologic examinations and may therefore be used repetitively, and without fear of radiation, as follow-up studies on constipated patients.     

Motilin in chronic idiopathic constipation

The plasma motilin levels were studied in seven patients with severe long-standing idiopathic constipation before and after a fat-rich test meal. The results were compared with those of a control group consisting of 10 apparently healthy persons with normal bowel function. The constipated patients had reduced basal motilin levels and a reduced motilin release after the test meal. Motilin is known to stimulate intestinal motility by inducing interdigestive descending contractions in the stomach and small intestine. A defective motilin release may therefore play a part in the pathogenesis of idiopathic constipation.     

Anorectal manometric abnormalities and effect of cisapride in patients with chronic idiopathic constipation

OBJECTIVES : To investigate abnormalities in anorectal motility, changes in rectal visceral perception of balloon distention and the effect of cisapride on patients with chronic idiopathic constipation (CIC). METHODS : Anorectal manometry was carried out in 30 CIC patients using the Synectics Visceral Stimulator combined with PcPolygraf before and after treatment with cisapride (10 mg three times daily for 4 weeks). Twenty age‐matched controls were also studied before cisapride therapy. RESULTS : Patients with CIC had lower anorectal sphincter squeeze pressures (P < 0.05), larger minimum relaxation volumes necessary to elicit the anorectal inhibitory reflux (P < 0.05), higher rectal defecation volume thresholds and higher rectal maximum tolerable volume thresholds (P < 0.01) compared with the controls. All of the abnormalities significantly improved and defecation frequency greatly increased after 4 weeks of cisapride therapy (P < 0.01). Cisapride was effective in 46.67% of patients with CIC. CONCLUSIONS : Patients with CIC have abnormalities of both anorectal motility and rectal visceral perception of balloon distention. Cisapride can improve these abnormalities and is effective in approximately one‐half of CIC cases.     

大鼠胃肠道不同部位Cajal间质细胞与慢传输型便秘的关系

目的观察慢传输型便秘(slow transit constipation,STC)大鼠模型胃肠道Cajal间质细胞(interstitial cell of cajal,ICC)的分布特点与含量改变,全面评估ICC在STC发病机制中的作用。方法 24只健康Wistar大鼠随机分成便秘组和对照组,分别饲喂含复方苯乙哌啶的混悬液和生理盐水,每5 d记录1次大鼠大便粒数、大便干质量及大鼠体质量。饲养90 d后停药1周,测定胃肠道传输功能并通过免疫组化的方法测定ICC的特异性标志物c-kit+细胞在胃窦、小肠、结肠的分布情况与含量变化。结果便秘组日均粪便粒数少于对照组(P<0.01),平均每粒粪便质量大于对照组(P<0.05);便秘组首粒黑便排出时间长于对照组(P<0.05);与对照组比较,便秘组胃窦部位c-kit+细胞数量无明显变化(P>0.05)。而c-kit+细胞在便秘组大鼠小肠、结肠的数目均少于对照组(P<0.05)。结论在STC模型中,胃窦ICC变化不明显,小肠ICC数量有减少趋势,可能对STC有一定影响,结肠部位ICC数量明显减少,可能是慢传输型便秘大鼠的主要病理生理机制。     

Prospective study of biofeedback retraining in patients with chronic idiopathic functional constipation

AIM: To determine the efficacy and long-term outcome of biofeedback treatment for chronic idiopathic constipation and to compare the efficacy of two modes of biofeedback(EMG-based and manometry-based biofeedback).METHODS: Fifty consecutive contactable patients included 8 cases of slow transit constipation, 36 cases of anorectic outlet obstruction and 6 cases of mixed constipation. Two modes of biofeedback were used for these 50 patients, 30 of whom had EMG-based biofeedback, and 20 had manometry-based biofeedback. Before treatment, a consultation and physical examination were done for all the patients, related information such as bowel function and gut transit time was documented, psychological test (symptom checklist 90, SCL90)and anorectic physiological test and defecography were applied. After biofeedback management, all the patients were followed up. The Student‘s t-test, chi-squared test and Logistic regression were used for statistical analysis.RESULTS: The period of following up ranged from 12 to 24 months (Median 18 months). 70 % of patients felt that biofeedback was helpful, and 62.5 % of patients with constipation were improved. Clinical manifestations induding straining, abdominal pain, bloating, were relieved, and less oral laxative was used. Spontaneous bowel frequency and psychological state were improved significantly after treatment. Patients with slow and normal transit, and those with and without paradoxical contraction of the anal sphincter on straining, benefited equally from the treatment. Thepsychological status rather than anorectal test could pre dictoutcome. The efficacy of the two modes of biofeedback was similar without side effects.CONCLUSION: This study suggests that biofeedback has a long-term effect with no side effects, for the majority of patients with chronic idiopathic constipation unresponsive to traditional treatment. Pelvic floor abnormalities and transit time should not be the selection criteria for treatment.     

Slow transit colon constipation is not related to the number of interstitial cells of Cajal

Background and aims Recent studies have demonstrated decreased numbers of interstitial cells of Cajal in patients suffering from severe chronic constipation as measured by c-Kit (CD117) and CD34 immunohistology. In this study, we wished to determine whether there were abnormalities in the number of neurons of the Auerbach's plexus, their CD117 and CD34 immunoreactivity, or the thickness of colon wall sections in patients with refractory slow transit colonic constipation as compared with control subjects.Patients and methods Specimens from 13 patients who had undergone subtotal colectomy for severe chronic constipation refractory to medical treatment were compared with normal controls. Enteric neurons of Auerbach's plexus were counted, and thickness of the circular and longitudinal layer of the muscularis externa as well as total muscularis externa was measured. Quantitative assessment of anti-CD117 and anti-CD34 immunoreactivity was performed using an Automated Cellular Imaging System and expressed as fractional scores.Results Except for a decreased circular muscle layer thickness in the constipated patients, no statistically significant differences were observed between the two groups. In particular, there was no relationship between CD117/CD34 fractional staining score and the duration or severity of disease, despite the selection of highly symptomatic individuals requiring colonic resection.Conclusion Using quantitative immunohistochemistry for CD117/CD34, we could not detect a relationship between fractional CD117/CD34 staining score and chronic constipation as compared to controls.     

老年特发性便秘患者结肠、直肠和肛门动力学变化

目的　探讨老年慢性特发性便秘 (CIC)患者结肠、直肠和肛门运动功能变化。方法　应用不透 X线标记物法 ,采用 8通道水灌注式消化道压力检测系统 ,对 5 9例老年慢性特发性便秘 (CIC)患者及 36例对照者进行结肠通过时间检查及直肠肛门压力测定。结果　 1老年 CIC组全结肠及分段结肠通过时间较对照组明显延长(P<0 .0 5 ) ;2长期服用泻药的老年 CIC患者其全结肠通过时间较间断服药和不服药组明显延长 (P<0 .0 5 ) ;3老年 CIC患者最大缩榨压、模拟排便时肛管压力变化低于对照组 (P<0 .0 5 ) ,直肠初始感觉阈值、排便阈值和最大耐受容量均高于对照组 (P<0 .0 5 ) ,并有 2 8例 (4 7.5 % )老年 CIC患者模拟排便时出现肛管压力异常升高。结论　老年 CIC患者存在结肠动力学异常 ,与直肠低敏感、高耐受及排便时直肠肛管运动不协调有关