Novel Classification and Pathogenetic Analysis of Hypoganglionosis and Adult-Onset Hirschsprung’s Disease

Young, Mi; Myung, Seung‐Jae; Park, Hyojin; Chung, Jae‐Yong; Kim, In Wha; Lee, Sun Mi; Yu, Chang Sik; Lee, Hye Kyung; Lee, Jong Keuk; Park, Young Soo; Jang, Se Jin; Kim, Hye Jin; Ye, Byong Duk; Byeon, Jeong Sik; Yang, Suk Kyun; Kim, Jin Ho

doi:10.1007/s10620-010-1522-9

Cited by 42 publications

(50 citation statements)

References 29 publications

(38 reference statements)

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“…In the colon of these patients, distinct luminal narrowing was apparent in the intersection of proximal dilated and distal non-dilated loop (referred to as the transition zone [TZ]). [6][7][8][9][10] Consistent observations of the TZ by us 9 and others [6][7][8]10 lead us to hypothesize that the TZ may be the site of functional obstruction and involved in the pathogenesis/pathophysiology of CPO. Given that gastrointestinal (GI) motility depends on the coordinated activity of 3 major cell types, ie, smooth muscle, interstitial cells of Cajal (ICC) and enteric neurons, we studied these cells in the TZ region using morphological, functional and molecular techniques, which were compared with other regions of the CPO colons and to region-matched controls obtained from colon cancer cases.…”

Section: Introductionmentioning

confidence: 88%

“…A narrowing of the lumen was observed near the distal end of the PD region, usually around the splenic flexure or upper descending colon, which has been previously referred to as the transition zone (TZ; Fig. 1A) [6][7][8][9][10] due to its location between the dilated and distal non-dilated loops. The external diameter of the TZ region was on average approximately 70% of the control (P ＜ 0.01, Fig.…”

Section: Morphometric Analysismentioning

confidence: 99%

“…Although CIPO conventionally referred to pediatric cases that generally involved the small bowel, 3,4 primary CIPO has also been reported in adults, [5][6][7][8][9][10][11] where over 60% of primary cases involved the large bowel. 11 Relative to the pediatric type, adult type has not been extensively studied.…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we observed a subset of adult patients with chronic intractable constipation exhibited clinical/pathological features of CIPO in the colon. 9 Some of these patients with colonic pseudo-obstruction (CPO) underwent surgical treatment because their symptoms did not improve by conventional medical treatments and frequent hospitalizations were required to drain the contents, which resulted in poor quality of life. In the colon of these patients, distinct luminal narrowing was apparent in the intersection of proximal dilated and distal non-dilated loop (referred to as the transition zone [TZ]).…”

Section: Introductionmentioning

confidence: 99%

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Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation

Suh

Myung

Kwak

et al. 2015

J Neurogastroenterol Motil

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Background/AimsChronic intestinal pseudo-obstruction (CIPO) is a disorder characterized by recurrent symptoms suggestive of obstruction such as abdominal pain, proximal distension with extremely suppressed motility in the absence of lumen-occluding lesion, whose etiology/pathophysiology is poorly understood. In this study we investigated a functionally obstructive lesion that could underlie symptoms of CIPO. MethodsWe studied colons surgically removed from 13 patients exhibiting clinical/pathological features of pseudo-obstruction but were unresponsive to standard medical treatments. The colons were characterized morphologically, functionally and molecularly, which were compared between regions and to 28 region-matched controls obtained from colon cancer patients. ResultsThe colons with pseudo-obstruction exhibited persistent luminal distension proximally, where the smooth muscle was hypertrophied with changes in the cell phenotypes. Distinct luminal narrowing was observed near the distal end of the dilated region, close to the splenic flexure, previously referred to as the "transition zone (TZ)" between the dilated and non-dilated loops. Circular muscles from the TZ responded less to depolarization and cholinergic stimulation, which was associated with downregulation of L-type calcium channel expression. Smooth muscle contractile protein was also downregulated. Myenteric ganglia and neuronal nitric oxide synthase (nNOS) positive cells were deficient, more severely in the TZ region. Interstitial cells of Cajal was relatively less affected. 561 ConclusionsThe TZ may be the principal site of functional obstruction, leading to proximal distension and smooth muscle hypertrophy, in which partial nNOS depletion could play a key role. The neuromuscular abnormalities probably synergistically contributed to the extremely suppressed motility observed in the colonic pseudo-obstruction.(J Neurogastroenterol Motil 2015;21:560-570)

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Section: Introductionmentioning

confidence: 88%

Section: Morphometric Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation

Suh

Myung

Kwak

et al. 2015

J Neurogastroenterol Motil

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“…This diffuse reduction in the number of ganglion cells along the colon is often seen in chronic constipation, so this type of disease can be considered as a possible reason for chronic idiopathic constipation 3 .…”

Section: Anomalies Of Intestinal Nervous Plexus Includingmentioning

confidence: 99%

Abnormalities of digestive tract innervation in rat fetus treated with ethylenethiourea

et al. 2012

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PURPOSE: The pathophysiology of abnormalities associated with myenteric plexus lesions remains imperfectly understood. Such abnormalities have been correlated with subocclusive intestinal conditions in children with Hirschsprung's disease, cases of chronic constipation and, postoperatively, in cases of anorectal anomalies. This study evaluated abnormalities of the myenteric plexus in fetus from female rats that received ethylenethiourea. METHODS: Female rats were exposed to ethylenethiourea on the 11th day of pregnancy (experimental group) or to 0.9% physiological solution (control group). Abnormalities were only found in the experimental group. The digestive tract muscle layer was analyzed morphometrically and changes to the frequencies of nerve plexus cells and interstitial cells of Cajal were evaluated, using hematoxylin-eosin, S-100 protein, neuron-specific enolase and C-Kit, respectively. RESULTS: Muscle and skeletal abnormalities were observed in 100%, anorectal anomalies in 86%, absent tail in 71%, short tail in 29%, duodenal atresia in 5%, esophageal atresia in 5% and persistent omphalomesenteric duct in 5%. Histopathological analysis showed a thinner muscle layer associated with lower frequencies of ganglion cells and interstitial cells of Cajal, in all gastrointestinal tract. CONCLUSION: Severe nerve plexus abnormalities associated with muscle layer atrophy were observed throughout the gastrointestinal tract in newborn rats exposed to ethylenethiourea.

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Chronic intestinal pseudo‐obstruction in a child harboring a founder Hirschsprung RET mutation

Rossi

Mosconi

Nozza

et al. 2016

American J of Med Genetics Pt A

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Chronic intestinal pseudo obstruction (CIPO) is a rare clinical entity characterized by symptoms and signs of intestinal obstruction without either recognizable anatomical abnormalities or intestinal aganglionosis. A Chinese female infant presented to our institution with a clinical diagnosis of CIPO. Aganglionosis was ruled out by full thickness colonic and ileal biopsies and by rectal suction biopsies. Unexpectedly, direct sequencing and PCR amplification of RET proto-oncogene from peripheral blood extracted DNA identified a RET R114H mutation. This mutation has already been reported as strongly associated with Asian patients affected by Hirschsprung's disease (HSCR) and is considered a founder mutation in Asia. The same mutation has never been reported in patients with CIPO, so far. These findings support the role of RET in the development of the enteric nervous system but underline the importance of other genetic or environmental factors contributing to the gastrointestinal phenotype of the disease. Somehow, this RET R114H mutation proved to have a role in the etiology of both CIPO and HSCR and could contribute to a more diffuse imbalance of gut dysmotility. © 2016 Wiley Periodicals, Inc.

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Novel Classification and Pathogenetic Analysis of Hypoganglionosis and Adult-Onset Hirschsprung’s Disease

Cited by 42 publications

References 29 publications

Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation

Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation

Abnormalities of digestive tract innervation in rat fetus treated with ethylenethiourea

Chronic intestinal pseudo‐obstruction in a child harboring a founder Hirschsprung RET mutation

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