Mini-review: Enteric glial cell reactions to inflammation and potential therapeutic implications for GI diseases, motility disorders, and abdominal pain.

Enteric glial cells are emerging as critical players in the regulation of intestinal motility, secretion, epithelial barrier function, and gut homeostasis in health and disease. Enteric glia react to intestinal inflammation by converting to a 'reactive glial phenotype' and enteric gliosis, contributing to neuroinflammation, enteric neuropathy, bowel motor dysfunction and dysmotility, diarrhea or constipation, 'leaky gut', and visceral pain. The focus of the minireview is on the impact of inflammation on enteric glia reactivity in response to diverse insults such as intestinal surgery, ischemia, infections (C. difficile infection, HIV-Tat-induced diarrhea, endotoxemia and paralytic ileus), GI diseases (inflammatory bowel diseases, diverticular disease, necrotizing enterocolitis, colorectal cancer) and functional GI disorders (postoperative ileus, chronic intestinal pseudo-obstruction, constipation, irritable bowel syndrome). Significant progress has been made in recent years on molecular pathogenic mechanisms of glial reactivity and enteric gliosis, resulting in enteric neuropathy, disruption of motility, diarrhea, visceral hypersensitivity and abdominal pain. There is a growing number of glial molecular targets with therapeutic implications that includes receptors for interleukin-1 (IL-1R), purines (P2X2R, A2BR), PPARα, lysophosphatidic acid (LPAR1), Toll-like receptor 4 (TLR4R), estrogen-ß receptor (ERß) adrenergic α-2 (α-2R) and endothelin B (ETBR), connexin-43 / Colony-stimulating factor 1 signaling (Cx43/CSF1) and the S100ß/RAGE signaling pathway. These exciting new developments are the subject of the minireview. Some of the findings in pre-clinical models may be translatable to humans, raising the possibility of designing future clinical trials to test therapeutic application(s). Overall, research on enteric glia has resulted in significant advances in our understanding of GI pathophysiology.

Dysgenesis of enteroendocrine cells in Aristaless-Related Homeobox polyalanine expansion mutations.

OBJECTIVES: Severe congenital diarrhea occurs in approximately half of patients with Aristaless-Related Homeobox (ARX) null mutations. The cause of this diarrhea is unknown. In a mouse model of intestinal Arx deficiency, the prevalence of a subset of enteroendocrine cells is altered, leading to diarrhea. Because polyalanine expansions within the ARX protein are the most common mutations found in ARX-related disorders, we sought to characterize the enteroendocrine population in human tissue of an ARX mutation and in a mouse model of the corresponding polyalanine expansion (Arx). METHODS: Immunohistochemistry and quantitative real-time polymerase chain reaction were the primary modalities used to characterize the enteroendocrine populations. Daily weights were determined for the growth curves, and Oil-Red-O staining on stool and tissue identified neutral fats. RESULTS: An expansion of 7 alanines in the first polyalanine tract of both human ARX and mouse Arx altered enteroendocrine differentiation. In human tissue, cholecystokinin, glucagon-like peptide 1, and somatostatin populations were reduced, whereas the chromogranin A population was unchanged. In the mouse model, cholecystokinin and glucagon-like peptide 1 populations were also lost, although the somatostatin-expressing population was increased. The ARX protein was present in human tissue, whereas the Arx protein was degraded in the mouse intestine. CONCLUSIONS: ARX/Arx is required for the specification of a subset of enteroendocrine cells in both humans and mice. Owing to protein degradation, the Arx mouse recapitulates findings of the intestinal Arx null model, but is not able to further the study of the differential effects of the ARX protein on its transcriptional targets in the intestine.

Pseudo-obstrução intestinal crônica em um cão: relato de caso / Chronic intestinal pseudo-obstruction in a dog: case report

Intestinal pseudo-obstruction is a rare disorder that affects gastrointestinal propulsion. It may be secondary to several pathological conditions or it may develop without a known cause. A 1.2 year-old intact Pug bitch had a history of vomiting and constipation, which were followed by diarrhea and distended abdomen. Hypomotility and dilation of the small intestine, which was filled with gas, were observed during laparotomy. Histologically, full thickness biopsy specimens demonstrated a severe loss and degeneration of leiomyocytes in the inner and outer muscular layers of the intestinal wall, whereas there was a marked hypertrophy and hyperplasia of smooth muscle cells in the lamina propria, and extremely thickened muscularis mucosae arranged in bundles oriented in different directions with marked hypertrophy and hyperplasia of leiomyocytes. Distribution of leiomyocytes was further characterized by immunohistochemistry. These findings support the diagnosis of intestinal pseudo-obstruction in a Pug, associated with degeneration and loss of leiomyocytes in the muscular layer.(AU)

A pseudo-obstrução intestinal é um distúrbio raro que afeta a propulsão gastrointestinal. Pode ser secundária a diversas condições patológicas ou pode ser idiopática. Uma cadela Pug de um ano e dois meses de idade apresentou histórico de vômitos e constipação, que foram seguidos por diarreia e distensão abdominal. Hipomotilidade e dilatação do intestino delgado, que estava cheio de gás, foram observados durante a laparotomia. Ao exame histológico, observou-se grande perda e degeneração de leiomiócitos das camadas musculares interiores e exteriores da parede intestinal, com acentuada hipertrofia e hiperplasia das células do músculo liso da lâmina própria e espessamento acentuado da muscularis mucosae com feixes orientados em direções diferentes e acentuada hipertrofia e hiperplasia dos leiomiócitos. A distribuição de leiomiócitos foi caracterizada por imunoistoquímica. Estes resultados suportam o diagnóstico de pseudo-obstrução intestinal em um Pug, associado à degeneração e perda de leiomiócitos da camada muscular.(AU)

Small bowel gastric metaplasia: a report of three cases in children.

AIMS: To report three children displaying gastric metaplasia antral pyloric type of the small bowel mucosa. METHODS: Analysis of clinical, histopathological and immunohistochemical data. RESULTS: The first patient was a 14-year-old girl with history of chronic intestinal pseudo-obstruction and chronic jejunitis; the second patient was a 6-year-old girl with a long-lasting jejunostomy; and the third patient was a 5-year-old girl with ileal-rectal anastomosis. The foci of gastric metaplasia were obvious with H&E-stained sections. The cells at the gastric metaplasia mucosa proved to be MUC-1 and sialyl-Tn positive by immunohistochemistry and they were in a pattern that was different from that of the adjacent mucosa; the cells were autofluorescent in H&E-stained sections. CONCLUSIONS: Gastric metaplasia of the small bowel mucosa in these cases seems to have resulted from chronic inflammation and persistent regenerative activity. This has rarely been reported outside Crohn disease, and if ever in children.

Neuronal intestinal dysplasia: a role for surgery?

Neuronal intestinal dysplasia (NID) is a poorly understood colonic motility disorder with characteristic histopathological findings and clinical presentation. It is often associated with Hirschsprung's disease (HD) and can constitute a cause of failure of clinical improvement after adequate resectional pull-through surgery. Other conditions associated with NID are: Chronic Intestinal Pseudo-obstruction (CIPO), anorectal malformations and Multiple Endocrine Neoplasia (MEN) II syndrome patients. To increase the diagnostic yield of NID the pathologist should be aware and use histochemistry evaluation of the rectal biopsy specimen in patients with history of constipation or unexplained bouts of diarrhea. Adequate sampling of the temporary proximal colostomy done to HD patients should be examined for NID pathological changes. Treatment has centered around the clinical picture with most cases managed medically with prokinetic agents, colonic irrigations, and bowel cathartics until improvement and normalization of histology occur. There is evidence of progressive maturation of the enteric nervous system with time. Surgery is indicated for patients with severe clinical deterioration after failed medical management

Neuronal intestinal dysplasia: a role for surgery?

Neuronal intestinal dysplasia (NID) is a poorly understood colonic motility disorder with characteristic histopathological findings and clinical presentation. It is often associated with Hirschsprung's disease (HD) and can constitute a cause of failure of clinical improvement after adequate resectional pull-through surgery. Other conditions associated with NID are: Chronic Intestinal Pseudo-obstruction (CIPO), anorectal malformations and Multiple Endocrine Neoplasia (MEN) II syndrome patients. To increase the diagnostic yield of NID the pathologist should be aware and use histochemistry evaluation of the rectal biopsy specimen in patients with history of constipation or unexplained bouts of diarrhea. Adequate sampling of the temporary proximal colostomy done to HD patients should be examined for NID pathological changes. Treatment has centered around the clinical picture with most cases managed medically with prokinetic agents, colonic irrigations, and bowel cathartics until improvement and normalization of histology occur. There is evidence of progressive maturation of the enteric nervous system with time. Surgery is indicated for patients with severe clinical deterioration after failed medical management.

Diffuse lymphoplasmacytic infiltration of the small intestine with damage to nerve plexus. A cause of intestinal pseudo-obstruction.

We describe the clinicopathologic characteristics of three patients with chronic intestinal pseudo-obstruction and malabsorption. The patients were young women (average age, 25 years) who presented with abdominal pain, nausea, vomiting, diarrhea, and weight loss that led to extreme inanition and death in two patients despite multiple treatment schemes. The evolution of the process averaged 8 years. No case manifested evidence of malignant lymphoproliferative progression. Histologically, a diffuse lymphoplasmacytic infiltrate that affected all the layers of the intestinal wall was observed in full-thickness biopsy specimens. The proliferating lymphocytes were small and mixed with mature plasma cells that proved to be polyclonal on immunohistochemical analysis. An outstanding finding in all three cases was extensive damage to submucosal and myenteric nerve plexus associated with a lymphoid infiltrate. Quantification of the myenteric plexus by using immunohistochemical and morphometric techniques also revealed a marked reduction in their number. We concluded that diffuse lymphoplasmacytic infiltration of the small intestine associated with damage to the intestinal nerve plexus constitutes a specific disorder that is different from other diseases that produce intestinal pseudo-obstruction.

Miopatía visceral: informe de dos casos / Visceral miopathy: two case report

Se informan dos casos de pacientes tratados en el Instituto Hondureño de Seguridad Social, durante el año 1992: ambos presentaban obstrucción intestinal y urinaria, que se mejoró a pesar de múltiples intervenciones quirúrgicas, su evolución fue tórpida, falleciendo sin encontrar las causas de dicha obstrucción, tanto urinaria como intestinal. La valoración postmortem del cuadro clínico, radiológico, hallazgos quirúrgicos y de Anatomía Patológica permitió hacer el diagnóstico de miopatía visceral. Existen únicamente 22 casos pediátricos de miopatía visceral informados en la literatura mundial, estos dos nuevos casos constituyen además, los primeros casos reportados en la literatura médica hondureña

[Chronic idiopathic intestinal pseudo-obstruction: visceral myopathy. Report of 4 cases]. / Pseudoobstrucción intestinal crónica idiopática: miopatía visceral. Presentación de 4 casos.

Chronic intestinal pseudo-obstruction is the term applied to a heterogeneous group of functional motility disorders sharing a common clinical expression: signs and symptoms of bowel obstruction in absence of mechanical occlusion. It is caused by ineffective intestinal propulsion. The chronic form of intestinal pseudo-obstruction may be primary or secondary. Primary pseudo-obstruction or chronic idiopathic pseudo-obstruction (CIIP) defines a group of propulsive disorders having no recognized underlying diseases. This study presents four female patients, aged between 4 months to 7 years, and makes a review of the literature. The symptoms, very similar in three of them, were bilious vomiting, abdominal distention and constipation, alternating with diarrhea and malnutrition. The fourth patient, different from the others in the age of onset and evolution, only had severe constipation and abdominal bloating. The diagnostic was made by full thickness biopsies during laparotomy, getting specimens by mapping, at different heights of intestine and stomach. Samples were studied by optic and electronic microscopy and visceral myopathies were found. None of them had urinary disorders. Medical treatment consisted of total parental nutrition and/or enteral nutrition. Cisapride was not effective in the two patients who received it.

Pseudoobstrucción intestinal crónica idiopática: miopatía visceral: presentación de 4 casos / Chronic idiopathic intestinal pseudo-obstruction: visceral myopathy: report of 4 cases

La pseudo-obstrucción crónica comprende un grupo heterogéneo de desórdenes de la motilidad intestinal, que tienen una expresión clínica común: signos y síntomas de obstrucción intestinal, en ausencia de una oclusión mecánica. La causa es una falla de la propulsión intestinal. La forma crónica de pseudo-obstrución intestinal puede ser primaria o secundaria. La primaria, o pseudo-oclusión intestinal crónica idiopática (CIP de la tierra anglosajona), define a un grupo de desórdenes propulsivos, sin una enfermedad subyacente. En esta comunicación se presentan 4 pacientes con esta patología, de sexo femenino y edades comprendidas entre 4 meses y 7 años, y se realiza una revisión de la bibliografía. Los sintomas, muy similares en 3 de ellos fueron vómitos biliosos, distensión abdominal y constipación, alternando con diarrea y desnutrición grave. La 4¬ paciente, diferente de las otras en edad de comienzo y evolución, presentó solo constipación importante y distensión abdominal. El diagnóstico se realizó con biopsias transmurales por mapeo en laparotomía exploratoria, a diferentes alturas del intestino y estómago. Se estudió por microscopía visceral. Ninguna presentó patología urinaria. El tratamiento médico consistió en alimentación parenteral y/o enteral. El cisapride no fué efectivo en los dos casos que se usó (AU)

Pseudoobstrucción intestinal crónica idiopática: miopatía visceral: presentación de 4 casos / Chronic idiopathic intestinal pseudo-obstruction: visceral myopathy: report of 4 cases

La pseudo-obstrucción crónica comprende un grupo heterogéneo de desórdenes de la motilidad intestinal, que tienen una expresión clínica común: signos y síntomas de obstrucción intestinal, en ausencia de una oclusión mecánica. La causa es una falla de la propulsión intestinal. La forma crónica de pseudo-obstrución intestinal puede ser primaria o secundaria. La primaria, o pseudo-oclusión intestinal crónica idiopática (CIP de la tierra anglosajona), define a un grupo de desórdenes propulsivos, sin una enfermedad subyacente. En esta comunicación se presentan 4 pacientes con esta patología, de sexo femenino y edades comprendidas entre 4 meses y 7 años, y se realiza una revisión de la bibliografía. Los sintomas, muy similares en 3 de ellos fueron vómitos biliosos, distensión abdominal y constipación, alternando con diarrea y desnutrición grave. La 4ª paciente, diferente de las otras en edad de comienzo y evolución, presentó solo constipación importante y distensión abdominal. El diagnóstico se realizó con biopsias transmurales por mapeo en laparotomía exploratoria, a diferentes alturas del intestino y estómago. Se estudió por microscopía visceral. Ninguna presentó patología urinaria. El tratamiento médico consistió en alimentación parenteral y/o enteral. El cisapride no fué efectivo en los dos casos que se usó

Síndrome de pseudoobstrucción cronica intestinal y nutrición parenteral / Chronic intestinal pseudobstruction syndrome and parenteral nutrition

Se comunican 5 pacientes con alteraciones en la propulsión intestinal con sintomas recurrentes de obstrucción intestinal, vomitos 5/5, distension abdominal 3/5, constipación 2/5, diarrea 2/5, en ausencia de oclusión mecánica comprobada por laparotomía exploradora. Un paciente presentó alteraciones histopatológicas compatibles con la variedad miopática del sindrome de pseudo obstrucción intestinal cronica idiopatica, en el resto no se encontraron anormalidades. Dos pacientes pertenecian a la misma familia. El tratamiento con cisapride fue ensayado en 2 casos, obteniendo resultado parcial en uno. Se realizó nutricion parenteral a 4 pacientes, 931 días en total de los cuales en 590 días se utilizó la modadlidad ciclica, en el 81 por ciento de los cuales (480 días) se efectuaron en el domicilio del paciente. Fallecieron 4 niñas, la paciente restante permanece en nutrición parenteral domiciliaria.

Síndrome de pseudoobstrucción cronica intestinal y nutrición parenteral / Chronic intestinal pseudobstruction syndrome and parenteral nutrition

Se comunican 5 pacientes con alteraciones en la propulsión intestinal con sintomas recurrentes de obstrucción intestinal, vomitos 5/5, distension abdominal 3/5, constipación 2/5, diarrea 2/5, en ausencia de oclusión mecánica comprobada por laparotomía exploradora. Un paciente presentó alteraciones histopatológicas compatibles con la variedad miopática del sindrome de pseudo obstrucción intestinal cronica idiopatica, en el resto no se encontraron anormalidades. Dos pacientes pertenecian a la misma familia. El tratamiento con cisapride fue ensayado en 2 casos, obteniendo resultado parcial en uno. Se realizó nutricion parenteral a 4 pacientes, 931 días en total de los cuales en 590 días se utilizó la modadlidad ciclica, en el 81 por ciento de los cuales (480 días) se efectuaron en el domicilio del paciente. Fallecieron 4 niñas, la paciente restante permanece en nutrición parenteral domiciliaria. (AU)

Air esophagogram and intestinal pseudoocclusion in a patient with scleroderma.

Air in the esophagus is unusual because it is collapsible. Its finding on a chest roentgenogram, particularly when not associated with a fluid level indicative of stricture, should strongly suggest systemic sclerosis (scleroderma). We describe a patient with scleroderma with intestinal pseudoocclusion and an air esophagogram. Study of chest roentgenograms of 83 patients with scleroderma, including those of 7 with pseudoocclusion, revealed no other instance of air esophagogram. This radiological sign, although rare, should suggest scleroderma and may be particularly useful in patients with "systemic sclerosis sine scleroderma."