Chronic rejection after combined liver and small bowel transplantation in a child with chronic intestinal pseudo-obstruction: a case report

An 11-year-old boy with irreversible intestinal failure secondary to chronic intestinal pseudo-obstruction (CIPO) and intestinal failure-associated liver disease (IFALD) underwent a combined en bloc reduced liver and small bowel transplantation. He was discharged home after 9 weeks on full oral intake without requiring intravenous nutritional or fluid supplementation. The first episode of mild acute rejection, which occurred 18 months after transplantation, was successfully treated with steroids. An episode of rotavirus gastroenteritis led to severe exfoliative rejection of the bowel graft, which was resistant to steroid and Infliximab treatment but responded to OKT3. There was associated Epstein-Barr virus viremia with no evidence of posttransplant lymphoproliferative disease. Another episode of moderate to severe acute liver rejection occurred 5 months later. At the same time, multiple biliary strictures were diagnosed and treated. Persistent clinical symptoms of abdominal pain and increased stomal output as well as atrophy of the ileal mucosa on several biopsies, suggested the possibility of chronic rejection (CR). A second combined whole liver and small bowel transplant was performed. The diagnosis of CR was confirmed on histology of the explanted graft. The postoperative course was severely complicated and 71 days after the retransplantation, the boy died because of respiratory failure and multiorgan failure. In summary, intestinal transplantation can be successfully performed in children with CIPO, giving them the opportunity to be free from total parenteral nutrition. As survival following intestinal transplantation continues to improve, the problem of CR has become increasingly important and the only treatment available is retransplantation, which is associated with poor outcomes.     

Caecal volvulus in a patient with chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder characterised by recurrent symptoms and signs of intestinal obstruction without an underlying mechanical cause. Caecal volvulus remains a rare cause of intestinal obstruction that often requires operative intervention. We describe the previously unreported case of caecal volvulus occurring in an adult patient with CIPO, together with his subsequent management.     

Morphologic evaluation of regenerated small bowel by small intestinal submucosa

Background/Purpose

Previous studies have shown small intestinal submucosa (SIS) can be used as biodegradable scaffolds in tissue engineering small intestine. The purpose of this study is to evaluate the regeneration of neointestine and its morphology using SIS.

Methods

A 2-cm tubular SIS graft from Sprague Dawley rat donors was interposed in the middle of a 6-cm ileal Thiry-Vella loop of Lewis rats, which was used to construct an ileostomy. The grafts were harvested at each of the time points ranging from 2 weeks to half a year after implantation, and native small intestine and grafts were investigated for morphology using histology and immunohistochemistry.

Results

At the early postoperative period, SIS grafts were colonized by numerous inflammatory cells. A mucosal epithelial layer began to line the luminal surface of the graft by 4 weeks, and by 12 weeks, the luminal surface was covered completely by a layer of neomucosa. Neomucosa with typical small bowel morphology was characterized by a columnar epithelial cell layer with goblet cells, Paneth cells, absorptive enterocytes, and enteroendocrine cells. Significant differences between neomucosa by 12 weeks and 24 weeks in the measurements of mucosal thickness, villus height, and crypt depth were found. The outer walls of SIS grafts were composed of distinct bundles of well-formed smooth muscle-like cells with some fibrovascular tissue.

Conclusions

This initial study suggests that tissue engineering neointestine using SIS can develop structural features of the normal intestine. Small intestinal submucosa might be a viable material in the creation of neointestine for patients suffering short bowel syndrome.     

Tolerance induced by bone marrow chimerism prevents transplant vascular sclerosis in a rat model of small bowel transplant chronic rejection

BACKGROUND: The major impediment to success in solid organ transplantation is chronic rejection (CR). The characteristic lesion of CR is transplant vascular sclerosis (TVS). Although the mechanism of TVS is thought to have an immunologic basis, in humans immunosuppression does not prevent or reverse it. One possible therapy to prevent TVS is induction of donor-specific tolerance. Bone marrow chimerism has been successful in inducing tolerance in acute and chronic rejection heart and kidney transplant models. The highly immunogenic small bowel (SB) allograft provides a rigorous test of the efficacy of this tolerance regimen. We examined whether induction of tolerance by bone marrow chimerism could prevent TVS in a model of Fisher 344 (F344) to Lewis (LEW) rat SB transplantation. METHODS: Bone marrow chimeras (BMC) were created by transplantation of T-cell-depleted F344 bone marrow into irradiated LEW rats. Chimerism was assessed by flow cytometric method. F344 SB, heterotopically transplanted into the chimeras, was clinically and histologically assessed for CR. F344 SB grafts, transplanted into cyclosporine-A-treated LEW recipients, served as control grafts for CR. RESULTS: Cyclosporine-A-treated LEW rats chronically rejected F344 SB grafts. By contrast, the BMC group demonstrated tolerance and had long-term SB graft survival (>120 days) without TVS. The BMC demonstrated immunocompetence by prompt rejection of third party ACI (RT1av1) SB allografts. CONCLUSIONS: Bone marrow chimerism prevents chronic graft failure secondary to TVS in a model of chronic SB rejection. TVS fails to develop when tolerance is established, suggesting that the mechanisms involved in TVS are, in part, immunologically mediated.     

Isolated liver transplant and sequential small bowel transplantation for intestinal failure and related liver disease in children

Liver dysfunction is a well-recognized complication of intestinal failure in children. Advances in total parenteral nutrition (TPN) have allowed these children to survive while their intestinal tract gradually adapts. Unfortunately TPN may lead to cholestatic liver disease particularly in the young children. Progression of liver disease is associated with a poor prognosis and is an indication for small bowel transplantation.We report our experience of orthotopic liver transplantation in four children with short gut and sequential liver and small bowel transplantation in one child. All children had TPN-related liver failure. Causes of intestinal failure included necrotising enterocolitis (n=2), gastroschisis (n=1), intestinal atresia (n=1), and megacystic, microcolon syndrome (n=1). At the time of liver transplantation the children's mean age was 10.9 months (2.5-24) and weight 6.7 kg (4.8-10.1). The mean serum bilirubin was 522 micromol/liter (299-823), aspartate transaminase 423 IU/liter (49-1024) and international normalized ratio 2.8 (2-3.9). There were two deaths both from respiratory failure secondary to adenovirus pneumonia including the child who received a sequential small bowel transplant. Three children with isolated liver grafts are alive and off TPN at 20 months (mean) follow up (range 6-35). Isolated orthotopic liver transplantation has a role in selected children with intestinal failure, particularly those with short but normally functioning gut and progressing with satisfactory intestinal adaptation but developing liver disease. Those children with TPN-related liver disease and unadapted gut or irreversible intestinal disease need combined liver and small bowel transplantation. Sequential small bowel transplantation is feasible after orthotopic liver transplantation and may provide an option for the child with terminal liver and small bowel failure.     

Surgical treatment and prognosis of chronic intestinal pseudo-obstruction in children

Background/Purpose

Chronic intestinal pseudo-obstruction (CIPO) is characterized by symptoms of intestinal obstruction in the absence mechanical blockage. The main objectives in the treatment of CIPO include maintenance of adequate nutrition and restoration of intestinal propulsion. Our aim was to document the results of surgical treatment and the long-term results of CIPO in children.

Methods

The cases of 22 children (14 boys and 8 girls) who underwent surgical treatment for CIPO between January 1985 and April 2004 were reviewed. Patients at initial presentation ranged in age from 1 day to 11 years (median, 3.5 months). The diagnosis of CIPO was based on clinical signs and symptoms, coupled with radiological and histological findings. Patients' outcomes fell into 4 groups, according to evaluations of oral intake, weight gain, and parenteral nutrition: expired, poor, fair, or good.

Results

In 3 cases of localized disease, both total gastrectomy and total colectomy were performed in combination. Of 19 cases of generalized disease, 7 patients received enterostomy and/or intestinal biopsy, followed by total colectomy and Duhamel operation. Another 4 of those 19 patients underwent enterostomy repair, and 2 were treated by small bowel resection. In terms of outcome, 5 patients were expired, 5 were classified as poor, 4 were described as fair, and 8 had outcomes that fell into the good category. In expired patients, the causes of death were either line-associated sepsis or hypovolemic shock associated with intestinal obstruction. The only cases in which the outcomes were good were cases in which there was evidence of intestinal neuronal dysplasias.

Conclusion

We suggest that operative treatment should be considered, because of a high probability of both difficult diagnosis and intractable symptoms, which are unresponsive to medical therapy.     

Use of hyperbaric oxygenation in small bowel preservation for transplant

INTRODUCTION: The aim of this work was to study the effects of hyperbaric oxygenation as a preservation technique for small bowel transplantation. METHODS: Twenty 2-month-old male Wistar rats weighting 250 g were divided into two groups: group A (n = 10) in which the small bowel was preserved for 12 hours, and group B (n = 10) in which the small bowel was preserved for 24 hours. After vascular and intraluminal perfusion, 3-cm segments were maintained in Ringer's solution at temperatures between 2 degrees C to 4 degrees C and in normobaric O2 conditions (groups A1, B1) or conditioned in an hyperbaric O2 metal chamber (100% oxygen at 5.5 absolute atmospheres) (groups A2, B2). After this preservation time, we studied intestinal tissue injury and morphometric analysis of the villi. RESULTS: Mucosal injury was significantly greater among group A1 compared to group A2 animals. The grade of the lesions was greater among group B1 compared to group B2 animals. Group A1 showed no difference from Group B1. For lesion grade, the range was smaller in group A2 and group B2 animals. The villi height was significantly smaller in groups A1 and B1 compared to the other groups; whereas it was higher in group A2 as compared with B2. CONCLUSION: Hyperbaric oxygenation may play a role as a preservation technique. Further research is necessary.     

Vascular access in patients affected by short bowel syndrome

The aim of this study was to evaluate the problems induced by the use of a central venous catheter (CVC) in a series of patients with short bowel syndrome observed at the university of Padua (Italy) between January 1981 and June 1997. During this period, 14 patients required central venous access for parenteral nutrition (PN); 55 catheters were inserted, 6 with percutaneous and 49 with surgical techniques. We divided the patients into two groups according to PN duration. The first group includes 11 children with short/medium-term PN 8 are now eating, and 3 died from respiratory failure) while the second group includes 3 patients on home long-term PN. Thirteen catheters were placed in the first group, and the mean PN duration was 173 days; the three patients on home PN required 42 catheters. It is our experience that the use of catehters in patients requiring short/medium- term PN is a safe procedure with few complications; patients on home long-term PN present an increasing number of complications, and the vascular access could become a serious problem as the number of PN-dependent increases.     

A rat small bowel transplant model of chronic rejection: histopathologic characteristics.

BACKGROUND: The major impediment to long-term success in solid organ transplantation is the development of chronic rejection (CR). The vascular lesion of CR, transplant vascular sclerosis (TVS) is characterized by neointimal smooth muscle cell proliferation, and is driven by both immune- and nonimmune-mediated mechanisms. Although the features of chronic heart and kidney allograft rejection have been well characterized, the more immunogenic small bowel allograft has not received similar study. METHODS: F344 small bowel (SB) was transplanted heterotopically into Lewis recipients that were treated with low-dose Cyclosporine A for 15 days. Lewis recipients of F344 or Lewis SB grafts without immunosuppression, served as controls. Grafts were assessed histologically when recipients showed clinical signs of rejection or at predetermined time points. The immunological components involved in the chronic rejection process were evaluated by immunohistochemical staining. RESULTS: All SB allografts (100%) developed histologic evidence of CR Cyclosporine A. TVS was seen in 36 of the 46 (78%) of these allografts. The median time to develop TVS was 45 days. Immunohistochemical staining of chronically rejected grafts showed infiltration predominantly by CD4+ cells and macrophages, uniform up-regulation of class II MHC molecule expression, moderate to intense ICAM-1 staining in grafts harvested at postoperative day 45, and uniform neointimal cell staining for smooth muscle cell alpha-actin in the TVS lesions. CONCLUSIONS: This F344 to Lewis SB transplant model is a useful model that reproduces significant features of CR. The highly immunogenic nature of the SB allografts allows this model to serve as a stringent test for protocols designed to prevent CR.     

Involvement of endogenous nitric oxide and c-kit-expressing cells in chronic intestinal pseudo-obstruction

BACKGROUND/PURPOSE: Chronic intestinal pseudo-obstruction (CIP) in infants and children is a motility disorder without apparent mechanical cause. Nitric oxide (NO), an inhibitory neurotransmitter and c-kit cells, essential for the intestinal pacemaker activity, both play a key role in the intestinal motility function. In the current study, the authors investigated the distributive change in the intestinal nitric oxide synthase (NOS) and c-kit cells of patients with CIP. METHODS: Tissues were obtained from 4 patients undergoing bowel resection or biopsy for CIP at laparotomy. For controls, the intestinal specimens were obtained from 4 age-matched cases of intestinal stricture, intussusception, and autopsy with no evidence of gastrointestinal disease. Immunohistochemical studies were performed on paraffin-embedded tissue cross sections with neuronal NOS and inducible NOS monoclonal antibody as well as a rabbit polyclonal antibody against the human c-kit receptor. RESULTS: Under immunohistochemical staining, a greatly increased density of neuronal NOS immunoreactivity and an evidently increased number of intense NOS immunoreactive nerve fibers were observed in the myenteric plexus and circular muscle layers compared with the control sections. In the submucosal plexus and longitudinal muscle layer, there was no change in NOS immunoreactivity. Inducible NOS immunoreactivity was not detected in the control cases. However, in tissues of CIP, almost all the epithelial cells were positively and strongly labeled for inducible NOS immunoreactivity. For c-kit cells staining, the number of c-kit-positive cells in the myenteric plexus and circular muscle layers were greatly less than that in the controls, especially in the myenteric plexus region. CONCLUSION: These findings suggest that sustained production of NO by an increased NOS activity and a deficiency of c-kit cells in the intestine may be related to the pathogenesis of CIP.     

Collaborative strategies to reduce mortality and morbidity in patients with chronic intestinal failure including those who are referred for small bowel transplantation

Intestinal transplant wait-list mortality is higher than for other organ transplants. The objective of this workshop was to identify the main problems contributing to high mortality in adults and children candidates for intestinal transplantation and provide recommendations on how to correct them. OUTCOME: To facilitate this, 63 relevant articles identified from the medical literature from 1987 to 2007 were reviewed. Consensus was achieved on several important definitions relevant to this review. For children and adults on parenteral nutrition (PN) the main mortality risk factors were identified as were the main risks of mortality for those on the waiting list for intestinal transplants. RECOMMENDATIONS: (1) Primary care givers managing intestinal failure patients should establish a link with an intestinal failure programs early and collaboration with intestinal failure programs should be initiated for patients whose PN requirements are anticipated to be more than 50% 3 months after initiating PN; (2) intestinal failure programs should include both intestinal rehabilitation and intestinal transplantation or have active collaborative relationships with centers performing intestinal transplantation; (3) National registries for intestinal failure patients should be established and organizations that provide home PN solutions should be expected to participate. CONCLUSION: There are many unresolved issues in adults and children with PN dependent intestinal failure. To address these, a key recommendation of this group is to establish national intestinal failure databases that can support multicenter studies and lead to the adoption of universally accepted standards of patient care with the goal of improving outcomes in all long-term intestinal failure patients including those requiring intestinal transplantation.     

Endoscopic-assisted colopexy and push percutaneous colostomy in the transverse colon for refractory chronic intestinal pseudo-obstruction

Percutaneous endoscopic colostomy (PEC), using the classic pull-through technique in the ascending or the descending colon, has been proven useful to treat chronic intestinal pseudo-obstruction. We report the case of a high-surgical risk 70-year-old male with refractory chronic intestinal pseudo-obstruction, in whom the ascending colon could not be reached due to tortuous left dolichocolon. Endoscopic-assisted colopexy and push colostomy in the proximal transverse colon was decided accordingly. Colopexy was performed under direct endoscopic vision in the proximal transverse colon using 3 preloaded T-fasteners surrounding the intended stoma site. The stoma tract was created with an introducer needle, allowing the advance of the 24 Fr 4-sleeve dilator over a guidewire. Afterwards, the dilator was removed and the peel-away sheath was left in place. Over the guidewire, a 20-Fr gastrostomy tube was advanced into the colon lumen through the covering, which was finally removed. The patient recovered uneventfully, despite postprocedure pneumoperitoneum, which was related to the technique. He died a month later due to unrelated comorbidities, without further abdominal complaints after discharge. This is the first report of PEC both using a push technique, and the first report in a different location than the ascending or the descending colon. We believe this novel push technique may be feasible for PEC, avoiding the need of reinsertion in patients with difficult colonoscopy.     

原发性慢性假性肠梗阻的诊治分析

目的 分析原发性慢性假性肠梗阻的临床特点及治疗方法,提高对该病的认识。方法 回顾性分析1980～1999年收治的8例原发性慢性假性肠梗阻病例资料。结果 本组患者平均年龄29岁,最早发病年龄为2岁;反复出现腹胀是最常见的症状;行影像学检查均未见器质性病变;胃肠动力试验显示胃肠通过时间明显延长;消化道压力测定提示消化道压力减低、动力减弱;2例行肠道活检,示慢性炎症;对1例病变局限在结肠者行全结肠切除;促胃肠动力药效果不佳,部分患者长期依赖静脉营养。结论 原发性慢性假性肠梗阻是一种少见疾病。保守治疗无明显疗效,手术治疗不是首选方法,患者预后不良。     

Impaired bowel motility following small intestinal transplantation

Little information is available concerning motility following bowel transplantation and the appropriate timing of offering enteral feedings. Eight Lewis rats (300 g) underwent small bowel transplant as described by R. P. Harmel, Jr., and H. Stanley (J. Pediatr. Surg. 21:214, 1986). Silver oxide electrodes were placed in the native proximal ileum and in the distal segment of the homograft. Four control rats underwent laparotomy and placement of silver oxide electrodes in the jejunum and proximal ileum. Leads were brought out through a stab wound and the abdominal incision was closed. The electrodes were connected to a continuous recorder. Basal electrical rhythm (BER) was recorded periodically and was evaluated daily as the average of three readings per animal per day. Homograft electrical activity was not observed until at least 40 hr post-transplant and never attained the level of BER of the native intestine (P less than 0.05). Myoelectric complex potentials were not observed in the transplanted rats until post-operative day 11. These data suggest that basal electrical activity is significantly impaired following bowel transplantation. This study indicates that intestinal activity can be monitored for extended periods of time and may be a useful method of evaluating recovery of motility post bowel transplant prior to initiating enteral intake.     

Nationwide survey on adult type chronic intestinal pseudo-obstruction in surgical institutions in Japan

Background  

No appropriate management of chronic intestinal pseudo-obstruction (CIP) has been established.