Development of a systematic approach to conversion of the ileoanal pouch into continent ileostomy.

Based on practical experience, a systematic approach to conversion of ileal J-pouches into continent ileostomies is developed by defining three types of conversion surgery, each with two subtypes. Type 1 refers to conversion without pouch reconstruction, type 2 to partial pouch reconstruction, and type 3 to complete pouch reconstruction. The subdivisions (a and b) take into account whether the afferent loop of the former pelvic pouch (a) or a higher ileal/jejunal segment of the small intestine (b) is used in conversion and/or reconstruction. The six resulting surgical variants are shown in schematic illustrations with accompanying descriptions of technical details to provide the specialized surgeon with comprehensive technical guidance.

Development of ulcerative colitis after heart transplantation during immunosuppressive therapy.

BACKGROUND: Cardiac transplantation has become an accepted treatment modality for end-stage heart failure. Immunosuppressive agents, which are used after transplantation, are considered as therapeutic options for inflammatory bowel disease. CASE REPORT: We report on a 53-year-old patient who was treated for 2 years with cyclosporine A, azathioprine and prednisolone after heart transplantation. He developed a distal colitis with all features of ulcerative colitis. An infectious or ischemic etiology was carefully excluded. In spite of high-dose treatment with prednisolone the patient's abdominal symptoms worsened and he developed a progression of the inflammation in the entire colon and a colectomy with ileostomy was necessary. The histology was consistent with ulcerative colitis. After colectomy he recovered and remained in a good state of health. CONCLUSIONS: This report supports the concept that new onset inflammatory bowel disease can develop in a heart transplantation recipient in spite of immunosuppression.

Oral budesonide significantly improves water absorption in patients with ileostomy for Crohn disease.

BACKGROUND: In addition to their anti-inflammatory effects, steroids influence electrolyte and water transport systems in the intestinal mucosa. This study analysed the effect of the topically acting glucocorticoid budesonide on ileostomy output in patients with Crohn disease. METHODS: Oral budesonide (3 mg/three times daily for 8 days; n = 20) was compared to placebo (n = 20) in a double-blind design using matched-pair randomization according to ileal resection length in patients without detectable inflammatory activity. Under controlled hospital conditions, absolute output volumes were measured and response was defined as a reduction in intestinal output of > 25% compared to pretreatment conditions. RESULTS: In the treatment group, we observed an absolute decrease in median intestinal output from 1,240 ml to 865 ml (30.2%), compared to 0.3% under placebo (from 950 ml to 947.5 ml). Response was documented in 60% (12/20 patients) in the treatment group compared to no response under placebo (P < 0.0001). While both treatment groups showed similar absolute median reductions (400 ml with ileal resection < or = 20 cm and 405 ml with ileal resection > 20 cm), the relative reduction (response rate) was lower in the subgroup of an ileal resection > 20 cm (36%) due to the greater increase in output secondary to the loss of ileum. CONCLUSIONS: These data support the assumption that the absorptive capacity of the intestinal mucosa for water may be improved by topically acting steroids and suggest that this occurs independently of their anti-inflammatory effect.

Increased expression of interleukin-12 receptor beta(2) on lamina propria mononuclear cells of patients with active Crohn's disease.

BACKGROUND AND AIMS: Since interleukin-12 is pathogenetically involved in Crohn's disease (CD) but not in ulcerative colitis (UC), expression and mechanisms of induction of interleukin-12 receptor (IL-12R) subunits beta(1) and beta(2) were analyzed in lamina propria mononuclear cells (LPMNC) of patients with CD and UC. PATIENTS AND METHODS: LPMNC from patients with CD ( n=17), UC ( n=14), and controls ( n=19) were isolated by standard techniques. IL-12R beta(1) and IL-12R beta(2) transcripts were semiquantified by RT-PCR, and expression of IL-12R beta(2) chain was characterized by flow cytometry. LPMNC were activated by cross-linking with anti-CD3 antibodies and B7-1 costimulation. RESULTS: IL-12R beta(1) and IL-12R beta(2) transcript concentrations were higher in inflamed specimens than in noninflamed segments of patients with CD but not in UC. Increased percentage of mucosal CD4(+)/IL-12R beta(2)(+) cells was observed in active CD, but not UC. In vitro stimulation of LPMNC with anti-CD3 antibodies resulted in an increase in IL-12R beta(1) transcripts irrespective of B7-1 mediated costimulation (84% and 95%, respectively). However, increased expression of IL-12R beta(2) mRNA (110%) was detected only after B7-1 costimulation. CONCLUSION: Our data indicate that increased mucosal expression of IL-12R beta(2) on LPMNC in CD but not in UC may be the result of B7-1 costimulation. Modulation or inhibition of IL-12R beta(2) expression on LPMNC could provide a selective therapeutic approach in CD.

The in vitro anti-inflammatory effects of recombinant anti-CD25 immunotoxin on lamina propria T cells of patients with inflammatory bowel disease are not sufficient to cure experimental colitis in mice.

BACKGROUND AND AIMS: In chronic inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis an aberrant mucosal immune regulation is observed accompanied by upregulation of proinflammatory cytokines. Lamina propria T cells of inflamed mucosa have an activated phenotype characterized by increased expression of surface markers such as CD25. We therefore determined the anti-inflammatory effect of a recombinant immunotoxin consisting of an anti-CD25 single chain variable fragment (scFv) fused to a deletion mutant of Pseudomonas exotoxin A [RFT5(scFv)ETA'] on isolated lamina propria lymphocytes of patients with IBD and in the murine model of trinitrobenzene sulfonic acid (TNBS) induced colitis. PATIENTS AND/METHODS: Lamina propria lymphocytes of 25 patients with IBD and 19 control patients were stimulated in absence or presence of RFT5(scFv)ETA'. Interferon-gamma production was determined in the supernatant by ELISA and the induction of apoptosis by flow cytometry after propidium iodide staining. BALB/c mice received TNBS intrarectally and were treated with RFT5(scFv)ETA'. RESULTS: In vitro the administration of RFT5(scFv)ETA' significantly reduced interferon-gamma production and increased apoptosis in lamina propria lymphocytes isolated of inflamed mucosa. However, this contrainflammatory regulation did not result in gain of weight or increased life span in experimental colitis in vivo. CONCLUSION: In addition to the downregulation of the proinflammatory cytokine in vitro, RFT5(scFv)ETA' induced neither a direct nor a bystander effect in an in vivo model of colitis. Therefore our data do not support potential therapeutic implications of targeting CD25 by RFT5(scFv)ETA' in chronic IBD.

Reoperations at the ileostomy in Crohn's disease reflect inflammatory activity rather than surgical stoma complications alone.

After ileostomy construction for Crohn's disease reoperations due to ileal recurrences are thought to be unusually rare, whereas reconstructions of the ileostomy due to stoma complications are considered to be unusually frequent. It remains unclear why the natural course of a disease as well as outstanding results of a standardized surgical procedure should be perverted. Therefore reconstructions of the ileostomy in 92 patients colectomized during a 12.5-year period and followed up for 5.4 years were analyzed concerning preoperative indication and postoperative histology. In 28 patients (30.4%) a total of 42 reoperations were necessary. The clinical indication was prestomal recurrence in 5 reoperations (11.9%) and stoma complications in 37 (88.1%). In contrast, ileal recurrence was demonstrated histologically in 28 specimens (66.7%) and healthy ileum in the rest. There was a statistically significant association between fibrotic recurrence and stoma stenosis/retraction and a trend for association between penetrating recurrence and peristomal ulceration. The cumulative risk for a first reoperation due to clinical recurrence was calculated at 3.3% and 14.0% at 5 and 10 years postoperatively, whereas the corresponding figures for stoma complications were 25.7% and 40.0%. In contrast, the cumulative risk that a recurrence was found histologically on the occasion of the reoperation was 23.0% and 35.0%, while the probability that the ileum was healthy in the case of a stoma complication remained low. In conclusion, most reoperations after ileostomy-construction in Crohn's disease are associated histologically with recurrent inflammation. The accentuation of the inflammatory recrudescence at the stoma itself or the prestomal ileum is decisive for the clinical presentation as stoma complication or intestinal complication. These findings reinforce both well known characteristics of the inflammatory disease and of established surgery.

Comparable expression of matrix metalloproteinases 1 and 2 in pouchitis and ulcerative colitis.

BACKGROUND AND AIMS: Matrix metalloproteinases (MMPs) are implicated in the tissue destruction associated with inflammatory diseases. Proctocolectomy with ileo-anal pouch (IAP) anastomosis is associated with pouchitis, particularly in patients with ulcerative colitis (UC). The aim of this study was to quantify MMP-1 and MMP-2 in inflamed and uninflamed pouches of patients with UC compared with those with active UC. IAP patients with familial adenomatous polyposis (FAP) served as controls. METHODS: Biopsies were taken from 33 patients with IAP (UC, n=25; FAP, n=8) and from 10 UC patients. MMP-1 and MMP-2 were quantified using sandwich enzyme linked immunosorbent assays. In addition, northern and western blotting and in situ hybridisation experiments were performed. RESULTS: In pouchitis (n=11), MMP-1 and MMP-2 concentrations were increased compared with uninflamed pouches of patients with UC (n=14) or FAP (n=8) (MMP-1 17.7 ng/mg protein v 7.8 (UC) v 7.6 (FAP), p

Establishment of an immunocompetent nipple valve anastomosis to prevent faecal reflux after ileocolic resection in dogs.

OBJECTIVE: To construct an immunocompetent nipple valve anastomosis (NVA) to exclude faecal reflux and compare it with an end-to-end anastomosis to see if it would prevent recurrent inflammation caused by intraluminal bacterial antigens in Crohn's disease. DESIGN: Laboratory study. SETTING: Teaching hospital, Germany. ANIMALS: Two groups of six beagle dogs each of which had NVA or end-to-end anastomosis. INTERVENTIONS: Construction of a NVA by stapling the telescoped nipple, and replacing the ileal mucosa on the valve by colonic mucosa; end-to-end anastomosis. MAIN OUTCOME MEASURES: Radiological, bacteriological, angiographic, and morphometric results. RESULTS: Absolute retrograde pressure-competence and free orthograde permeability of the NVA resulted in significantly lower intestinal bacterial counts compared with the end-to-end anastomosis (p < 0.05). Transposition of colonic mucosa was successful as demonstrated by revascularisation from the ileal nipple and looked normal on morphometry. CONCLUSION: If NVA were constructed in patients with Crohn's disease, recurrences should be prevented, which would verify the immunopathogenetic hypothesis of new inflammation.

Granulocyte elastase and systemic cytokine response after laparoscopic-assisted and open resections in Crohn's disease.

PURPOSE: The aim of this study was to assess whether systemic proinflammatory cytokines (IL-6), anti-inflammatory cytokines (IL-4, IL-10), acute phase proteins (C-reactive protein), or granulocyte elastase are valuable indicators for determining the degree of surgical trauma after open vs. laparoscopic-assisted resections in Crohn's disease. METHOD: Eleven patients in each group (open and laparoscopic-assisted surgery) were matched for indication, surgical procedure, and Crohn's disease activity index. Serum IL-4, IL-6, and IL-10 were measured using enzyme-linked immunosorbent assay. Serum C-reactive protein was determined by immunoturbidimetric assay. Plasma granulocyte elastase was determined by immunoactivation immunoassay. Blood was sampled preoperatively, six hours after the operation, and at postoperative Days 1 to 5. RESULTS: IL-4 was not detectable in any sample analyzed. Serum IL-6 and IL-10 levels peaked postoperatively in both groups without significant differences between laparoscopic-assisted (185.6 +/-54.1 pg/ml and 112.1 +/- 19.4 pg/ml, respectively; mean +/-standard error of the mean) and open surgery (431.1 +/-240.4 pg/ml and 196.7 +/- 56.5 pg/ml, respectively). Serum C-reactive protein levels also rose postoperatively, with a peak on the second day, but showed similar values after laparoscopic-assisted (107.1 +/- 12.1 mg/l) and open (128.3 +/- 17.5 mg/l) surgery. Plasma granulocyte elastase levels peaked on the first and second postoperative day and were found elevated almost throughout the five-day observation period. Comparison between the groups revealed significantly (P < 0.02) lower values after laparoscopic-assisted (Day 1, 46.5 +/- 8.9 microg/l; Day 2, 41.9 +/- 5.9 microg/l) when compared with open surgery (Day 1, 89.7 +/- 13.8 microg/l; Day 2, 91.4 +/- 14). CONCLUSIONS: Serum IL-6 and IL-10 may not be ideal measures for evaluation of the degree of tissue trauma in laparoscopic-assisted and open resections in Crohn's disease, probably because of interference with disease-specific cytokine interactions. In contrast, granulocyte elastase has to be considered a strong marker discriminating the different severity of surgical trauma induced by laparoscopic-assisted vs. open resection in Crohn's disease.

Pattern of mucosal adaptation in acute and chronic pouchitis.

PURPOSE: Variant pathological changes have been observed in ileoanal pouches, including inflammation, villous atrophy, and crypt hyperplasia. Therefore, we investigated the type and degree of mucosal adaptation in patients with ulcerative colitis and familial adenomatous polyposis. METHODS: Forty-two patients with ulcerative colitis and 14 patients with familial adenomatous polyposis with ileoanal pouches were assessed. Samples were taken from three months to eight years after creation of an ileoanal pouch. Mucosal architecture was examined by morphometry after microdissection. RESULTS: Structural changes of the mucosa can be categorized into three groups. Compared with preoperative values, patients without pouchitis (73 percent) has only minor decrease of villous length (402 microm vs. 540 microm) and increase in crypt depth (274.5 microm vs. 177 microm). In patients with acute pouchitis (20 percent), a slight increase in villous length (477 microm vs. 402 microm) and pronounced crypt hyperplasia (376 microm vs. 274.5 microm) was observed compared with noninflamed ileoanal pouches. In contrast, in patients with chronic pouchitis (7 percent), severe villous atrophy (62.5 microm) and crypt hyperplasia (543 microm) was found. CONCLUSIONS: Minor structural changes of ileoanal pouch mucosa develop early as an adaptive response to a new environment. Only in a small group of patients with chronic pouchitis does severe villous atrophy and crypt hyperplasia of the ileoanal pouch mucosa develop, most likely as a consequence of mucosal inflammation.

[The continent ileostomy. Current indications, techniques and results]. / Die kontinente Ileostomie. Gegenwärtige Indikationen, Vorgehensweisen und Ergebnisse.

Over a period of 12 years, 73 patients received a continent ileostomy. 19 Kock pouches were primarily constructed due to contraindications against the ileoanal pouch, 30 ileostomies were converted due to psychological rejection of the incontinent stoma and 9 ileoanal pouches for dysfunction. 15 Kock pouches had to be corrected for nipple valve complications. Perioperative complications (14/73) were related to the Kock pouch in only one third of cases. Surgical late complications of the nipple valve function decreased with technical modifications from 41.1% to 20.0% and then to 4.8%. They could always be dealt with surgically. Pouchitis was observed in 26.8% of cases of ulcerative colitis (11/41), and in 6/15 patients with Crohn's disease (40.0%) complicated ileal recurrences developed. The definitive rate of success over the time was 98.1% in ulcerative colitis and familial adenomatous polyposis (53/54) and 63.2% in other conditions (12/19). Continent ileostomy has become universal and safe method for conversion of any previous operation.

Low-dose budesonide treatment for prevention of postoperative recurrence of Crohn's disease: a multicentre randomized placebo-controlled trial. German Budesonide Study Group.

OBJECTIVE: Endoscopic recurrence of Crohn's disease frequently occurs within weeks after 'curative' operation. Treatment with 3 x 1 mg oral pH-modified release budesonide was tried to prevent postoperative recurrence. DESIGN: A multicentre randomized double-blind placebo-controlled trial of 1 year duration was performed. SETTING: Departments of surgery, endoscopy and pathology of three university hospitals participated in the trial. PATIENTS: Patients with Crohn's disease who underwent ileal and/or colonic resection and whose anastomosis was accessible to colonoscopy were admitted to the study. Of the 88 randomized patients, 83 patients were included in the efficacy analysis (budesonide n = 43, placebo n = 40). Treatment was started within 2 weeks after surgery. INTERVENTIONS: Colonoscopy was performed 3 and 12 months postoperatively. The anastomosis and the adjacent bowel were evaluated by endoscopy and histology. For follow-up of the clinical course of the disease the Crohn's disease activity index (CDAI) was used. MAIN OUTCOME MEASURES: The primary outcome variable was recurrence of Crohn's disease based on endoscopic findings. Secondary efficacy variables were histology scores, CDAI, time-to-failure and global judgement of well-being of the patient. RESULTS: The recurrence rate after 1 year (endoscopic and/or clinical) was 57% (20/35) in the budesonide group and 70% (19/27) in the placebo group (n.s.). Mean time-to-failure was 196 days under budesonide and 154 days under placebo (n.s.). Median CDAI (relapse 19% vs. 28%) and global patients' judgement at the end of treatment (bad 5% vs. 15%) was slightly in favour of budesonide. One patient in each group discontinued the trial because of adverse events. Potentially steroid-related side effects were reported more frequently in the placebo than in the budesonide group (32% vs. 17%) (n.s.). SUMMARY AND CONCLUSION: Although the effect of budesonide was altogether positive in almost all variables studied in this trial (e.g. endoscopic and histopathological score, time-to-failure, CDAI, patients' global judgement and rate of side effects), this increase in efficacy was small and the power for detecting differences versus placebo was too low to be statistically significant. According to these results, low-dose oral budesonide cannot be recommended to be used for the prevention of postoperative relapse in Crohn's disease.

IgG, albumin, and sCD44 in whole-gut lavage fluid are useful clinical markers for assessing the presence and activity of pouchitis.

Pouchitis is the most significant long-term complication in patients with ileoanal pouch anastomosis (IAP) and is especially frequent in patients with ulcerative colitis. There is an urgent need for simple and objective parameters to assess the presence and activity of pouchitis. Whole-gut lavage fluid (WGLF) was collected from 34 patients [8 with pouchitis (PDAI > or = 7 points) and 26 without pouchitis (Pouchitis Disease Activity Index, PDAI, < 7)]. Patients with active ulcerative colitis (n = 8) served as controls. Concentrations of IgG and sCD44 in WGLF were measured by enzyme-linked immunosorbent assays and those of albumin by immunoturbidimetry. Similar to the case in active ulcerative colitis, concentrations of IgG, albumin, and sCD44 in WGLF were significantly increased in acute pouchitis and reached high specificity (IgG 96%, albumin 96%, sCD44 100%) and acceptable sensitivity (75%) for the diagnosis of acute pouchitis. These parameters were also closely correlated with disease activity as determined by PDAI and endoscopic scoring indices. Assay of protein concentrations in WGLF is thus a simple and objective means for grading inflammation of the pouch and may be useful as a quantitative index of disease activity in clinical studies.

[Minimally invasive surgery and Crohn disease]. / Minimal-invasive Chirurgie und Morbus Crohn.

Patients with Crohn's disease are operated on with a morbidity of 15% and a mortality of 0% if the indication for surgery is decided in good time. After ileocecal resection the probability of having a second resection in 15-20 years is about 50%. When elective surgery is done at an early disease stage, ileocecal resections and reoperations for anastomotic stenosis can be performed by assisted laparoscopy assisted. Laparoscopic colonic resections are done more rarely. Acute and life-threatening conditions such as obstruction, perforation and sepsis are excluded from the laparoscopic approach. In a combined series of 222 laparoscopic resections for Crohn's disease, the following types of surgery were included: ileocecal resections (75), anastomotic resections (26), small intestinal resections (4), loop ileostomies (17), gastrojejunostomies (3), partial colonic resections (15), colectomies (16), loop colostomies (2) and one adhesiolysis. Two patients who sustained intraoperative bleeding underwent conversion of laparotomy. The conversion rate ranged from 0 to 22%. Reasons for 32 conversions were: large inflammatory mass (14), severe inflammation (5), fistula (3), abscess (1), perforation (1), small intestine dilation (1) and mesenteric thickening (1). Mean operative time for ileocecal resections ranged from 105 to 200 min. The postoperative hospital stay was 5 to 8 days. As more experience is gained and technical improvement is achieved, additional procedures such as resolution of severe adhesions, fistula closure and resections of colonic segments will be offered to the majority of patients who require elective surgery for localized Crohn's disease.

Increased state of activation of CD4 positive T cells and elevated interferon gamma production in pouchitis.

BACKGROUND: Immunoregulatory abnormalities of T cells might be of importance in the pathogenesis of pouchitis after ileoanal pouch anastomosis (IAP). AIMS: To characterise T cell subsets, their state of activation, and production of cytokines in inflamed and non-inflamed pouches in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The influence of T cell activation on mucosal transformation was also studied. PATIENTS: Mucosal biopsy specimens were taken from 42 patients with IAP (33 with UC and nine with FAP). METHODS: Mononuclear cells were isolated by standard techniques and characterised by three colour flow cytometry. Interferon gamma (IFN-gamma) production was studied using the ELISPOT technique. RESULTS: In patients with UC with pouchitis there was a significant increase in the CD4:CD8 ratio, expression of activation markers on CD3+ cells, and number of IFNgamma producing mononuclear cells compared with patients with UC without pouchitis (CD4:CD8 ratio 1.3 (range 0.7-2.7) versus 0.6 (0. 1-1.0), p=0.012). In addition, a positive correlation between increased crypt depth and the number of CD4+ cells (r=0.57) was shown. CONCLUSION: The observed increase in activated mucosal CD4+ T cells and IFN-gamma production might lead to mucosal destruction and crypt hyperplasia as seen in pouchitis.

Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn's disease. The Budesonide Study Group.

BACKGROUND: The relapse rate after steroid induced remission in Crohn's disease is high. AIMS: To test whether oral pH modified release budesonide (3 x 1 mg/day) reduces the relapse rate and to identify patient subgroups with an increased risk of relapse. METHODS: In a multicentre, randomised, double blind study, 179 patients with steroid induced remission of Crohn's disease received either 3 x 1 mg budesonide (n = 84) or placebo (n = 95) for one year. The primary study aim was the maintenance of remission of Crohn's disease for one year. RESULTS: Patient characteristics at study entry were similar for both groups. The relapse rate was 67% (56/84) in the budesonide group and 65% (62/95) in the placebo group. The relapse curves in both groups were similar. The mean time to relapse was 93.5 days in the budesonide group and 67.0 days in the placebo group. No prognostic factors allowing prediction of an increased risk for relapse or definition of patient subgroups who derived benefit from low dose budesonide were found. Drug related side effects were mild and no different between the budesonide and the placebo group. CONCLUSION: Oral pH modified release budesonide at a dose of 3 x 1 mg/day is not effective for maintaining steroid induced remission in Crohn's disease.

[Surgical concepts in Crohn disease of the terminal ileum and colon]. / Operative Konzepte bei M. Crohn des terminalen Ileums und des Kolons.

Most patients with Crohn's disease have to be operated on. Necessity to loose some amount of the intestine and time-point of the surgical intervention may be derived from the irreversible cascade of the inflammatory process and the limitations of the conservative treatment. In ileocecal disease indications for surgery are represented by stenotic and/or penetrating complications of the inflamed bowel, whereas in Crohn's colitis acute or terminal medical refractority is predominating. Standard-procedures result from constantly definable patterns of the disease manifestation: ileocecal resection and colectomy/-proctocolectomy. In segmental colitis sometimes "resections within Crohn's" may be adequate in a first attempt to avoid anticipating the natural course by surgical means. In these cases the further prognosis depends on the treatment possibilities of the remaining colon. In contrast, true recurrence is a new inflammation of the neoterminal ileum and may indicate repeated resections. The frequence decreases with the number of resections. Nevertheless nutritional status is restored even by multiple resections, whereas specific functional sequelae of the resection--distal resection- and dehydration syndromes--are well treatable mostly. In the case of appropriate timing of the operation and the reoperation operative morbidity and mortality are remarkable low today resulting in an almost normal life expectancy. Most important as negative prognostic factor remains sepsis resulting from pre-existing or postoperative infectious complications. Keeping this in mind experimental pharmaco-therapy to delay the operation and not profoundly substantiated tendencies to minimize surgery are to be considered only with critical scepticism. At the moment, future research is thought to be more successful in focussing prophylaxis of ileal recurrence than avoiding surgery.