Glutamine distribution in patients with ulcerative colitis and in patients with familial adenomatous polyposis coli before and after restorative proctocolectomy.

BACKGROUND AND AIMS: Restorative proctocolectomy with construction of an ileoanal pouch (IPAA) is the surgical treatment of choice for patients with ulcerative colitis (UC) or familial adenomatous polyposis (FAP). This procedure imposes an essential change in function on the terminal ileal mucosa and pouch mucosa. Glutamine is one of the major nutrients for the small-bowel mucosa; it is metabolized into glutamate and subsequently alanine in the human enterocyte. In a prospective clinical trial we compared glutamine distribution in patients with UC to that in patients with FAP before and after restorative proctocolectomy. METHODS AND PATIENTS: Concentrations of glutamine, glutamate, and alanine were measured pre- and postoperatively in the terminal ileal mucosa, pouch mucosa, skeletal muscle and venous blood of patients undergoing IPAA for UC or FAP. Healthy individuals served as controls for skeletal muscle glutamine concentration. RESULTS: After IPAA the glutamine concentration in UC patients was decreased in skeletal muscle. In the mucosa glutamine remained unaltered while glutamate and alanine concentrations increased. In plasma the glutamine concentration increased, the glutamate level fell, and the alanine level increased. In FAP patients the glutamine level was unchanged in skeletal muscle after IPAA. In mucosa the glutamine level did not change, but glutamate and alanine increased. In plasma the glutamine level remained unaltered, glutamate decreased, and alanine increased. CONCLUSION: Patients with UC or FAP before surgical therapy do not suffer from glutamine depletion. IPAA resulted in changes in the distribution of glutamine and its metabolites in skeletal muscle, plasma, and ileal pouch mucosa, particularly in patients with UC. Further studies should investigate whether characteristics in the glutamine distribution have any impact for the long-term outcome after IPAA.

Outcome after septic complications in J pouch procedures.

BACKGROUND: Despite the wide range of surgical approaches for pouch salvage, septic complications are among the main causes of pouch failure. METHODS: This study analysed the mode and outcome of various therapeutic approaches for pouch salvage and the impact of time of diagnosis, localization and form of septic complications on the risk of pouch failure in 131 patients with septic complications of a total of 706 patients undergoing a J pouch procedure. RESULTS: Septic complications consisted of 76.3 per cent fistulas, 15.3 per cent anastomotic breakdowns and 8.4 per cent pelvic abscesses. A total of 107 patients (81.7 per cent) with septic complications required a mean of 2.2 surgical procedures. The frequency of permanent defunctioning and excision of the pouch in the 131 patients with septic complications was 23.7 and 6.1 per cent respectively. The estimated cumulative 3-, 5- and 10-year rate of pouch failure in patients with septic complications was 19.6, 31.1 and 39.2 per cent respectively. The risk of pouch failure was significantly affected by the site of origin of septic complications (P = 0.02). The 5-year pouch failure rate increased in a subgroup of patients with septic complications at the pouch-anal anastomosis when the anal sphincter was involved (50.1 versus 29.2 per cent; P = 0.18). CONCLUSION: Pouch failure as a result of septic complications may occur several years after ileal pouch-anal anastomosis. For prevention of pouch failure, surgery for septic complications is required in a high percentage of patients and repeated attempts are justified. Follow-up studies are required for further analysis of pouch failure.

One- or two-stage procedure for restorative proctocolectomy: rationale for a surgical strategy in ulcerative colitis.

OBJECTIVE: To analyze the results of different strategies for restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) in ulcerative colitis. SUMMARY BACKGROUND DATA: No commonly accepted criteria exist for choosing between the one-stage or the two-stage procedure (with or without temporary diverting ileostomy) for IPAA. The authors analyzed the outcome of patients principally suitable for either of the two alternative surgical strategies. METHODS: A matched-pair control study was performed, comparing surgical details and the early and late outcome of the one-stage (study group, n = 57) versus the two-stage procedure (control group, n = 114), for IPAA. RESULTS: No differences were found between the study group and the control group regarding the matching criteria gender, median age at IPAA, systemic corticoid medication, or activity of colitis. Comparing the patients who underwent a one-stage procedure with those who underwent a two-stage procedure, the proportion of patients without complications was significantly higher (P =.0042) and the frequency of late complications was significantly lower (P =.0022) in patients who underwent the one-stage procedure. The percentage of patients with anastomotic strictures was significantly higher in the control group than in the study group (P =.0022). No significant difference was found between the two groups regarding early complications, pouch-related septic complications, pouchitis, median duration of surgery for IPAA, median blood loss, need for transfusion, or median hospital stay. CONCLUSIONS: In patients with ulcerative colitis in whom there is a choice between a one-stage procedure or a two-stage procedure with a defunctioning ileostomy, the one-stage procedure is clearly superior. This finding is of great clinical relevance both for the subjective interests of the patient and from an economic point of view.

Expression of clusterin in Crohn's disease of the terminal ileum.

Crohn's disease (CD) is a chronic inflammatory intestinal disorder with disturbance and injury of the intestinal mucosal barrier, in which various proinflammatory molecules as well as molecules with antiinflammatory activity and cytoprotective function are found to be expressed. We investigated whether clusterin, a multifunctional cytoprotective protein, is upregulated in Crohn's disease, because augmented expression of clusterin is seen in many organs following various forms of tissue injury. Human actively and inactively inflamed ileal tissues from CD patients as well as normal intestinal specimens from control patients (normal ileum) were investigated by Western blot analysis, immunohistochemisty and in situ hybridization. As compared with controls, a strongly enhanced expression of clusterin was found in CD tissues, correlating with disease activity. Immunohistochemistry and in situ hybridization analysis revealed foci of crypts almost completely lined by clusterin expressing enterocytes in CD, a feature that was never seen in controls. Such crypts appeared especially within the morphologically intact mucosa apart from erosive or ulcerative lesions. Besides epithelia, clusterin was also expressed by inflammatory mononuclear cells. Enhanced expression of clusterin by crypt epithelia might reflect a cytoprotective function of the protein in order to prevent further injury of the intestinal mucosal barrier in CD.

Adenocarcinoma in the ileal pouch: late risk of cancer after restorative proctocolectomy.

Restorative proctocolectomy and ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis. As a long-term complication of this procedure, chronic pouchitis impairs the outcome in a number of patients. Aneuploidia and dysplasia have been observed after long-lasting inflammation of ileal mucosa. The question arises whether chronic inflammation of ileal mucosa predisposes to malignant transformation similar to the situation in the chronically inflamed colon. Cancer of the ileal mucosa has been reported in patients with Brooke's ileostomy and in patients with Kock pouch but not as yet in those with an ileoanal pouch. We report a patient with carcinoma in an ileoanal pouch originating from terminal ileal mucosa who had been suffering from pancolitis with long-term backwash ileitis before, and from chronic pouchitis after, restorative proctocolectomy. This case demonstrates the importance of regular follow-up with pouchoscopy and random biopsies in all patients with long-standing inflammation of the ileal mucosa.

Long-term follow-up after ileoanal pouch procedure: algorithm for diagnosis, classification, and management of pouchitis.

PURPOSE: Inflammation of the ileoanal pouch (pouchitis) is one of the main complications after restorative proctocolectomy, yet its cause remains poorly understood. A standardized definition and diagnostic procedures in pouchitis are lacking. METHOD: We analyzed all cases of pouchitis occurring in a group of 308 patients (210 with ulcerative colitis, 98 with familial adenomatous polyposis) who took part in a prospective long-term follow-up program. The severity of pouchitis was measured using a pouchitis activity score (Heidelberg Pouchitis Activity Score). An algorithm for the classification and management of pouchitis was established which enables the clinician: 1) to determine the severity of pouchitis, 2) to differentiate between primary pouchitis and pouchitis caused by surgical complications (secondary pouchitis), and 3) to evaluate the course (acute vs. chronic (> 3 months)). RESULTS: The median duration of follow-up was 48 (range, 13-119) months. At least one episode of pouchitis was diagnosed in 29 percent of patients with ulcerative colitis and in 2 percent of familial adenomatous polyposis patients. Secondary pouchitis occurred in 6 percent of ulcerative colitis patients and was cured by surgical treatment in 13 (87 percent) of 15 cases. Primary pouchitis was diagnosed in 23 percent of ulcerative colitis patients, including 6 percent of all ulcerative colitis patients with chronic primary pouchitis. The latter showed poor response to medical treatment. In one case multifocal high-grade dysplasia occurred. Histologic examination of the excised pouch identified a carcinoma originating from the ileal mucosa. CONCLUSIONS: Ulcerative colitis patients after restorative proctocolectomy face a high risk of developing pouchitis. The algorithm used in this study was highly efficient in identifying patients with a secondary pouchitis who require surgical treatment and patients with chronic primary pouchitis. For the latter, long-term surveillance seems mandatory because of the risk of malignant transformation of the pouch mucosa.

Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis.

BACKGROUND & AIMS: Commonly accepted risk factors for colorectal carcinoma (CRC) in ulcerative colitis are duration and extent of disease. By identifying still unknown risk factors, surveillance strategies may be improved further. We investigated whether backwash ileitis is also a factor associated with CRC in ulcerative colitis. METHODS: Five hundred ninety consecutive patients with ulcerative colitis who received restorative proctocolectomy were classified into 3 groups: (1) pancolitis with backwash ileitis, (2) pancolitis without backwash ileitis, and (3) left-sided colitis. The association with CRC was analyzed in these 3 groups of patients. As further risk factors, we investigated disease duration, dysplasia, primary sclerosing cholangitis, age at diagnosis of disease, disease activity, and gender. Univariate and multivariate logistic regression were used for analysis. RESULTS: CRC was diagnosed in 11.2% of all patients. CRC was found in 29.0% of 107 patients in group 1, compared with 9.0% of 369 patients in group 2, and in 1.8% of 114 patients in group 3 (P < 0.001). Cancer patients in group 1 showed significantly more multiple tumor growth (45.2%) than patients in group 2 (24.2%) and group 3 (0%) (P = 0.041). Estimating the relative risk for CRC in the multivariate analysis, patients in group 1 showed a significantly higher odds ratio than patients in groups 2 and 3 (odds ratio: 19.36 vs. 9.58 vs. 1; P < 0.001). High-grade dysplasia, low-grade dysplasia, disease duration of more than 10 years, and disease duration of less than 10 years in patients older than 45 years were further factors with significantly increased risk (odds ratios: 21.69, 6.36, 3.63, 4.37), but primary sclerosing cholangitis was not (P = 0.080). However, primary sclerosing cholangitis was strongly associated with backwash ileitis. CONCLUSIONS: There is a strong association of backwash ileitis with CRC in patients with ulcerative colitis who undergo proctocolectomy. The predictive value of backwash ileitis for CRC and premalignant dysplasia in patients with ulcerative colitis should be investigated in future studies based on colonoscopic surveillance.

[The ileo-anal pouch procedure: Complications, quality of life, and long-term results]. / Der ileoanale Pouch - Komplikationen, Lebensqualität und Spätergebnisse.

The ileo-anal pouch procedure: Complications, quality of life, and long-term results. Restorative proctocolectomy with construction of an ileal pouch-anal anastomosis (IPAA) has evolved as the surgical therapy of choice for patients with ulcerative colitis (UC) and patients with familial adenomatous polyposis (FAP). 662 patients (493 UC, 169 FAP) consecutively received IPAA. Marked differences were observed between UC and FAP patients regarding the rates of overall complications (33.1 % vs. 12.5 %), pouchitis (29 % vs. 2 %), and pouch extirpation (3.2 % vs. 0.6 %). Pouchitis occurred as primary (79 %) and secundary (21 %) form, with acute (67.2 %) or chronic (32.8 %) course. Each form and course required specific therapy. Chronic pouchitis implies the risk of malignant transformation of the pouch mucosa. Quality of life improves significantly after IPAA in patients with UC and is equal to that in normal individuals, in UC and FAP, if postoperative complications are either prevented or under control.

[Ileoanal pouch as rectal substitute]. / Der ileoanale Pouch als Rectumersatz.

The ileoanal pouch procedure (IAPP) was the most remarkable breakthrough in the surgical therapy of ulcerative colitis (UC) and familial adenomatous polyposis (FAP) in the last 20 years. The underlying disease is under control, the function preserved and the quality of life markedly improved. Alternative procedures (terminal ileostomy, ileorectal anastomosis) are only indicated in special cases. In the last 16 years we have operated on 662 patients (n = 493 UC; n = 169 FAP) with an ileoanal J-pouch, short rectal cuff, complete mucosectomy and hand-sewn anastomosis. Normally there is a good function for UC and FAP patients after IAPP. Surgical experience, technical modifications concerning the pouch design and the pouch-anal anastomosis, and a differentiated indication lead to a further improvement of these complex procedures with consecutive reduction of complications. Specific complications concerned mainly the pouch-anal anastomosis (fistulas, abscesses, consecutive stenosis) and inflammation of the pouch mucosa (pouchitis). A multivariate analysis showed, that increasing experience of the specialized center is a significant factor reducing inflammatory problems at the anastomosis. The cumulative incidence of pouchitis was 29%. In general there is no problem in successful treatment. But patients with chronic pouchitis are a problematic group (6.2%). Chronic pouchitis is difficult to treat. It is likely that there exists an inflammation dysplasia carcinoma sequence for the ileal pouch mucosa, analogous to the colorectum. Recently we diagnosed the first case of a real ileum pouch carcinoma with associated epithelial dysplasias following chronic pouchitis. Therefore patients with chronic pouchitis must be followed up by endoscopy and random biopsies in a surveillance program. Patients with UC and FAP can gain the life quality of healthy controls, if postoperative complications can be avoided or treated successfully. For the further development of the procedure and the individual long-term success a qualified follow-up and therapy of complications is essential. Both can be carried out only by a specialized center.

No evidence for cancer-related CD44 splice variants in primary and metastatic colorectal cancer.

The expression of alternatively spliced CD44 adhesion molecules has been implicated in the pathogenesis and metastasis of colorectal cancer. Using a new set of primers for exon-specific reverse transcription-polymerase chain reaction (RT-PCR) we delineated the exact exon composition of CD44 mRNAs in normal colorectal mucosa, including isolated colonic crypts, in colorectal carcinomas and in their hepatic metastases. In addition, the surface expression of CD44 isoforms was analysed by immunohistochemistry. We identified by RT-PCR eight variant transcripts expressed in colorectal carcinomas and their metastases, but also constitutively in normal colorectal epithelia. In the normal colorectal epithelium, the surface expression of CD44 standard and variant molecules was restricted to proliferating cells at the bottom of the crypts. Despite expression of these transcripts in colorectal cancers and their metastases, monoclonal antibodies specific for standard or variant epitopes encoded by exons v5 and v6 stained only a few neoplastic lesions. These data point to a differentiation-specific CD44 expression and splicing pattern in proliferating colorectal epithelia. However, they do not support a cancer- or metastasis-specific CD44 splicing pattern. Instead, cell surface availability of CD44 epitopes was reduced rather than increased in primary tumours and particularly in liver metastases.

[Malignant transformation in ulcerative colitis and surgical implications]. / Die maligne Entartung im Verlauf der Colitis ulcerosa und ihre chirurgischen Implikationen.

Patients with ulcerative colitis (UC) are at higher risk for cancer. Risk factors are duration of disease, extent of colitis, associated primary sclerosing cholangitis and possibly early onset of UC in childhood. Epithelial dysplasias are considered as precursors of colorectal cancer within the concept of an inflammation-dysplasia-carcinoma sequence. Dysplasia originates multifocally and is difficult to identify by colonoscopy. Histomorphological diagnosis can also be problematical. Surveillance programs utilize colonoscopy with random biopsies to diagnose dysplasia in patients with risk factors. The efficiency of these programs can be markedly increased when certain rules are applied. The ultimate aim must be to perform a proctocolectomy in patients at higher risk before invasive cancer develops. With only a few exceptions, colorectal cancer in UC can be treated by restorative proctocolectomy. Partial resection of the colon should be avoided because of the high frequency of occult carcinomas and multifocal carcinogenesis. There are first results that indicate a higher risk for malignant deterioration in the terminal ileum. After an ileoanal pouch procedure patients with chronic pouchitis seem to have a higher risk for dysplasia. At the moment the risk for malignancy cannot be calculated because of the relatively short follow-up time after ileoanal pouch procedures. However, it is recommended that after restorative proctocolectomy patients be followed by endoscopy and random biopsies for the rest of their lives.

[Primary sclerosing cholangitis--an ulcerative colitis-associated illness with surgical consequences]. / Primär sklerosierende Cholangitis--Colitis-ulcerosa-assoziierte Erkrankung mit chirurgischen Konsequenzen.

Primary sclerosing cholangitis (PSC) is generally associated with ulcerative colitis (UC). The disease typically progresses slowly, but ultimately, and leads to cirrhosis, liver failure or bile duct cancer. PSC patients with simultaneous ulcerative colitis are also at higher risk for colorectal cancer. At the present time, there is no effective treatment for PSC, although preliminary data show encouraging results after treatment with ursodeoxycholic acid. However, there are no data concerning the delay or prevention of progress of the disease with this drug, because follow-up time is not yet long enough. Isolated bile duct strictures should be treated endoscopically. The possible effect of proctocolectomy on the course of PSC is controversial. Liver transplantation is the therapy of choice for PSC in its final stage. The 5-year survival rate (89%) is significantly better than after transplantation for other indications. Patients with ulcerative colitis have to be followed up by lifelong colonoscopy. Although the course of UC after transplantation is mostly asymptomatic, these patients are at higher risk for colorectal cancer.

[Quality of life after proctocolectomy for ulcerative colitis]. / Lebensqualität nach Proktocolektomie wegen Colitis ulcerosa.

Nowadays, restorative proctocolectomy is considered the "gold standard" in the surgical therapy of ulcerative colitis. Alternative procedures such as Brooke ileostomy or Kock pouch are limited to special indications. Preservation of function is the decisive advantage of the ileoanal pouch, but preservation of function is not equal to quality of life. Quality of life is a multidimensional concept that is difficult to define and measure. Quality of life can only be assessed by standardized and validated quality-of-life questionnaires. Preoperatively, patients with ulcerative colitis have a restricted quality of life, depending on the intensity of their disease. Proctocolectomy is the curative therapy and improves quality of life. When evaluating quality of life it is not essential if patients are treated by Brooke ileostomy or restorative proctocolectomy. The advantage of restorative proctocolectomy is the improvement in some aspects such as sexuality and physical activity. The "Total Quality-of-Life Index" is not improved. Preoperatively, patients should be informed that preservation of function by restorative proctocolectomy is accompanied by an increased postoperative morbidity in comparison to other procedures. Decreased quality-of-life results when complications occur postoperatively that cannot be controlled over a long period of time. In some cases excision of the ileoanal pouch may be the most sensible way of solving the problems. On the other hand, patients without complications and good function after ileoanal pouch procedure may achieve a quality of life comparable to that of healthy controls. Preoperatively, patients should be aware of this risk-benefit relationship and should share the responsibility of the decision for or against restorative proctocolectomy.

[Long-term quality of life after continence-preserving proctocolectomy for ulcerative colitis and familial adenomatous polyposis]. / Lebensqualität im Langzeitverlauf nach kontinenzerhaltender Proktocolektomie wegen Colitis ulcerosa und familiärer adenomatöser Polyposis.

After ileal pouch-anal anastomosis in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP), quality of life is a relevant factor for the assessment of the operation's success, in addition to postoperative morbidity and functional outcome. Between 1982 and 1995 restorative proctocolectomy was performed in 453 patients (UC: n = 332; FAP: n = 121) at the Department of Surgery, University of Heidelberg. We studied postoperative quality of life through a long-term follow-up study (median follow-up time 43.2 months). This study 1 year or more following ileostomy closure of persons who had undergone J-pouch anastomosis (n = 243 total; UC n = 185, FAP n = 58) revealed that at the time of follow-up, the underlying disease (UC versus FAP) and successfully treated complications are without influence on the quality of life. The patient's age (P < 0.01) and the presence of unsuccessfully treated complications (P < 0.0001) showed a significant influence on the quality of life. There was a distinct relation between the functional index and the quality of life index (coefficient of correlation r = -0.714). However, quality of life, comparable to that of healthy controls, can be achieved with UC and FAP patients by restorative proctocolectomy only if postoperative complications can be avoided or are successfully treated.

[Pre- and postoperative quality of life of patients with ulcerative colitis and familial adenomatous polyposis with ileoanal pouch operation]. / Prä- und postoperative Lebensqualität von Patienten mit Colitis ulcerosa und familiärer adenomatöser Polyposis bei ileoanaler Pouchoperation.

After ileal pouch-anal anastomosis in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP), in addition to postoperative morbidity and functional outcome quality of life is a relevant factor for assessment of the operation's success. Between 1982 and 1997 restorative proctocolectomy was performed in 602 patients (UC: n = 424; FAP: n = 178) at the Department of Surgery, University of Heidelberg. The assessment of pre- and postoperative quality of life was done through a prospective study (before restorative proctocolectomy, before and 1 year after closure of ileostomy). This study (UC: n = 27; FAP: n = 7) revealed a poor preoperative quality of life in patients with ulcerative colitis. Proctocolectomy is the decisive factor for the improvement of quality of life in the surgical treatment in UC. Quality of life could not be further significantly improved by ileostomy closure. Before proctocolectomy, FAP patients showed a quality of life, activity and function similar to that of healthy controls. In FAP patients proctocolectomy led to a significant loss of quality of life. This loss could only partly be regained by ileostomy closure. Quality of life and activity comparable to that of healthy controls can be achieved in UC patients by restorative proctocolectomy.

[Complications and late outcome of restorative proctocolectomy]. / Komplikationen und Spätergebnisse nach restaurativer Proktokolektomie.

The restorative proctocolectomy with ileoanal pouch is a sophisticated operative procedure with considerable postoperative complications. The main problems are postoperative ileus (11%), anastomotic stricture (9%), local septic complications (13%) and pouchitis (29%). A variety of other complications also occur. Most of the problems can be successfully managed by conservative or surgical treatment. In only 2.5% (n = 15/593) was final pouch extirpation necessary. Postoperative function showed elevated stool frequency (6 per day) and slightly compromised stool continence. Most patients confirm good quality of life.