The functional outcome after IPAA is acceptable.

32 Pouchitis: clinical cliaracteristics and management

UMA MAHADEVAN AND WILLIAM J. SANDBORN

Introduction

The term 'pouchitis' was coined by Kock et al. [1] in 1977 to describe an inflammatory condition of the continent ileal reservoir in patients who have under- gone a proctocolectomy. This procedure was first described in 1969 [2]. In 1980 Parks et al. and Utsunomiya et al [3, 4] independently described a procedure consisting of a proctocolectomy with ileal reservoir and anal anastomosis. With minor modifi- cations the ileal pouch-anal anastomosis (IPAA) is currently the surgical option of choice in patients with familial adenomatous polyposis (FAP) and ulcerative colitis (UC) with either dysplasia or disease refractory to medical therapy.

The functional outcome after IPAA is acceptable.

The median number of bowel movements in 24 h is six. Soiling at night occurs in approximately one- third of patients and 24% need to wear a pad occasionally [5]. Despite these numbers, the health- related quality of life after IPAA has consistently been comparable to normal populations and better than in those with active UC or inflammatory bowel disease (IBD) in general [5-7]. However, Tiainen et al. found that the health-related quality of life decreased with poor functional status, increased number of bowel movements and chronic pouchitis [5].

Pouchitis is the most common long-term compli- cation of IPAA in U C [8]. Its definition and diagnostic criteria have evolved over time and its etiology is unknown. This chapter will review the current knowledge base for this frequent and some- times debilitating form of IBD.

Diagnosis

The diagnosis of pouchitis should be made on a combination of clinical, endoscopic and histologic grounds. Patients will usually present with diarrhea, watery stools, fecal urgency, abdominal cramps and

occasional rectal bleeding. An endoscopy with biopsies of the pouch is done to confirm the diag- nosis. The neoterminal ileum above the pouch should be normal; inflammation and ulceration here raises the suspicion of possible Crohn's disease (CD).

Inflammation of the pouch mucosa with granularity, edema, mucosal hemorrhages, contact bleeding and superficial ulcers is present in pouchitis with varying degrees of severity [9]. Inflammation is either uniform throughout the pouch or more severe in the distal pouch [10].

In 1987 the Mayo Clinic defined pouchitis as a clinical syndrome of watery, frequent, at times bloody stool accompanied by urgency, incontinence, abdominal cramps, malaise and fever. The symp- toms must be present for at least 2 days and should be relieved within 48 h with metronidazole therapy [8]. While this definition is sensitive for pouchitis, it is not specific and may include other clinical entities such as CD, pouch ischemia and anastomotic stricture.

The St Marks Hospital developed a diagnostic criteria for pouchitis based on a triad of diarrhea (6 or more stools/day), endoscopic findings (four or more of edema, granularity, friability, loss of vascu- lar pattern, mucosal hemorrhage or ulceration), and a minimum grade of 4 on a 6-point histopathologic index (polymorphonuclear leukocyte infiltration and percent ulceration per low-power field) [11]. This definition was very specific, but would exclude less severe cases of pouchitis.

In 1994 Sandborn et al. developed the Pouchitis Disease Activity Index (PDAI) incorporating the Mayo Clinic definition and the pouchitis triad and histopathologic index defined by the St Marks group [12]. The PDAI attempts to provide a standardized definition of pouchitis based on clinical, endoscopic and histologic markers (Table 1), with pouchitis defined as a score of seven or more points. Diarrhea was defined based on an increase from the baseline number of bowel movements. Other clinical manifes-

Stephan R. Targan, Fergus Shanahan andLoren C. Karp (eds.), Inflammatory Bowel Disease: From Bench to Bedside, 2nd Edition, 643-658.

© 2003 Kluwer Academic Publishers. Printed in Great Britain

Table I.The Pouchitis Disease Activity Index

Clinical criteria Stool frequency

Usual postoperative stool frequency 1-2 stools/day > postoperative usual 3 or more stools/day > postoperative usual

Rectal bleeding None or rare Present daily

Fecal urgency/abdominal cramps None

Occasional Usual

Fever (temperature > 100 F) Absent

Present

Endoscopic criteria Edema

Granularity Friability

Loss of vascular pattern Mucus exudates Ulceration

Acute histologic criteria Polymorph Infiltration

Mild

Moderate + crypt abscess Severe + crypt abscess

Ulceration per low-power field (average)

< 2 5 %

^ 2 5 % ^ 5 0 %

> 50%

Score

0 1 2

0 1

0 1 2

0 1

1 1 1 1 1 1

1 2 3

1 2 3

Pouchitis is defined as a total PDAI score of seven or more points.

Adapted with permission form: Sandborn WJ, Tremaine WJ, Batts KP, Pemberton JH, Phillips SF. Pouchitis following ileal pouch-anal anastomosis: a pouchitis disease activity index. Mayo Clin Proc 1 9 9 4 ; 6 9 : 4 0 9 - 1 5 .

tations such as rectal bleeding, abdominal cramps and urgency were also included. The specificity and sensitivity of diagnosis is increased by defining the disease as a continuum from mild to severe pouchitis with symptoms individualized to the norms of each patient.

A pouchitis classification scheme was also proposed by Sandborn in 1996 [13]. The degree of activity of pouchitis can be delineated as either remission (no active pouchitis), mild to moderate activity (increased stool frequency, urgency, infre- quent incontinence), or severely active (hospitaliza-

tion for dehydration, frequent incontinence). Dura- tion is defined as acute ( < 4 weeks) or chronic ( > 4 weeks). The pattern of pouchitis is described as infrequent (one or two acute episodes), relapsing (three or more acute episodes), or continuous.

Finally, the response to medical therapy is labeled as treatment-responsive or treatment-refractory with the medications for either case specified.

If pouchitis is refractory to medical therapy, or has atypical components, further diagnostic tests should be done to exclude alternate diagnoses such as pouch dysfunction. Infectious etiologies should be ruled out by stool sampling and pouch biopsy. There are three cases in the literature of chronic treatment-refractory pouchitis eventually diagnosed as cytomegalovirus infection of the pouch. Therapeutic response to ganciclovir was achieved [14, 15].

Pouchogram X-ray (luminal contrast study) will demonstrate ileoanal anastomotic separations, pouch fistulas and anastomotic strictures. If CD is suspected, a small bowel follow-through X-ray will rule out disease above the pouch. A computerized axial tomograph (CT) of the pelvis will detect peripouch abscesses or inflammatory phlegmons.

Endoluminal transpouch ultrasonography has also been used in pouch dysfunction with reported higher rates of fistula and abscess detection than both CT scan and pouchography [16]. Anorectal manometry can be used to rule out pelvic floor dysfunction.

Finally, scintigraphic pelvic pouch emptying scans can be used to evaluate patients with inefficient or inadequate pouch evacuation [17].

Pathophysiology

The ileal pouch undergoes adaptive changes once it

is exposed to the fecal stream. Functionally, it

changes from a primarily absorptive organ to an

organ of storage. The histopathologic changes that

follow likely reflect this transition. However, the

efficiency of pouch emptying or fecal stasis does not

appear to be a factor in the degree of mucosal change

[18]. The mucosal permeability in the pouch also

changes after ileostomy closure. The initially high

permeability of the isolated pouch decreases with

reanastomosis. This suggests an adaptive mucosal

response to reanastomosis and exposure to the fecal

stream. The permeability increases again in the

presence of pouchitis. Whether this is a cause or

effect of inflammation from the invasion of fecal

bacteria is unknown [19].

Inflammatory and morphologic changes occur in the pouch mucosa early after ileostomy closure and subsequently do not show a significant difference from 6 weeks to 6 months after reanastomosis [20].

A normal pouch, in both FAP and UC patients, will undergo a minor decrease in the length of the vilH and an increase in crypt depth. With acute pouchitis there is a slight increase in villous length and pronounced crypt hyperplasia. Chronic pouchitis, however, will demonstrate severe villous atrophy and crypt hyperplasia [21].

Ileal pouches acquire certain colonic characteris- tics including goblet cells, villous atrophy and crypt hyperplasia; however, complete colonic metaplasia does not seem to occur [20, 22]. A study of 25 pouch patients found that the nine with the most severe villous changes produce colorectal-type sulfomucin.

However, all patients had small bowel sucrase-iso- maltase activity regardless of the severity of inflam- mation [23]. The inflammation tends to be macro- scopically and histologically most severe in the distal versus the more proximal zone of the pouch [10].

Sheperd et al. showed that there was greater inflam- mation in the posterior wall where the mucosa is in contact with the fecal stream than in the anterior wall, which may be protected from prolonged contact by gas in the lumen. Some colonic pheno- typic expression was found in 96% of pouches, with- out complete colonic metaplasia [24].

Etiology

The etiology of pouchitis is unknown. Speculation has centered on the possibility of fecal stasis and/or bacterial overgrowth, nutritional deficiencies, ischemic complications of surgery, a novel third form of IBD, a recurrence of UC in the pouch, or a missed diagnosis of CD. The significantly higher occurrence of pouchitis in patients with UC versus FAP suggests that the mechanism is not related to surgical changes common to both diseases - i.e. ischemia and fecal stasis. However, the efficacy of allopurinol and anti- biotics in treating pouchitis suggests that these mechanisms may play a role. The UC host may be genetically more susceptible to having an inflamma- tory response to these insults in the pouch, much as they are theorized to be susceptible to such insults in their now-resected colon.

Lichtman etal. described a model of pouchitis [25].

in both Lewis and Sprague-Dawley rats that under- went ileal pouch rectal anastomosis. This model demonstrates many of the possible etiologic theories

of pouchitis. Increased anaerobic bacterial flora in the pouch versus normal ileum was noted and inflammation was present within 4 weeks of surgery.

Postsurgical treatment with both metronidazole and allopurinol, a xanthine oxidase inhibitor thought to decrease post-ischemic damage mediated by free radicals, led to histologic improvement in the pouches. A more severe pouchitis developed in the Lewis rats versus the Sprague-Dawley rats, suggest- ing a host genetic susceptibility to pouchitis.

Autoimmune mechanisms

There is evidence to suggest that pouchitis is a recurrence of UC or a novel, third form of IBD.

When the ileal reservoir undergoes adaptive changes in its histology and physiology resembhng colonic mucosa, it may become more susceptible to the autoimmune mechanisms that underlie UC.

Mucosal cellular infiltrates in ileal reservoirs demonstrate intraepithelial lymphocyte densities similar to counts in the normal colon and signifi- cantly less than expected in normal ileum. An increase in RFD9'^ macrophages is known to occur in IBD, but not in acute infections. The proportions of RFD9"^ and 3G8^ macrophages were found to be significantly higher in pouchitis reservoirs versus normal reservoirs [26].

Increased levels of interleukins IL-ip, IL-6 and IL-8 are found in patients with pouchitis versus those with normal ileal mucosa or ileal reservoirs without pouchitis [27]. These cytokine levels were also found to be significantly higher in active pouchitis and chronic active UC compared to healthy controls [28]. In addition, activation of cytokine transcription factors STAT-lot and STAT-ip in pouchitis resem- bles patterns of activation in UC [29]. These levels decrease after treatment of the pouchitis [30].

Mucosal biopsy specimens from patients with

pouchitis demonstrate an increase in activated

CD4'^ T ceUs and interferon-gamma (IFN-y) pro-

duction. The authors suggested that this might lead

to the mucosal destruction and crypt hyperplasia

seen in pouchitis patients [31]. Leukotriene B4, an

eicosanoid involved in mucosal inflammation, has

increased concentrations in UC compared to normal

controls. Concentrations have also been found to be

increased in patients with pouchitis versus those

without [32, 33]. Though these in-vitro studies may

only be detecting markers of inflammation, they

suggest that autoimmune mechanisms similar to

UC are at play in the inflamed ileal reservoir.

Genetics: pANCA and extraintestinal manifestations

The association of the serologic marker antineutro- phil cytoplasmic antibody-perinuclear staining pat- tern (pANCA) with pouchitis is controversial. The prevalence of pANCA in UC patients is 60% [34].

Whether this number is decreased after proctocolect- omy [35, 36] or unchanged [37-40] is a matter of debate. The literature is also divided as to whether there is a correlation between pANCA and the development of pouchitis. Four studies have found that the prevalence of pANCA is higher than expected in I PA A patients with pouchitis (89-100%) and lower than expected in patients without pouchi- tis (18-74%) [34, 38, 39, 41]. However, six more recent studies have shown that there is no correlation between pANCA and the occurrence of pouchitis [36, 40, 42-45]. Whether the failure of these later studies to demonstrate an association is based on the definitions of pouchitis used, the ANCA assay methodology, disease heterogenicity or a true absence of association remains to be determined.

However, pANCA levels are increased in patients with primary sclerosing cholangitis (PSC) [46]. PSC, in turn, is a risk factor for pouchitis [35, 47, 48].

Patients with PSC who undergo IPAA have a 63%

chance of developing pouchitis versus only 32% for those without PSC. The cumulative risk of develop- ing pouchitis in PSC patients is also higher at 1, 2, 5 and 10 years than in UC patients without pouchitis (22%, 43%, 61% and 79% respectively versus 15.5%, 22.5%, 36% and 45.5%) [48].

Extraintestinal manifestations (EIM) are also increased in patients with pouchitis [42, 49-51]. The increased incidence of pouchitis in patients with PSC and other EIM suggests that there may be a particu- lar genotype of UC that has a stronger predisposition to develop pouchitis. pANCA may or may not be a serological m a r k e r for that genotype. These correlations also support the theory that pouchitis may be either a recurrence of UC in the pouch or a third, new form of IBD.

IVIissed diagnosis of Cretin's disease

Patients with pouchitis may have findings that over- lap with CD. Often, ulcerations and fistulas occur at the site of anastomotic suture lines and have features consistent with CD [9, 52]. However, histologic and endoscopic studies of refractory pouchitis have shown no evidence of CD [9, 53]. Multiple investiga-

tors have suggested that a diagnosis of CD should never be made based on findings in the pouch. This diagnosis requires disease in the neoterminal ileum above the pouch, the presence of fistulas, reexamina- tion of the original proctocolectomy specimen or disease in the remaining gut consistent with CD.

Fecal stasis and bacterial overgrowth

After colectomy the ileal reservoir develops a micro- bial flora count that is between what is expected in the normal terminal ileum and the colon [54]. This find- ing, as well as the response of the inflamed pouch mucosa to antibiotics (see below) has led to the theory that pouchitis is the result of inflammation caused by fecal stasis and bacterial overgrowth in the new ileal reservoir. Studies of the ileal pouch have varied. Some authors found that patients with pouchitis did indeed have greater counts of anaerobic and/or aerobic bacteria, when compared to controls without pouchi- tis [55-59]. Others have found an increase in the bacterial count in all ileal pouches when compared to ileostomy controls and the normal colon, but without a significant difference between those with and with- out pouchitis [60-64]. This suggests that, if a relation- ship exists between bacterial overgrowth and pouchi- tis, it is not a direct one.

Fecal bile acids

Alterations in bile acid metabolism occur after IPAA. Natori et al. found increased levels of cholic acid and chenodeoxycholic acid and decreased levels of the secondary bile acids deoxycholic acid and lithocholic acid in ileal pouches versus healthy con- trols. However, these secondary bile acids were greater in the ileal pouch compared to ileostomy patients, suggesting that a degree of normalization occurs in pouch patients secondary to fecal stasis and bacterial overgrowth in the pouch [65].

Bile acids were found to be cytotoxic to epithelial

cells [66], suggesting they have a role in pouchitis and

colonic metaplasia. However, later studies by the

same author showed that the ileal dialysate was not

cytotoxic to the epithelial monolayers. Epithelial

resistance and histologic structure was actually pre-

served, suggesting the presence of a protective factor

in the dialysate [67]. Further studies also disputed the

role of bile acids in pouchitis by demonstrating no

difference in the total bile acid concentration or daily

fecal bile acid output in pouchitis patients versus

those with a healthy ileal reservoir [52, 64, 68].

Short-chain fatty acids (SCFA)

Short-chain fatty acids (acetate, propionate, buty- rate), are products of anaerobic bacterial fermenta- tion of carbohydrates. They are the major source of energy for the colonic mucosa [69] and are involved in crypt cell production and the absorption of water and electrolytes [70]. While patients with IPAA have been found to have the same mean total concentra- tions of SCFA as normal controls [71] some authors have found decreased levels of SCFA in both active ulcerative colitis [72, 73] and active pouchitis [74- 77]. However, Sandborn et al. found no difference in the total fecal SCFA concentrations between patients with and without pouchitis, no correlation between fecal bacterial concentrations and total fecal SCFA, and no correlation between fecal concentrations of bacteria or SCFA and chronic inflammation or villous atrophy [64].

ischemia

Construction of the ileal pouch may require division of mesenteric vessels to avoid tension on the anasto- mosis, resulting in some degree of ischemia in the pouch [78]. This ischemia may not be a single post- operative injury, but chronic transient damage aggravated by distension of the pouch. Mild endo- scopic and histologic changes consistent with ischemia have been found in the ileal reservoirs of IPAA patients [52, 79]. Patients with pouchitis were also found to have lower rates of mucosal blood flow on endoscopic Doppler readings in the pouch than healthy controls [80].

The villi of the small intestine are reported to contain the highest concentration of xanthine dehydrogenase of any tissue [81]. It has been hypothesized that transient ischemia in the pouch leads to conversion of xanthine dehydrogenase to xanthine oxidase. During subsequent reperfusion, xanthine oxidase catalyzes the formation of oxygen free radicals, possibly leading to cellular injury and pouchitis [82-84]. However, the same surgical techniques are used in both UC and FAP patients, the latter of whom have far fewer episodes of pouchitis. It is unlikely that ischemia is itself a direct cause of pouchitis, but it may play a role in the susceptible host.

Epidemiology

incidence

The cumulative risk of having one or more episode of pouchitis varies from 15% to 53% in patients with UC. This variation in range likely results from the different diagnostic criteria used for pouchitis over the years [48, 85-91]. The rate is much lower in patients with FAP, ranging from 3% tol4%o [85, 87, 92]. The rates of refractory pouchitis range from 4.5% to 5.5%, with severe intractable pouchitis leading to excision of the pouch in 0.3%o to 1.3%) of patients. Fig. 1 shows the clinical outcome of 100 UC patients at the Mayo Clinic who underwent IPAA [13].

Predictive factors

Penna et al. found a cumulative risk of pouchitis in UC patients to be 15.5%, 22.5%, 36% and 45.5% at 1, 2, 5 and 10 years after IPAA, respectively. This risk was much higher in patients who had PSC, whose risk at 1, 2, 5 and 10 years was 22%, 43%, 61% and 79% respectively [48]. Stahlberg et al. found similar results with a cumulative risk of 51%o at 4 years. All six patients (100%) with PSC developed pouchitis, and extracolonic manifestations as a whole were a predictive factor for pouchitis [89].

Multiple other studies lend support to the belief that there is an increased incidence of pouchitis in patients with EIMs [42, 49-51]. Lohmuller et al.

studied 734 patients who underwent IPAA. Patients who had preoperative EIM had a 39% incidence of pouchitis versus an incidence of 26%o for those who did not. Those who developed EIM postoperatively had a 53%o incidence of pouchitis versus 25%) in those who did not.

As in UC smoking has been found to be protective against the development of pouchitis. Merrett et al.

found an incidence of pouchitis of 33% in ex-smo- kers, 25% in non-smokers and 6% in current smokers [93]. These findings have been supported by others [49, 89].

The role of the extent of preoperative UC on the development of pouchitis is more controversial.

Samarasekera et al. found no correlation between distal colitis or more extensive disease and the incidence of pouchitis in 177 patients studied [94].

However, Schmidt et al. found that colonic extension

had a statistically significant association with the

development of pouchitis after IPAA with a linear

UC patients with IPAA 100

. — ' — .

No pouchitis

68 Pouchitis

32 I Recurrent

pouchitis 21

1-2 episodes of acute pouchitis

11

I

Maintenance suppressive therapy

3

Chronic pouchitis 5

i

Frequent relapses of acute pouchitis

16 Pouch

excision 2

Figure 1.The clinical outcome of 100 patients at the Mayo Clinic who underwent ileal pouch-anal anastomosis for ulcerative colitis.

Republished with permission from: Sandborn WJ. Pouchitis: definition, risk factors, frequency, natural history, classification, and public health perspective. In McLeod RS, Martin F, Sutherland LR et al. (eds.). Trends in Inflammatory Bowel Disease 1996.

Lancaster, UK: Kluwer Academic Publishers, 1997: 51-63.

association between the gross extent of colonic disease and pouch inflammation. However, the severity of the disease was not predictive [95].

Interestingly, inflammation in the terminal ileum with eosinophils and villous blunting was also pre- dictive with a linear association with the degree of pouch inflammation [95]. The role of eosinophils is further supported by the finding of a threefold elevation in the preoperative colonic mucosa of patients who subsequently developed pouchitis versus those who did not [96].

Pouchitis does not appear to have a predilection for age, sex or race, though one small study did note a decreased incidence in African-Americans when compared to Caucasians [49]. The presence of PSC or other EIM, however, does appear to be predictive for the development of pouchitis. Likewise, the risk of developing pouchitis in smokers is decreased. The role played by the extent of preoperative disease and the histopathology of the colon and terminal ileum needs to be further assessed.

Dysplasia

The risk of dysplasia and adenocarcinoma in the pelvic pouch has been mostly a theoretical concern, but one which may become increasingly real in the near future as pouches surpass the age of 20. While cancer in the rectal cuff' following IPAA was described in 1990 [97], an adenocarcinoma of the actual ileal pouch has yet to be described. This may just be a matter of time.

In 1990 Heppell et al. demonstrated a rodent

model of cancer in the Sprague-Dawley rat ileal

reservoir using a chemical carcinogen, 1,2-dimethyl-

hydrazine (DMH), and a tumor promoter, sodium

butyrate [98]. Two of 20 rats with a total colectomy

and ileal reconstruction developed ileal pouch carci-

noma. This was similar to the rate of ileal cancer in

the rats without surgery or with ileorectal anastomo-

sis. However, there was a high death rate in the rats

with an ileal reservoir, precluding randomization

and possibly biasing the results. Lichtman et al. [25]

found lower rates of pouchitis in Sprague-Dawley rats versus Lewis rats undergoing ileal pouch formation. If pouchitis and chronic inflammation predispose to dysplasia, Lewis rats with higher pouchitis rates would theoretically demonstrate higher rates of adenocarcinoma in the ileal pouch.

There have been at least 17 cases of adenocarci- noma arising in the permanent ileostomy of patients with UC. The case described by Reissman et al notes diffuse colonic metaplasia in the ileostomy around the adenocarcinoma with sulfomucin production [99]. In 1997 the first case of an adenocarcinoma arising in a continent ileostomy was described in a patient with UC. The pouch mucosa showed chronic inflammation with villous atrophy and mild to mod- erate dysplasia [100]. It was not clear if this patient suflered from recurrent pouchitis. Also in 1997 a case of large cell lymphoma arising in the pouch of a patient who had had UC was described. This patient suffered from chronic refractory pouchitis, which may in retrospect have been due to the invasive lymphoma, undetected until surgical resection of the pouch for pouch dysfunction [101].

The first reported case of dysplasia in a patient with an IPAA was in 1991 [102]. In 1995 the same group reported the results of 87 patients with IPAA for UC, followed for a mean of 6.3 years. Three types of mucosal adaptation were noted in the reservoir.

Type A (51% of patients) was characterized by normal mucosa or a mild villous atrophy and no or mild inflammation. Type B (40% of patients) demon- strated transient atrophy with temporary moderate or severe villous atrophy followed by normalization.

Finally, type C (9%) demonstrated constant atrophy with permanent total or subtotal villous atrophy accompanied by severe pouchitis. It was in this last group that low-grade dysplasia was found in three of eight patients. This group also had the greatest detection of sulfomucin-producing goblet cells in the pouch [103]. A prospective follow-up of seven patients with type C mucosa and 14 with type A patterns was done. Dysplasia was noted in five of seven pouches (71%) - four low-grade dysplasia and one high-grade dysplasia. There was no correlation with dysplasia in the colectomy specimen but there was an association with an early onset of UC. The authors felt that patients identified as having a type C response 4 years after ileostomy closure should have at least annual pouchoscopy with surveillance for dysplasia [104].

Other authors have not found dysplasia on surveil- lance of the pouch [105-108]. However, similar rates

of type A, B and C mucosa were found in adults [107]

and children [108] with an ileoanal pouch for UC.

Setti Carraro et al. confirmed the finding that only patients with type C mucosa developed chronic pouchitis. They also noted that the categorization of response type could be made at 6 months after ileostomy closure [107].

In 1991 Lofberg etal. [102] reported a case of a 36- year-old Sri Lankan man with intractable UC who underwent a colectomy, mucosal proctectomy and IPAA with an S-type pelvic pouch. No dysplasia was noted in the colectomy specimen. The patient suffered from chronic pouchitis and was on long- term metronidazole therapy. Four years after pouch creation he was noted to have low-grade dysplasia on biopsy and DNA aneuploidy by flow cytometry. The patient then underwent periodic surveillance pouchoscopy with biopsy and in 1996 high-grade dysplasia was detected [104]. In 1997 the patient experienced abdominal pain. Further investigation led to the diagnosis of a p r i m a r y cholangio- carcinoma, with likely underlying subclinical PSC.

The patient expired 3 months later [109].

This case illustrates much of the epidemiology of pouchitis and dysplasia discussed above. The patient had an increased risk of developing pouchitis because of his underlying PSC. The presence of both chronic pouchitis and PSC (by extrapolation from the dysplasia data in patients with UC and PSC [110-

115]) increased his risk of dysplasia. Patients with chronic and severe inflammation have a greater degree of colonic metaplastic changes in their pouch.

This may expose them to the same factors - auto- immune, bacterial, genetic - that lead to their initial UC. This partially colon-like mucosa is now suscep- tible to develop an IBD type illness with its inherent risk of dysplasia.

No screening program is currently advocated for patients with IPAA after colectomy for UC. Further studies are needed to delineate which patients need screening, when, where in the pouch and how often.

It is reasonable, based on the available data, to do

random mucosal sampling in the reservoir of all

patients with a history of UC and a pouch 4 years

after closure of the ileostomy. Those found to have

type C mucosal changes and/or chronic pouchitis

should undergo annual surveillance pouchoscopy,

much as is done in UC.

Treatment

The treatment of pouchitis is predominantly empiric given the few controlled trials available. In a review of medical therapy in pouchitis, Sandborn et al.

identified only four randomized controlled trials for the treatment of pouchitis [116]. Antibiotics are the mainstay of treatment, lending credence to theories of bacterial overgrowth and fecal stasis having a primary role in the pathogenesis of pouchitis. Other treatments are based on therapy used in UC as well as pathophysiologic changes noted in the pouch.

Table 2 lists the treatment options available [117].

Antibiotics

Metronidazole is the first-line therapy for pouchitis.

Support for metronidazole comes from a W-of-T

Class

randomized trial [118] and a randomized controlled crossover trial which demonstrated a 73% response (defined as a decrease in stool frequency) in 13 patients with chronic pouchitis. The placebo response was 9% [119]. Hurst et al. found that 41 of 52 patients (79%) with acute pouchitis responded to a 7-day course of metronidazole at 250 mg orally three times a day with complete relief [92]. Two small series found metronidazole to have a response rate of 100% when given as a topical solution instilled at 7 5 - 150 mg daily [120] or 40-160 mg daily [ 121 ]. The 20%

of patients who fail to respond to oral metronidazole, or who suffer from side-effects such as dysgeusia, dyspepsia, nausea and peripheral neuropathy, can be tried on alternate antibiotics.

Hurst et al. found that 11 of 52 patients did not respond to metronidazole. These patients were then given ciprofloxacin at 500 mg twice a day, with eight

Example

1. Antibiotics

2. Probiotics

3. 5-Aminosalicylates

A. Metronidazole B. Ciprofloxacin

C. Amoxicillin/clavulanic acid D. Erythromycin E. Tetracycline F. Rifaximin

A. Lactobacilli, Bifidobacteria, Streptococcus salivarius subsp. ttiermoptiilus

A. Mesalamine enemas B. Sulfasalazine C. Oral mesalamine

4. Corticosteroids

5. Nutritional agents

6. Immune modifier agents

7. Oxygen free radical inhibitor

8. Smoking/nicotine

A. Conventional corticosteroid enemas B. Budesonide enemas

C. Oral corticosteroids

A. Short-chain fatty acid enemas or suppositories B. Glutamine suppositories

A. Cyclosporine enemas

B. Azathioprine

A. Allopurinol

A. Smoking B. ?Transdermal nicotine 9. Antidiarrheal/antimicrobial A. Bismuth subsalicylate

B. Bismuth carbomer enemas

10. Surgical options A. Ileal pouch exclusion

B. Ileal pouch excision

Modified with permission from: Sandborn WJ.

Gastroenterology 1994; 107:1856-60.

Pouchitis following ileal pouch-anal anastomosis: definition, pathogenesis, and treatment.

(73%) responding. This gave an overall antibiotic response rate of 96% [86]. Gionchetti et al used rifaximin 1 g twice a day in combination with ciprofloxacin 500 mg twice a day for 15 days in 18 patients with chronic treatment-resistant pouchitis [122]. Sixof 18 (33%) had complete remission defined as a PDAI of 0. Ten of 18 (55.6%) had clinical improvement with a decrease of three points on their PDAI, for a total response rate of 88.8%). Other antibiotics used with some success include amoxicil- lin/clavulanic acid, erythromycin and tetracycline [123].

An initial episode of pouchitis should be treated with metronidazole 250 mg three times a day for 7 - 10 days. Response should be seen within 2-3 days.

Responders who have repeat episodes and are able to tolerate the medication should be re-treated with the

same regimen. Some patients with chronic pouchitis will require anywhere from 250 mg every third day to 250 mg three times daily to maintain their response.

Others may develop resistance and require a rotating schedule of three or more antibiotics. If antibiotics fail, other therapeutic options should be considered (Fig. 2) [117].

5-Aminosalicylates (5-ASA)

Anecdotal reports suggest a benefit from oral and topical mesalamine [9, 52, 124]. Miglioli et al.

describe three patients with pouchitis after IPAA for UC. They were given 5-ASA as a suppository or enema at 1.2-4 g daily. After 20-30 days a clinical and endoscopic improvement was noted with partial histological recovery [125].

Symptoms of pouchitis

1

Endoscopy with biopsy

Pouchitis

\

-*• Metronidazole

I

\ Distant recurrence

Response

—h-

— \ No recurrence

Response

I

. Distant recurrence

Prompt recurrence [\/laintenance metronidazole

—I

No response <

\

• No pouchitis l\/letamucil

Imodium Lomotil

* No response

• Other antibiotics ^ Anti-inflammatory drugs ° Immunosuppressive drugs ^

Nutritional replacement^

Allopurinol Surgical consult

\

Consider reconstruction Consider pouch excision Figure 2, Treatment algorithm for pouchitis. Other antibiotics^ indicates: ciprofloxacin, rifaximin, amoxicillin/clavulanate, erythromycin, tetracycline, and cycling of multiple antibiotics. Anti-inflammatory drugs^ indicates: mesalamine enemas, sulfasalazine, and oral mesalamine. Immunosuppressive drugs^ indicates: steroid enemas, oral steroids, budesonide suppositories, azathloprine, and cyclosporlne enemas. Nutritional replacement^ indicates: SCFA enemas and glutamine suppositories. Probiotics are not available in the United States. Reproduced with permission from: Sandborn WJ. Pouchitis following ileal pouch-anal anastomosis:

definition, pathogenesis, and treatment. Gastroenterology 1994; 107:1856-60.

The bacteria required to split the azo bond in sulfasalazine and release the 5-ASA moiety are present in the reservoir of patients after IPAA [126], suggesting sulfasalazine will be a viable treatment modality. Pentasa may also achieve some release of mesalamine into the ileal pouch. However, no trials were found in the literature for oral 5-ASA agents in the treatment of pouchitis.

Corticosteroids

When antibiotics fail, oral and topical corticoster- oids have been tried with limited anecdotal success [52, 124]. A small trial of budesonide suppositories was conducted in 10 patients with active pouchitis.

After 1.5 mg/day for 4 weeks all patients had clinical and endoscopic improvement or remission, but six (60%) relapsed within 8 weeks [127].

Immunosuppressive therapy

Immunosuppressives have been anecdotally surpris- ingly ineffective, as well as poorly studied. MacMil- lan et al. did report a small retrospective series of four patients with chronic pouchitis [128]. Patients were treated with varying doses of azathioprine or 6- mercaptopurine. Within 6 months of starting ther- apy, steroids were discontinued and a sustained response was maintained for up to 3 years. Cyclos- porine (CSA) enemas were used in 12 patients with distal UC and one patient with pouchitis while continuing prior therapy. This 250 mg CSA retention enema resulted in symptomatic and endoscopic but not histologic improvement within 8 weeks in the patient with pouchitis [129].

Transplant data demonstrate that immunosup- pression is not protective against pouchitis. Zins et al. report seven patients with IPAA who underwent orthotopic liver transplantation for PSC [130]. Five of the seven had chronic or recurrent pouchitis prior to transplant, of whom four continued to have chronic pouchitis after transplant despite a triple i m m u n o s u p p r e s s i v e regimen of p r e d n i s o n e , azathioprine and either cyclosporine or FK506. One patient who had been free of pouchitis prior to transplant developed a single acute episode post- transplant. Rowley et al. report a series of four patients with IPAA and orthotopic liver transplant for PSC. One of the four developed chronic pouchitis despite cyclosporine use [131].

Bismuth

Bismuth carbomer foam enemas showed promising results in an open-label trial [132]. Twelve patients with treatment-refractory chronic pouchitis were treated with 230 mg elemental bismuth containing carbomer foam enemas. The enemas were given nightly for 45 days. Ten of 12 (83%) patients had a clinical response with a decrease in their PDAI by 2 or more points. Of these 10, six (60%) maintained their remission over 12 months while receiving an enema every third night. No side-effects were reported.

However, a randomized double-blind placebo- controlled trial in 40 patients demonstrated no difference between placebo and bismuth carbomer foam enema in the treatment of chronic pouchitis [133]. Twenty patients received a placebo enema containing gum resin, and 20 received 270 mg of elemental bismuth complexed with carbomer deliv- ered as foam enemas for 3 weeks. No patients achieved remission (PDAI of 0) but nine patients (45%) in each group achieved a clinical response with a three-point decrease in their PDAI. The authors site low concentrations of bismuth in the enemas, short duration of treatment, therapeutic efficacy of gum resin (given the high placebo rate of 45%) or a true treatment failure to explain the lack of efficacy of bismuth. As in UC and CD, promising pilot studies do not always translate into positive randomized controlled trials.

A retrospective series of 13 patients with chronic pouchitis studied the effect of oral bismuth subsali- cylate tablets (Pepto-Bismol) on disease course. All patients were receiving antibiotics (metronidazole or ciprofloxacin) but remained symptomatic. All patients had an initial dose of eight chewable bismuth subsalicylate tablets (each 262 mg) per day for 4 weeks. Eleven of the 13 had a clinical response with a decrease in stool frequency, fecal incontinence and/or abdominal cramping. One patient reduced the dose secondary to bloating while the seven others reduced their dose because of equal efficacy at the lower dose. Five of the 11 responders were able to discontinue antibiotic use after 4 weeks [134]. Thus, bismuth appears safe and efficacious and warrants further trials.

Allopurinol

Allopurinol is a xanthine oxidase inhibitor. The

theoretical basis for its use in pouchitis is to inhibit

the production of free radicals and thus inhibit mucosal injury. A small trial by Levin et al. demon- strated a 50% response rate in acute and chronic pouchitis [83]. Eight patients with acute pouchitis received 300 mg twice daily of allopurinol. Four had resolution of symptoms. Fourteen patients with chronic pouchitis were treated with the same dose for 28 days; seven of the 14 had a clinical response.

These findings lend credence to the theory of ischemic damage and free radical injury contributing to the pathogenesis of pouchitis. A randomized controlled trial of allopurinol for the treatment of pouchitis is currently ongoing in Scandinavia.

Nutritional agents Fiber

Thrilby et al. demonstrated that oral fiber supple- mentation has no benefit on stool frequency, pouch function, bloating or stool consistency in patients after IPAA [135]. Fiber is equally unlikely to be of benefit in the treatment of pouchitis.

SCFA/glutamine

SCFA (acetate, propionate, butyrate) are products of anaerobic bacterial fermentation. They are the major source of energy for the colonic mucosa [69] while glutamine is the major energy source for enterocytes.

Data for their use in the treatment of pouchitis are limited and mostly negative. Two small series used the same SCFA enema formulation of 60 mM sodium acetate, 30 mM sodium propionate and 40 mM sodium ^-butyrate in a combined total of 10 patients with chronic pouchitis [136, 137]. Only three patients had a clinical response while two patients actually showed worsening of their clinical symp- toms. In contrast, den Hoed et al. described a patient with treatment-refractory pouchitis who was given a similar SCFA enema combination twice daily for 4 weeks. After this treatment she had complete resolu- tion of her symptoms and remained symptom-free during 2 years of follow-up [138]. Another series used either butyrate or glutamine suppositories for 10 days in patients with chronic pouchitis. Six of the nine (67%) patients treated with butyrate, and four of the 10 (40%) patients treated with glutamine, failed, remaining symptomatic without measurable clinical response [77]. Given the lack of a placebo control it is unclear whether these two therapies are equally effective or equally ineffective.

Smoking/nicotine

Smoking has been found to be protective against pouchitis [49, 89, 93]. However, to date there have been no trials of nicotine enemas or transdermal nicotine patch for the treatment of pouchitis.

Probiotics

Probiotics are live organisms, usually bacteria, found as commensals in the human gastrointestinal tract.

Based on the hypothesis that an imbalance in these organisms may result in inflammatory conditions such as pouchitis, Gionchetti et al. conducted a randomized double-blind placebo-controlled trial of the probiotic VSL-3 (Sitia-Yomo, Milano, Italy) [139]. Forty patients with chronic pouchitis in remis- sion (PDAI of 0) received either placebo or a 6 g daily oral dose of VSL-3 for 9 months. VSL-3 contains 5 X 10^ Vg of viable lyophilized bacteria consisting of four strains of lactobacilli (L. acidophilus, L. del- brueckii subsp. bulgaricus, L. plantarum, L. casei), three strains of bifidobacteria {B. infantis, B. longum, B. breve) and one strain of Streptococcus salivarius subsp. thermophilus. Seventeen (85%o) of the patients who received VSL-3 were free of recurrence (defined as an increase in the PDAI by 2 or more points) as opposed to none of the 20 patients who received placebo. No side-effects were reported. The VSL-3- treated group was found to have an increase in fecal concentrations of lactobacilli, bifidobacteria and S.

thermophilus by day 15. The safety and efficacy of this therapy for chronic pouchitis appears promising;

however, currently the formulation has limited availability.

Crolin's disease

When CD is diagnosed in the pouch, treatment is along the lines of Crohn's elsewhere in the gastro- intestinal tract. Berrebi et al. report a series of two patients with IPAA diagnosed with CD in the reser- voir. Both r e s p o n d e d to c o r t i c o s t e r o i d and azathioprine therapy, with eventual maintenance on azathioprine alone [140]. Recently, Ricart et al.

reported a series of seven patients with IPAA for UC who were subsequently diagnosed with CD.

These patients had active inflammatory or fistulizing

CD in the pouch and were refractory to conventional

therapy. They were treated with varying doses of the

murine chimeric anti-tumor necrosis factor (TNF)-a

antibody, infliximab. Six patients had a complete

response with closure of all fistulous tracts, and one had a partial response [141].

Pouch excision

Pouch excision is rare, and occurs more commonly for pouch dysfunction than for true chronic pouchi- tis. However, Penna et al. estimate that approxi- mately 1.3% of patients who undergo IPAA for UC will need a pouch excision for chronic treatment- refractory pouchitis [48]. Sachar noted that resorting to pouch removal for confirmed refractory pouchitis is largely a quality-of-life decision for the patients themselves, and should be made in conjunction with a supportive gastroenterologist and surgeon [142].

Summary

Pouchitis is an idiopathic inflammatory disease of the ileal reservoir in patients who have undergone IPAA. Approximately half of all UC patients who undergo this procedure will have at least one episode of pouchitis, with approximately 15% experiencing a chronic course. PSC and other EIM increase the Hkelihood of developing pouchitis while smoking is protective. Similar genetic and autoimmune mechan- isms to UC appear to occur in an ileal reservoir that demonstrates increasingly colon-like adaptations with respect to bacterial content and mucosal characteristics. While most patients have a good response to antibiotic therapy, those with chronic disease become a therapeutic challenge with the specter of dysplasia looming in the foreground.

References

1. Kock NG, Darle N, Hulten L, Kewenter J, Myrvold H, Philipson B. Ileostomy. Curr Prob Surg 1977; 14: 1-52.

2. Kock NG. Intra-abdominal 'reservoir' in patients with permanent ileostomy. Preliminary observations on a proce- dure resulting in fecal 'continence' in five ileostomy patients.

Arch Surg 1969;99:223-31.

3. Parks AG, Nicholls RJ, Belliveau P. Proctocolectomy with ileal reservoir and anal anastomosis. Br J Surg 1980; 67:

533-8.

4. Utsunomiya J, Iwama T, Imajo M et al. Total colectomy, mucosal proctectomy, and ileoanal anastomosis. Dis Colon Rectum 1980; 23: 459-66.

5. Tiainen J, Matikainen M. Health-related quality of life after ileal J-pouch-anal anastomosis for ulcerative colitis: long- term results. Scand J Gastroenterol 1999; 34: 601-5.

6. Martin A, Dinca M, Leone L et al. Quality of life after proctocolectomy and ileo-anal anastomosis for severe ul- cerative colitis. Am J Gastroenterol 1998; 93: 166-9.

7. Provenzale D, Shearin M, Phillips-Bute BG et al. Health- related quality of life after ileoanal pull-through evaluation and assessment of new health status measures. Gastroenter- ology 1997; 113:7-14.

8. Pemberton JH, Kelly KA, Beart RW, Jr, Dozois RR, Wolff BG, Ilstrup DM. Ileal pouch-anal anastomosis for chronic ulcerative colitis. Long-term results. Ann Surg 1987; 206(4):

504-13.

9. Di Febo G, Miglioli M, Lauri A et al. Endoscopic assess- ment of acute inflammation of the ileal reservoir after restorative ileo-anal anastomosis. Gastrointest Endosc 1990;36:6-9.

10. SeUi Carraro PG, Talbot IC, Nicholls JR. Patterns of distribution of endoscopic and histological changes in the ileal reservoir after restorative proctocolectomy for ulcera- tive colitis. A long-term follow-up study. Int J Colored Dis

1998; 13: 103-7.

11. Moskowitz RL, Shepherd NA, Nicholls RJ. An assessment of inflammation in the reservoir after restorative proctoco- lectomy with ileoanal ileal reservoir. Int J Colorect Dis

1986; 1: 167 74.

12. Sandborn WJ, Tremaine WJ, Batts KP, Pemberton JH, Phillips SF. Pouchitis after ileal pouch anal anastomosis: a Pouchitis Disease Activity Index. Mayo Clin Proc 1994; 69:

409 15.

13. Sandborn W. Pouchitis: Dcfuiition, Risk Factors, Fre- quency, Natural History, Classification, and Public Health Perspective. Lancaster, England: Kluwcr Academic Publish- ers; 1997.

14. Moonka D, Furth EE, MacDermott RP, Lichtenstcin GR.

Pouchitis associated with primary cytomegalovirus infec- tion. Am J Gastroenterol 1998; 93: 264 6.

15. Munoz-Juarez M, Pemberton JH, Sandborn WJ, Tremaine WJ, Dozois RR. Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as refractory idiopathic chronic pouchitis: report of two cases. Dis Colon Rectum

1999; 42: 117 20.

16. Solomon MJ, McLeod RS, O'Connor BI, Cohen Z. Assess- ment of peripouch inflammation after ileoanal anastomosis using endoluminal ultrasonography. Dis Colon Rectum 1995; 38: 182-7.

17. Woolfson K, McLeod RS, Walfisch S, Yip K, Cohen Z.

Pelvic pouch emptying scan: an evaluation of scintigraphic assessment of the neorectum. Int J Colorect Dis 1991; 6: 29 32.

18. de Silva HJ, Millard PR, Soper N, Kettlewell M, Mortensen N, Jewell DP. Effects of the faecal stream and stasis on the ileal pouch mucosa. Gut 1991; 32: 1166-9.

19. Merrett MN, Soper N, Mortensen N, Jewell DP. Intestinal permeability in the ileal pouch. Gut 1996; 39: 226-30.

20. Apel R, Cohen Z, Andrews CW, Jr, McLeod R, Steinhart H, Odze RD. Prospective evaluation of early morphological changes in pelvic ileal pouches. Gastroenterology 1994; 107:

435-43.

21. Stallmach A, Moser C, Hero-Gross R et al. Pattern of mucosal adaptation in acute and chronic pouchitis. Dis Colon Rectum 1999; 42: 1311-7.

22. Campbell AP, Merrett MN, Kettlewell M, Mortensen NJ, Jewell DP. Expression of colonic antigens by goblet and columnar epithelial cells in ileal pouch mucosa: their association with inflammatory change and faecal stasis. J Clin Pathol 1994;47:834-8.

23. de Silva HJ, Millard PR, Kettlewell M, Mortensen NJ, Prince C, Jewell DP. Mucosal characteristics of pelvic ileal pouches. Gut 1991; 32: 61-5.

24. Shepherd NA, Healey CJ, Warren BF, Richman PI, Thom- son WH, Wilkinson SP. Distribution of mucosal pathology and an assessment of colonic phenotypic change in the pelvic ileal reservoir. Gut 1993; 34: 101-5.

25. Lichtman SN, Wang J, Hummel B, Lacey S, Sartor RB. A rat model of ileal pouch-rectal anastomosis. Inflam Bowel D i s l 9 9 8 ; 4 : 187-95.

26. de Silva HJ, Jones M, Prince C, Kettlewell M, Mortensen NJ, Jewell DP. Lymphocyte and macrophage subpopula- tions in pelvic ileal pouches. Gut 1991; 32: 1160-5.

27. Gionchetti P, Campieri M, Belluzzi A et al. Mucosal concentrations of interleukin-1 beta, interleukin-6, interleu- kin-8, and tumor necrosis factor-alpha in pelvic ileal pouches. Dig Dis Sci 1994; 39: 1525-31.

28. Patel RT, Bain I, Youngs D, Keighley MR. Cytokine production in pouchitis is similar to that in ulcerative colitis.

Dis Colon Rectum 1995; 38: 831-7.

29. Schreiber S, Gionchetti P, Hampe J et al. Pouchitis shares similarities with ulcerative colitis in the pattern of cytokine transcription factor activation. Gastroenterology 1997; 112:

A10086.

30. Kuhbacher T, Gionchetti P, Hampe J. Pouchitis shares similarities with ulcerative colitis in the pattern of cytokine transcription factor activation. Gut 1997 1997; 41(Suppl. 3):

A-P148.

31. Stallmach A, Schafer F, Hoffmann S et al. Increased state of activation of CD4 positive T cells and elevated interferon gamma production in pouchitis. Gut 1998; 43: 499-505.

32. Gertner DJ, Rampton DS, Madden MV, Talbot IC, Nicholls RJ, Lennard-Jones JE. Increased leukotriene B4 release from ileal pouch mucosa in ulcerative colitis compared with familial adenomatous polyposis. Gut 1994; 35: 1429-32.

33. Boerr LA, Sambuelli AM, Filinger E et al. Increased mucosal levels of leukotriene B4 in pouchitis: evidence for a persistent inflammatory state. Eur J Gastroenterol Hepa- tol 1996; 8: 57-61.

34. Sandborn WJ, Landers CJ, Tremaine WJ, Targan SR. Anti- neutrophil cytoplasmic antibody correlates with chronic pouchitis after ileal pouch-anal anastomosis. Am J Gastro- enterol 1995; 90: 740-7.

35. Aitola P, Matikainen M, Mattila J, Tomminen T, Hiltunen KM. Chronic inflammatory changes in the pouch mucosa are associated with cholangitis found on peroperative liver biopsy specimens at restorative proctocolectomy for ulcera- tive colitis. Scand J Gastroenterol 1998; 33: 289-93.

36. Esteve M, Mallolas J, Klaassen J et al. Antineutrophil cytoplasmic antibodies in sera from colectomised ulcerative colitis patients and its relation to the presence of pouchitis.

Gut 1996; 38: 894-8.

37. Reumaux D, Colombel JF, Duclos B et al. Antineutrophil cytoplasmic auto-antibodies in sera from patients with ulcerative colitis after proctocolectomy with ileo-anal ana- stomosis. Adv Exp Med Biol 1993; 336: 523-5.

38. Patel RT, Stokes R, Birch D, Ibbotson J, Keighley MR.

Influence of total colectomy on serum antineutrophil cyto- plasmic antibodies in inflammatory bowel disease. Br J Surg

1994;81:724-6.

39. Yang P, Oresland T, Jarnerot G, Hulten L, Danielsson D.

Perinuclear antineutrophil cytoplasmic antibody in pouchi- tis after proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. Scand J Gastroenterol 1996; 31: 594-8.

40. Freeman HJ, Roeck B, Devine DV, Carter CJ. Atypical perinuclear antineutrophil cytoplasmic antibodies after co- lectomy in inflammatory bowel disease. Can J Gastroenterol

1997; 11:305-10.

41. Vecchi M, Gionchetti P, Bianchi MB et al. p-ANCA and development of pouchitis in ulcerative colitis patients after proctocolectomy and ileoanal pouch anastomosis [Letter;

published erratum appears in Lancet 1994; 344: 1168].

Lancet 1994; 344: 886-7.

42. Aisenberg J, Wagreich J, Shim J et al. Perinuclear anti- neutrophil cytoplasmic antibody and refractory pouchitis.

A case-control study. Dig Dis Sci 1995; 40: 1866-72.

43. Brett PM, Yasuda N, Yiannakou JY et al. Genetic and immunological markers in pouchitis. Eur J Gastroenterol Hepatol 1996; 8: 951-5.

44. Kaditis AG, Perrault J, Sandborn WJ, Landers CJ, Zinsme- ister AR, Targan SR. Antineutrophil cytoplasmic antibody subtypes in children and adolescents after ileal pouch-anal anastomosis for ulcerative colitis. J Pediatr Gastroenterol Nutr 1998; 26: 386-92.

45. Yasuda N, Thomas P, Ellis H, Herbst F, Nichofls J, Ciclitira P. Perinuclear anti-neutrophil cytoplasmic antibodies in ulcerative colitis after restorative protocolectomy do not correlate with the presence of pouchitis. Scand J Gastro- enterol 1998;33:509-13.

46. Duerr RH, Targan SR, Landers CJ et al. Neutrophil cytoplasmic antibodies: a link between primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 1991;

100: 1385-91.

47. Kartheuser AH, Dozois RR, Wiesner RH, LaRusso NF, Ilstrup DM, Schleck CD. Complications and risk factors after ileal pouch-anal anastomosis for ulcerative colitis associated with primary sclerosing cholangitis. Ann Surg 1993;217:314-20.

48. Penna C, Dozois R, Tremaine W et al. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut 1996; 38: 234-9.

49. Klenzak J, Isaacs K, Koruda M. Predicting pouchitis: race, extraintestinal manifestations of disease and tobacco use.

Am J Gastroenterol 1997; 92: A1679 # 3 8 5 .

50. Lohmuller JL, Pemberton JH, Dozois RR, Ilstrup D, van Heerden J. Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch-anal anasto- mosis. Ann Surg 1990; 211: 622-7; discussion 627-9.

51. ter Borg EJ, Nadorp JH, Fibers JR. Ileal pouch arthritis: a case report. Eur J Gastroenterol Hepatol 1996; 8: 957-9.

52. Shepherd NA, Hulten L, Tytgat GN, Nicholls RJ, Nasmyth DG, Hill MJ et al. Pouchitis. Int J Colorect Dis 1989; 4:

205-29.

53. Subramani K, Harpaz N, Bilotta J et al. Refractory pou- chitis: does it reflect underlying Crohn's disease? Gut 1993;

34: 1539-42.

54. Gorbach SL, Nahas L, Weinstein L, Levitan R, Patterson JF. Studies of intestinal microflora. IV. The microflora of ileostomy effluent: a unique microbial ecology. Gastroenter- ology 1967; 53: 874-80.

55. Santavirta J, Mattila J, Kokki M, Matikainen M. Mucosal morphology and faecal bacteriology after ileoanal anasto- mosis. Int J Colorect Dis 1991; 6: 38-41.

56. Onderdonk AB, Dvorak AM, Cisneros RL et al. Micro- biologic assessment of tissue biopsy samples from ileal pouch patients. J Clin Microbiol 1992; 30: 312-7.

57. McLeod RS, Antonioli D, Cullen J et al. Histologic and microbiologic features of biopsy samples from patients with normal and inflamed pouches. Dis Colon Rectum 1994; 37:

26-31.

58. Ruseler-van Embden JG, Schouten WR, van Lieshout LM.

Pouchitis: result of microbial imbalance? Gut 1994; 35: 658- 64.

59. Becker J, Onderdonk A. Bacterial dysbiosis in the pathogen- esis of ileal pouchitis. Gastroenterology 1994; 106(Suppl. 4):

A650.

60. Kelly DG, Phillips SF, Kelly KA, Weinstein WM, Gilchrist MJ. Dysfunction of the continent ileostomy: clinical fea- tures and bacteriology. Gut 1983; 24: 193-201.

61. O'Connell PR, Rankin DR, Weiland LH, Kelly KA. Enteric bacteriology, absorption, morphology and emptying after ileal pouch-anal anastomosis. Br J Surg 1986; 73: 909-14.

62. Luukkonen P, Valtonen V, Sivonen A, Sipponen P, Jarvinen H. Fecal bacteriology and reservoir ileitis in patients oper-

ated on for ulcerative colitis. Dis Colon Rectum 1988; 31:

864-7.

63. Kmiot WA, Youngs D, Tudor R, Thompson H, Keighley MR. Mucosal morphology, cell proliferation and faecal bacteriology in acute pouchitis. Br J Surg 1993; 80: 1445-9.

64. Sandborn WJ, Tremaine WJ, Batts KP et ai Fecal bile acids, short-chain fatty acids, and bacteria after ileal pouch-anal anastomosis do not differ in patients with pouchitis. Dig Dis Sci 1995; 40: 1474-83.

65. Natori H, Utsunomiya J, Yamamura T, Benno Y, Uchida K.

Fecal and stomal bile acid composition after ileostomy or ileoanal anastomosis in patients with chronic ulcerative colitis and adenomatosis coli. Gastroenterology 1992; 102:

1278-88.

66. Merrett M, Crotty B, Mortensen N, Jewell D. Ileal pouch dialysate is cytotoxic to Caco-2 cells at levels assayed in ileal pouch dialysate. Gut 1992; 33(S51).

67. Merrett MN, Owen RW, Jewell DR Ileal pouch dialysate is cytotoxic to epithelial cell lines, but not to CaCo-2 mono- layers. Eur J Gastroenterol Hepatol 1997; 9: 1219 26.

68. Becker J, Mou C, Hocking G. Fecal bile acid composition in patients with pouchitis following colectomy and ileal pouch anal anastomosis. Gastroenterology 1994; 106:

A650.

69. Rocdiger WE. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 1980; 21: 793 8.

70. Binder HJ, Mehta R Short-chain fatly acids stimulate active sodium and chloride absorption in vitro in the rat distal colon. Gastroenterology 1989; 96: 989 96.

71. Ambroze WL, Jr, Pcmbcrton JH, Phillips SF, Bell AM, Haddad AC. Fecal short-chain fatty acid concentrations and effect on ileal pouch function. Dis Colon Rectum 1993;

36: 235 9.

72. Scheppach W, Sommer H, Kirchncr T ct al. Effect of butyratc enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 1992; 103: 51 6.

73. Brcuer RI, Buto SK, Christ ML c^/ al. Rectal irrigation with short-chain fatty acids for distal ulcerative colitis. Prelimin- ary report. Dig Dis Sci 1991; 36: 185 7.

74. Nasmyth DG, Johnston D, Williams NS, King RF, Burkin- shaw L, Brooks K. Changes in the absorption of bile acids after total colectomy in patients with an ileostomy or pouch anal anastomosis. Dis Colon Rectum 1989; 32:

230 4.

75. Clausen MR, Tvede M, Mortensen PB. Short-chain fatty acids in pouch contents from patients with and without pouchitis after ileal pouch-anal anastomosis. Gastroenter- ology 1992;103: 1144-53.

76. Sagar PM, Taylor BA, Godwin P et ai Acute pouchitis and deficiencies of fuel. Dis Colon Rectum 1995; 38: 488-93.

77. Wischmeyer P, Pemberton JH, Phillips SF. Chronic pou- chitis after ileal pouch-anal anastomosis: responses to butyrate and glutamine suppositories in a pilot study. Mayo ClinProc 1993;68:978-81.

78. Smith L, Friend WG, Medwell SJ. The superior mesenteric artery. The critical factor in the pouch pull-through proce- dure. Dis Colon Rectum 1984; 27: 741-4.

79. Warren BF, Shepherd NA. The role of pathology in pelvic ileal reservoir surgery. Int J Colorect Dis 1992; 7: 68-75.

80. Hosie K, Sachaguchi M, Tudor R, Gourevitch D, Kmiot W, Keighley M. Pouchitis after restorative proctocolectomy is associated with mucosal ischaemia. Gut 1989; 30: A1471.

81. Sackler ML. Xanthine oxidase from liver and duodenum of the rat: histochemical localization and electrophoretic het- erogeneity. J Histochem Cytochem 1966; 14: 326-33.

82. Fozard BJ, Pemberton JH. Results of pouch surgery after ileo-anal anastomosis: the implications of pouchitis. World J Surg 1992; 16:880-4.

83. Levin KE, Pemberton JH, Phillips SF, Zinsmeister AR, Pezim ME. Role of oxygen free radicals in the etiology of pouchitis. Dis Colon Rectum 1992; 35: 452-6.

84. Parks DA. Oxygen radicals: mediators of gastrointestinal pathophysiology. Gut 1989; 30: 293-8.

85. vonHerbay A, Stern J, Buhr H, Otto H, Herfarth C.

Heterogeneity of pouchitis after restorative proctocolect- omy for ulcerative colitis. Gastroenterology 1994;

106(Suppl. 4): A790.

86. Hurst RD, Chung TP, Rubin M, Michelassi F. The implica- tions of acute pouchitis on the long-term functional results after restorative proctocolectomy. Inflam Bowel Dis 1998; 4:

280-4.

87. Perrault J, Berry R, Greseth J, Sinsmeister A, Telander R.

Pouchitis in young patients after the ileal pouch anal anastomosis. Inflam Bowel Dis 1997; 3: 181 5.

88. Keranen U, Luukkonen P, Jarvinen H. Functional results after restorative proctocolectomy complicated by pouchitis.

Dis Colon Rectum 1997; 40: 764 9.

89. Stahlberg D, Gullberg K, Liljeqvist L, Hellers G, Lofberg R. Pouchitis following pelvic pouch operation for ulcerative colitis. Incidence, cumulative risk, and risk factors. Dis Colon Rectum 1996; 39: 1012 18.

90. Luukkonen P, Jarvinen H, Tanskanen M, Kahri A. Pou- chitis recurrence of the inflammatory bowel disease? Gut

1994; 35: 243 6.

91. Svaninger G, Nordgren S, Oresland T, Hulten L. Incidence and characteristics of pouchitis in the Kock continent ileostomy and the pelvic pouch. Scand J Gastroenterol 1993; 28: 695 700.

92. Hurst RD, Molinari M, Chung TP, Rubin M, Michelassi F.

Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proc- tocolectomy Arch Surg 1996; 131: 497 500; discussion 501 2.

93. Merrett MN, Mortensen N, Kettlewell M, Jewell DO.

Smoking may prevent pouchitis in patients with restorative proctocolectomy for ulcerative colitis. Gut 1996; 38: 362 4.

94. Samarasckera DN, Stebbing JF, Kettlewell MG, Jewell DP, Mortensen NJ. Outcome of restorative proctocolectomy with ileal reservoir for ulcerative colitis: comparison of distal colitis with more proximal disease. Gut 1996; 38:

574 7.

95. Schmidt CM, Lazenby AJ, Hendrickson RJ, Sitzmann JV.

Preoperative terminal ileal and colonic resection histo- pathology predicts risk of pouchitis in patients after ileoanal pull-through procedure. Ann Surg 1998; 227: 654-62; dis- cussion 663-5.

96. Mesiya S, Lerner M, Kida M, DJ B. Increased colonic eosinophils may predict pouchitis preoperatively. Am J Gastroenterol 1999; 94: 2679: A407.

97. Stern H, Walfisch S, Mullen B, McLeod R, Cohen Z. Cancer in an ileoanal reservoir: a new late complication?. Gut 1990;

31:473-5.

98. Heppell J, De Zubiria M, Brais MF et al. An assessment of the risk of neoplasia in long-term ileal reservoirs using the DMH rodent model. Dis Colon Rectum 1990; 33: 26-31.

99. Reissman P, Avroutis O, Cohen DY, Shiloni E. Ileostomy- site colonic metaplasia with adenocarcinoma after procto- colectomy for ulcerative colitis. Am J Gastroenterol 1997;

92:1932-3.

100. Cox CL, Butts DR, Roberts MP, Wessels RA, Bailey HR.

Development of invasive adenocarcinoma in a long-stand- ing Kock continent ileostomy: report of a case. Dis Colon Rectum 1997; 40: 500-3.

101. Nyam DC, Pemberton JH, Sandborn WJ, Savcenko M.

Lymphoma of the pouch after ileal pouch-anal anastomo- sis: report of a case. Dis Colon Rectum 1997; 40: 971-2.